CEBPA (CCAAT Enhancer Binding Protein Alpha) (19Q13.1)

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal

Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS

Volume 10, Number 4, Oct-Dec2006 Previous Issue / Next Issue Genes

JARID1A (Jumonji, AT rich interactive domain 1A (RBBP2-like)) (12p13).

Laura JCM van Zutven, Anne RM von Bergh.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 460-465. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/JARID1AID41033ch12p13.html

SS18 (synovial sarcoma translocation, chromosome 18) (18q11.2).

Mamoru Ouchida.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 466-470. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/SS18ID84ch18q11.html

PDE4DIP (phosphodiesterase 4D interacting protein (myomegalin)) (1q22).

Jean Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 471-475. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/PDE4DIP01q22ID180.html

MYST4 (MYST histone acetyltransferase (monocytic leukemia) 4) (10q22.2).

José Luis Vizmanos.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 476-483. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MYST4ID41488ch10q22.html

CRTC1 (CREB regulated transcription coactivator 1) (19p13.11) - updated.

Afrouz Behboudi, Gôran Stenman.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 484-489. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/CRTC1ID471ch19p13.html

CEBPA (CCAAT enhancer binding protein alpha) (19q13.1).

Lan-Lan Smith.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 490-501. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/CEBPAID40050ch19q13.html

TRIM37 (tripartite motif-containing 37) (17q23.2).

Elif Ayse Erson, Elizabeth M Petty.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 502-510. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/TRIM37ID42703ch17q23.html

MUTYH (mutY homolog (E. coli)) (1p34).

Maurizio Genuardi, Rossella Tricarico.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 511-519. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/MUTYHID41464ch1p34.html

HOXA11 (homeobox A11) (7p15).

Barbara Cauwelier, Frank Speleman.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 520-525. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/HOXA11ID40847ch7p15.html

ALOX15 (Arachidonate 15-Lipoxygenase) (17p13.3).

Sreeparna Banerjee.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 526-535. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/ALOX15ID42986ch17p13.html

PAX3 (paired box gene 3 (Waardenburg syndrome 1)) (2q36.1).

Eun Hyun Ahn, Frederic G. Barr. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 536-548. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/PAX3ID70ch2q35.html

MSH3 (mutS homolog 3 (E coli)) (5q14.1).

Enric Domingo, Simo Schwartz Jr.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 549-553. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/MSH3ID341ch5q11.html

FH (fumarate hydratase) (1q42.1) .

Allison M Lynch, Cynthia C Morton.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 554-561. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/FHID40573ch1q42.html

ALOX5 (Arachidonate 5-Lipoxygenase) (10q11.2) .

Sreeparna Banerjee, Seda Tuncay .

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 562-572. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/ALOX5ID42985ch10q11.html Leukaemias

t(1;5)(q22;q33).

Jean Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 573-575. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0105q22q33ID1115.html

t(12;17)(p13;q11-21) in ALL.

David Betts.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 576-577. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t1217p13q21ALLID1072.html

t(11;12)(p15;p13).

Laura JCM van Zutven, H Berna Beverloo.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 578-580. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t1112p15p13ID1428.html Trisomy 2.

Amanda Dixon-McIver.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 581-584. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/Tri2ID1429.html t(10;16)(q22;p13).

José Luis Vizmanos.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 585-588. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t1016q22p13ID1332.html i(9q) in ALL.

Noel A Brownlee, Patrick Koty, David H Buss, Mark J Pettenati.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 589-592. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/i9qID1066.html

+10 or trisomy 10 (solely) - updated.

Zachary T Lewis, Patrick P Koty, Mark J Pettenati.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 593-597. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/tri10ID1063.html t(7;14)(p15;q11).

Julie Bergeron, Elizabeth Macintyre, Vahid Asnafi.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 598-602. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0714p15q11ID1435.html t(1;1)(p36;q21) in Non Hodgkin Lymphoma.

Valia S Lestou.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 603-608. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0101p36q21ID1431.html t(7;12)(q34;p13); t(12;14)(p13;q11).

Emmanuelle Clappier, Jean Soulier.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 609-612. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0712q34p13ID1434.html

Polycythemia Vera (PV) - updated.

Antonio Cuneo, Francesco Cavazzini.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 614-618. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/PV.html Solid Tumours

Clear Cell Hidradenoma of the Skin.

Afrouz Behboudi, Gôran Stenman.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 619-622. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Tumors/ClearCelHidradID5419.html Cancer Prone Diseases

Schinzel-Giedion midface retraction syndrome.

Elizabeth McPherson.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 623-628. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/SchinzelGiedionID10129.html

Melanoma-Astrocytoma syndrome.

Juliette Randerson-Moor, Kairen Kukalizch, D Timothy Bishop.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 629-634. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/MelanomAstrocytomID10115.html

MUTYH associated polyposis.

Maartje Nielsen, Frederik J. Hes.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 635-645. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/MYHpolypID10121.html

MAP (MUTYH-Associated Polyposis) .

Benedetta Toschi, Maurizio Genuardi .

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 646-650. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/MAPID10092.html Dianzani Autoimmune Lymphoproliferative Disease (DALD).

Umberto Dianzani, Ugo Ramenghi, Annalisa Chiocchetti.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 651-654. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/DianzaniALDID10111.html

Autoimmune Lymphoproliferative Syndrome .

Umberto Dianzani, Ugo Ramenghi.

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 655-660. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/AutoimmLymphoID10116.html Deep Insights Case Reports Educational Items

Architecture de la chromatine dans le noyau interphasique.

Jean Michel Dupont .

Atlas Genet Cytogenet Oncol Haematol 2006; 10 (4): 661-668. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Educ/ArchitectChromatinID30016FS.html

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

JARID1A (Jumonji, AT rich interactive domain 1A (RBBP2-like)) Identity Other RBBP2 names RBP2 Hugo JARID1A Location 12p13 Local_order very telomeric side of 12p13 DNA/RNA Description 31 exons over 105 kb Transcription from centromere to telomere, yielding mRNA of 6,5 kb Protein

Description JARID1A (Jumonji, AT-rich interactive domain 1A) encodes the 196 kDa retinoblastoma binding protein 2 (1722 amino acids). It contains several motifs, including a leucine-X-cysteine-X-glutamic acid (LXCXE) motif, which is important for association with the T/E1A pocket domain of the retinoblastoma protein. Additionally, the protein contains ARID, Jumonji, and 3 PHD (LAP) domains, which are frequent in proteins regulating transcription through changes in chromatin structure. Expression Widely expressed Localisation Nuclear Function Probably in regulating transcription through changes in chromatin structure Homology RBP2 homologue 1 (RBP2-H1) Implicated in Entity t(11;12)(p15;p13) in Acute megakaryoblastic leukemia (AML -M7) --> NUP98/JARID1A Note Only one case to date, a 1- year-old boy Prognosis Patient reached complete remission and remains in complete remission (CR) for at least 5 years Cytogenetics complex/variant t(11;12)(p15;p13); i.e. t(11;21;12)(p15;p13;p13), but

Atlas Genet Cytogenet Oncol Haematol 2006; 4 460 misdiagnosed as add(11)(p15) and der(21)t(11;21)(p15;p13). Chromosome 12 was cytogenetically normal by conventional banding techniques and only identified as a partner in this translocation after FISH.

Hybrid/Mutated 5' NUP98 - 3' JARID1A, including the first 13 exons of NUP98 and Gene exons 28-31 of JARID1A Abnormal The NUP98-JARID1A fusion protein contains the Phe-Gly (FG) Protein repeats of the N-terminal part of NUP98. The JARID1A sequence starting with exon 28 still contains the sequence encoding the C- terminal PHD domain.

External links Nomenclature Hugo JARID1A GDB JARID1A Entrez_Gene JARID1A 5927 jumonji, AT rich interactive domain 1A Cards Atlas JARID1AID41033ch12p13 GeneCards JARID1A Ensembl JARID1A Genatlas JARID1A GeneLynx JARID1A eGenome JARID1A euGene 5927 Genomic and cartography JARID1A - 12p13 chr12:259484-368881 - 12p13.33 (hg18- GoldenPath Mar_2006)

Atlas Genet Cytogenet Oncol Haematol 2006; 4 461 Ensembl JARID1A - 12p13.33 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene JARID1A Gene and transcription Genbank AA101935 [ ENTREZ ] Genbank AB209999 [ ENTREZ ] Genbank AF007135 [ ENTREZ ] Genbank AK057703 [ ENTREZ ] Genbank AK225060 [ ENTREZ ] RefSeq NM_001042603 [ SRS ] NM_001042603 [ ENTREZ ] RefSeq NM_005056 [ SRS ] NM_005056 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_009759 [ SRS ] NT_009759 [ ENTREZ ] RefSeq NW_925295 [ SRS ] NW_925295 [ ENTREZ ] AceView JARID1A AceView - NCBI TRASER JARID1A Traser - Stanford Unigene Hs.76272 [ SRS ] Hs.76272 [ NCBI ] HS76272 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P29375 [ SRS] P29375 [ EXPASY ] P29375 [ INTERPRO ] Prosite PS51011 ARID [ SRS ] PS51011 ARID [ Expasy ] Prosite PS51184 JMJC [ SRS ] PS51184 JMJC [ Expasy ] Prosite PS51183 JMJN [ SRS ] PS51183 JMJN [ Expasy ] Prosite PS01359 ZF_PHD_1 [ SRS ] PS01359 ZF_PHD_1 [ Expasy ] Prosite PS50016 ZF_PHD_2 [ SRS ] PS50016 ZF_PHD_2 [ Expasy ] Interpro IPR001606 ARID [ SRS ] IPR001606 ARID [ EBI ] Interpro IPR013637 PLU-1 [ SRS ] IPR013637 PLU-1 [ EBI ] Interpro IPR013129 TF_JmjC [ SRS ] IPR013129 TF_JmjC [ EBI ] IPR003347 TF_JmjC_AAH [ SRS ] IPR003347 TF_JmjC_AAH [ Interpro EBI ] Interpro IPR003349 TF_JmjN [ SRS ] IPR003349 TF_JmjN [ EBI ] Interpro IPR004198 Znf_C5HC2 [ SRS ] IPR004198 Znf_C5HC2 [ EBI ] IPR011011 Znf_FYVE_PHD [ SRS ] IPR011011 Znf_FYVE_PHD [ Interpro EBI ] Interpro IPR001965 Znf_PHD [ SRS ] IPR001965 Znf_PHD [ EBI ] CluSTr P29375 PF01388 ARID [ SRS ] PF01388 ARID [ Sanger ] pfam01388 [ Pfam NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 462 PF02373 JmjC [ SRS ] PF02373 JmjC [ Sanger ] pfam02373 [ Pfam NCBI-CDD ] PF02375 JmjN [ SRS ] PF02375 JmjN [ Sanger ] pfam02375 [ Pfam NCBI-CDD ] PF00628 PHD [ SRS ] PF00628 PHD [ Sanger ] pfam00628 [ Pfam NCBI-CDD ] PF08429 PLU-1 [ SRS ] PF08429 PLU-1 [ Sanger ] pfam08429 [ Pfam NCBI-CDD ] PF02928 zf-C5HC2 [ SRS ] PF02928 zf-C5HC2 [ Sanger Pfam ] pfam02928 [ NCBI-CDD ] Smart SM00501 BRIGHT [EMBL] Smart SM00558 JmjC [EMBL] Smart SM00545 JmjN [EMBL] Smart SM00249 PHD [EMBL] Blocks P29375 HPRD P29375 Protein Interaction databases DIP P29375 IntAct P29375 Polymorphism : SNP, mutations, diseases OMIM 180202 [ map ] GENECLINICS 180202 SNP JARID1A [dbSNP-NCBI] SNP NM_001042603 [SNP-NCI] SNP NM_005056 [SNP-NCI] SNP JARID1A [GeneSNPs - Utah] JARID1A] [HGBASE - SRS] HAPMAP JARID1A [HAPMAP] General knowledge Family JARID1A [UCSC Family Browser] Browser SOURCE NM_001042603 SOURCE NM_005056 SMD Hs.76272 SAGE Hs.76272 transcription factor activity[Amigo] transcription factor activity[EGO- Amigo EBI] Amigo protein binding[Amigo] protein binding[EGO-EBI] Amigo intracellular[Amigo] intracellular[EGO-EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 463 Amigo transcription[Amigo] transcription[EGO-EBI] regulation of transcription, DNA-dependent[Amigo] regulation of Amigo transcription, DNA-dependent[EGO-EBI] transcription from RNA polymerase II promoter[Amigo] transcription Amigo from RNA polymerase II promoter[EGO-EBI] Amigo zinc ion binding[Amigo] zinc ion binding[EGO-EBI] transcriptional activator activity[Amigo] transcriptional activator Amigo activity[EGO-EBI] positive regulation of transcription[Amigo] positive regulation of Amigo transcription[EGO-EBI] Amigo metal ion binding[Amigo] metal ion binding[EGO-EBI] PubGene JARID1A Other databases Probes Probe JARID1A Related clones (RZPD - Berlin) PubMed PubMed 16 Pubmed reference(s) in LocusLink Bibliography Differential specificity for binding of retinoblastoma binding protein 2 to RB, p107, and TATA-binding protein. Kim YW, Otterson GA, Kratzke RA, Coxon AB, Kaye FJ. Mol Cell Biol 1994; 14: 7256-7264. Medline 7935440

Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Benevolenskaya EV, Murray HL, Branton P, Young RA, Kaelin WG Jr. Mol Cell 2005; 18: 623-635. Medline 15949438

Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. van Zutven LJ, Onen E, Velthuizen SC, van Drunen E, von Bergh AR, van den Heuvel-Eibrink MM, Veronese A, Mecucci C, Negrini M, de Greef GE, Beverloo HB Genes Chromosomes Cancer 2006; 45: 437-446. Medline 16419055

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Laura J.C.M. van Zutven, Anne R.M. von Bergh 2006

Atlas Genet Cytogenet Oncol Haematol 2006; 4 464 Citation This paper should be referenced as such : van Zutven LJCM, von Bergh ARM . JARID1A (Jumonji, AT rich interactive domain 1A (RBBP2-like)). Atlas Genet Cytogenet Oncol Haematol. April 2006 . URL : http://AtlasGeneticsOncology.org/Genes/JARID1AID41033ch12p13.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 465 Atlas of Genetics and Cytogenetics in Oncology and Haematology

SS18 (synovial sarcoma translocation, chromosome 18) Identity Other MGC116875 names SSXT SYT Hugo SS18 Location 18q11.2 DNA/RNA Note Member of the SS18 family. SYT, one of the alternative gene names, has continued to be used in the literature for this gene. Description 11 exons, spaning approximately 75 kb of genomic DNA in the telomere-to-centromere orientation on chromosome 18q11.2 The promoter region lacks CAAT and TATA boxes but contains CpG islands, suggesting that SS18 is a housekeeping gene. Transcription Exon 8 is spliced out with different ratio in the various tissues by alternative splicing. Pseudogene SS18L2 (3p21) Protein

Description 418 amino acids. 2 domains; the SHN domain (the SYT N-terminal homology domain) that is found in proteins from a wide variety of species ranging from plants to human, and the QPGY domain at the C- terminal part, rich in glutamine, proline, glycine and tyrosine. Four putative src-homology binding domains and two annexin-like direct repeats were exhibited in the SS18 protein. SS18 protein binds to p300, hBRM, AF10 and SIN3A proteins. The QPGY domain activates transcription when coupled to a DNA-binding domain. Expression Ubiquitous Localisation Nuclear Function Transcriptional coactivator Homology SS18L1, SS18L2 Implicated in Entity Synovial sarcoma Prognosis A high grade sarcoma that leads to death in at least 25% of patients within five years of diagnosis. Prognosis may be different between the synovial sarcoma patients with SYT-SSX1 and SYT-SSX2.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 466 Cytogenetics t(X;18)(p11.2;q11.2) Hybrid/Mutated SYT-SSX1, SYT-SSX2, SYT-SSX4; the exon 10 of the SS18 (SYT) Gene gene is fused to exon 6 of the SSX genes. Abnormal The last 8 amino acid residues of the SS18 (SYT) protein are Protein replaced by 78 amino acids from the C-terminal part of SSX proteins.

External links Nomenclature Hugo SS18 GDB SS18 Entrez_Gene SS18 6760 synovial sarcoma translocation, chromosome 18 Cards Atlas SS18ID84ch18q11 GeneCards SS18 Ensembl SS18 Genatlas SS18 GeneLynx SS18 eGenome SS18 euGene 6760 Genomic and cartography SS18 - 18q11.2 chr18:21850217-21924609 - 18q11.2 (hg18- GoldenPath Mar_2006) Ensembl SS18 - 18q11.2 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene SS18 Gene and transcription Genbank AF244972 [ ENTREZ ] Genbank AF257501 [ ENTREZ ] Genbank AF343880 [ ENTREZ ] Genbank AU279615 [ ENTREZ ] Genbank AW081610 [ ENTREZ ] RefSeq NM_001007559 [ SRS ] NM_001007559 [ ENTREZ ] RefSeq NM_005637 [ SRS ] NM_005637 [ ENTREZ ] RefSeq AC_000061 [ SRS ] AC_000061 [ ENTREZ ] RefSeq NC_000018 [ SRS ] NC_000018 [ ENTREZ ] RefSeq NT_010966 [ SRS ] NT_010966 [ ENTREZ ] RefSeq NW_927095 [ SRS ] NW_927095 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 467 AceView SS18 AceView - NCBI TRASER SS18 Traser - Stanford Unigene Hs.404263 [ SRS ] Hs.404263 [ NCBI ] HS404263 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q15532 [ SRS] Q15532 [ EXPASY ] Q15532 [ INTERPRO ] Interpro IPR007726 SSXT [ SRS ] IPR007726 SSXT [ EBI ] CluSTr Q15532 PF05030 SSXT [ SRS ] PF05030 SSXT [ Sanger ] pfam05030 [ Pfam NCBI-CDD ] Blocks Q15532 HPRD Q15532 Protein Interaction databases DIP Q15532 IntAct Q15532 Polymorphism : SNP, mutations, diseases OMIM 600192 [ map ] GENECLINICS 600192 SNP SS18 [dbSNP-NCBI] SNP NM_001007559 [SNP-NCI] SNP NM_005637 [SNP-NCI] SNP SS18 [GeneSNPs - Utah] SS18] [HGBASE - SRS] HAPMAP SS18 [HAPMAP] General knowledge Family SS18 [UCSC Family Browser] Browser SOURCE NM_001007559 SOURCE NM_005637 SMD Hs.404263 SAGE Hs.404263 Amigo protein binding[Amigo] protein binding[EGO-EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI] PubGene SS18 Other databases Probes Probe SS18 Related clones (RZPD - Berlin) PubMed PubMed 20 Pubmed reference(s) in LocusLink Bibliography

Atlas Genet Cytogenet Oncol Haematol 2006; 4 468 Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Clark J, Rocques PJ, Crew AJ, Gill S, Shipley J, Chan AM-L, Gusterson BA, Cooper CS. Nature Genet 1944; 7: 502-508. Medline 7951320

Isolation and characterization of the mouse homolog of SYT, a gene implicated in the development of human synovial sarcomas. de Bruijn DRH, Baats E, Zechner U, de Leeuw B, Balemans M, Olde Weghuis D, Hirning-Folz U, Geurts van Kessel A. . Oncogene 1996; 13: 643-648. Medline 8760306

SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. Kawai A, Woodruff J, Healey JH, Brennan MF, Antonescu CR, Ladanyi M. New Eng J Med 1998; 338: 153-160. Medline 9428816

A novel fusion gene, SYT-SSX4, in synovial sarcoma. Skytting B, Nilsson G, Brodin B, Xie Y, Lundeberg J, Uhlen M, Larsson O J Nat Cancer Inst 1999; 91: 974-975. Medline 10359553

Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus. Thaete C, Brett D, Monaghan P, Whitehouse S, Rennie G, Rayner E, Cooper CS, Goodwin G. Hum Molec Genet 1999; 8: 585-591. Medline 10072425 p300 interacts with the nuclear proto-oncoprotein SYT as part of the active control of cell adhesion. Eid JE, Kung AL, Scully R, Livingston DM. Cell 2000; 102(6): 839-848. Medline 11030627

A reverse transcriptase-polymerase chain reaction assay in the diagnosis of soft tissue sarcomas. Naito N, Kawai A, Ouchida M, Dan'ura T, Morimoto Y, Ozaki T, Shimizu K, Inoue H. Cancer 2000; 89(9): 1992-1998. Medline 11064357

The synovial sarcoma associated protein SYT interacts with the acute leukemia associated protein AF10

Atlas Genet Cytogenet Oncol Haematol 2006; 4 469 de Bruijn DRH, dos Santos NR, Thijssen J, Balemans M, Debernardi S, Linder B, Young BD, Geurts van Kessel A. Oncogene 2001; 20(25): 3281-3289. Medline 11423977

Mapping and characterization of the mouse and human SS18 genes, two human SS18-like genes and a mouse Ss18 pseudogene. de Bruijn DRH, Kater-Baats E, Eleveld M, Merkx G, van Kessel AG. Cytogenet Cell Genet 2001; 92: 310-319. Medline 11435705

Splicing isoform of SYT-SSX fusion protein accelerates transcriptional activity and cell proliferation. Morimoto Y, Ouchida M, Ozaki T, Kawai A, Ito T, Yoshida A, Inoue H, Shimizu K. Cancer Lett 2003; 199(1): 35-43. Medline 12963121

SYT, a partner of SYT-SSX oncoprotein in synovial sarcomas, interacts with mSin3A, a component of histone deacetylase complex. Ito T, Ouchida M, Ito S, Jitsumori Y, Morimoto Y, Ozaki T, Kawai A, Inoue H, Shimizu K. Lab Invest 2004; 84(11): 1484-1490. Medline 15467731

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Mamoru Ouchida 2006 Citation This paper should be referenced as such : Ouchida M . SS18 (synovial sarcoma translocation, chromosome 18). Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Genes/SS18ID84ch18q11.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 470 Atlas of Genetics and Cytogenetics in Oncology and Haematology

PDE4DIP (phosphodiesterase 4D interacting protein (myomegalin)) Identity Other CMYA2 names KIAA0477 KIAA0454 MMGL Myomegalin Hugo PDE4DIP Location 1q22 DNA/RNA Transcription Various splicing forms, in particular KIAA0477 and KIAA0454 Protein

Note The protein encoded by PDE4DIP is called myomegalin Description Large protein; some isoforms having more than 2300 aminoacids (62 kDa and 230-250 kDa proteins in the rat ortholog); mainly composed of alpha-helical and coiled-coil structures; includes a leucine zipper in N- term, a dynactin-centractin binding domain, and a helix-loop-helix. Expression in heart and skeletal muscles; little expression in other tissues Localisation Cytoplasm in the Golgi/centrosomal area in non muscle cells and nucleus; in the sarcomeres of muscle cells Function Interacts with the cyclic nucleotide phosphodiesterase PDE4D, enzymes that degrade and inactivate cAMP; may oligomerize Homology With the Drosophila centrosomin (a component of the centrosome and the mitotic spindle) Implicated in Entity t(1;5)(q22;q33) in chronic eosinophilic leukemia --> PDE4DIP - PDGFRB Note KIAA0477 isoforms was found involved in the hybrid gene / fusion protein. Disease Rare disease mainly found in infants. Prognosis Treatment with imatinib may be relevant.

External links

Atlas Genet Cytogenet Oncol Haematol 2006; 4 471 Nomenclature Hugo PDE4DIP GDB PDE4DIP PDE4DIP 9659 phosphodiesterase 4D interacting protein Entrez_Gene (myomegalin) Cards Atlas PDE4DIP01q22ID180 GeneCards PDE4DIP Ensembl PDE4DIP Genatlas PDE4DIP GeneLynx PDE4DIP eGenome PDE4DIP euGene 9659 Genomic and cartography PDE4DIP - 1q22 chr1:143663118-143706379 - 1q21.1 (hg18- GoldenPath Mar_2006) Ensembl PDE4DIP - 1q21.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

HomoloGene PDE4DIP Gene and transcription Genbank AA707296 [ ENTREZ ] Genbank AB007923 [ ENTREZ ] Genbank AB007946 [ ENTREZ ] Genbank AB042555 [ ENTREZ ] Genbank AB042556 [ ENTREZ ] RefSeq NM_001002810 [ SRS ] NM_001002810 [ ENTREZ ] RefSeq NM_001002811 [ SRS ] NM_001002811 [ ENTREZ ] RefSeq NM_001002812 [ SRS ] NM_001002812 [ ENTREZ ] RefSeq NM_014644 [ SRS ] NM_014644 [ ENTREZ ] RefSeq NM_022359 [ SRS ] NM_022359 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004434 [ SRS ] NT_004434 [ ENTREZ ] AceView PDE4DIP AceView - NCBI TRASER PDE4DIP Traser - Stanford Unigene Hs.632438 [ SRS ] Hs.632438 [ NCBI ] HS632438 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2006; 4 472 SwissProt O75042 [ SRS] O75042 [ EXPASY ] O75042 [ INTERPRO ] Interpro IPR010630 DUF1220 [ SRS ] IPR010630 DUF1220 [ EBI ] IPR012943 Spindle_assoc [ SRS ] IPR012943 Spindle_assoc [ EBI Interpro ] CluSTr O75042 PF06758 DUF1220 [ SRS ] PF06758 DUF1220 [ Sanger Pfam ] pfam06758 [ NCBI-CDD ] PF07989 Microtub_assoc [ SRS ] PF07989 Microtub_assoc [ Pfam Sanger ] pfam07989 [ NCBI-CDD ] Blocks O75042 HPRD O75042 Protein Interaction databases DIP O75042 IntAct O75042 Polymorphism : SNP, mutations, diseases OMIM 608117 [ map ] GENECLINICS 608117 SNP PDE4DIP [dbSNP-NCBI] SNP NM_001002810 [SNP-NCI] SNP NM_001002811 [SNP-NCI] SNP NM_001002812 [SNP-NCI] SNP NM_014644 [SNP-NCI] SNP NM_022359 [SNP-NCI] SNP PDE4DIP [GeneSNPs - Utah] PDE4DIP] [HGBASE - SRS] HAPMAP PDE4DIP [HAPMAP] General knowledge Family PDE4DIP [UCSC Family Browser] Browser SOURCE NM_001002810 SOURCE NM_001002811 SOURCE NM_001002812 SOURCE NM_014644 SOURCE NM_022359 SMD Hs.632438 SAGE Hs.632438 structural constituent of ribosome[Amigo] structural constituent of Amigo ribosome[EGO-EBI] Amigo actin binding[Amigo] actin binding[EGO-EBI] Amigo intracellular[Amigo] intracellular[EGO-EBI]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 473 Amigo ribosome[Amigo] ribosome[EGO-EBI] Amigo protein biosynthesis[Amigo] protein biosynthesis[EGO-EBI] cytoskeleton organization and biogenesis[Amigo] cytoskeleton Amigo organization and biogenesis[EGO-EBI] Amigo actin cytoskeleton[Amigo] actin cytoskeleton[EGO-EBI] actin cytoskeleton organization and biogenesis[Amigo] actin Amigo cytoskeleton organization and biogenesis[EGO-EBI] PubGene PDE4DIP Other databases Probes Probe PDE4DIP Related clones (RZPD - Berlin) PubMed PubMed 7 Pubmed reference(s) in LocusLink Bibliography Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, Onuffer J, Jin SL, Conti M. J Biol Chem. 2001; 276: 11189-11198. Medline 11134006

Isolation of novel heart-specific genes using the BodyMap database. Soejima H, Kawamoto S, Akai J, Miyoshi O, Arai Y, Morohka T, Matsuo S, Niikawa N, Kimura A, Okubo K, Mukai T. Genomics. 2001; 74: 115-120. Medline 11374908

Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Wilkinson K, Velloso ER, Lopes LF, Lee C, Aster JC, Shipp MA, Aguiar RC. Blood. 2003; 102: 4187-4190. Medline 12907457

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Jean Loup Huret 2006 Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2006; 4 474 Huret JL . PDE4DIP (phosphodiesterase 4D interacting protein (myomegalin)). Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Genes/PDE4DIP01q22ID180.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 475 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MYST4 (MYST histone acetyltransferase (monocytic leukemia) 4) Identity Other qkf names MORF MOZ2 FLJ90335 KIAA0383 querkopf DKFZp313G1618 EC 2.3.1.- EC 2.3.1.48 Hugo MYST4 Location 10q22.2 ADK (adenosine kinase isoform a) is more centromeric. DUPD1 (dual Local_order specificity phosphatase and pro isomerase) is more telomeric.

Genomic structure of MYST4. Black boxes indicate exons.

DNA/RNA Description 18 exons spanning 206.0 Kb on 10q22.2. Transcription is from centromere to telomere. Transcription 1 transcript Protein

Schematic representation of MYST4 protein. H15 domain: domain in histone families 1 and 5; PHD zinc fingers: plant homeodomain (PHD)

Atlas Genet Cytogenet Oncol Haematol 2006; 4 476 with a C4HC3-type motif, this domain is widely distributed in eukaryotes and it has been found in many chromatin regulatory factors; MOZ-SAS family region: this region has been suggested to be homologous to acetyltransferases but this similarity is not supported by sequence analysis.

Note MYST4_HUMAN; Histone acetyltransferase MYST4, MYST protein 4, MOZ, YBF2/SAS3, SAS2 and TIP60 protein 4, Histone acetyltransferase MOZ2, Monocytic leukemia zinc finger protein-related factor, or Histone acetyltransferase MORF. Description Histone acetyltransferase MYST4. Localisation Nucleous (probable). Function It is a histone acetyltransferase probably involved in both positive (N- terminus) and negative (C-terminus) regulation of transcription, maybe involved in cerebral cortex development, required for RUNX2- dependent transcriptional activation and ubiquitously expressed in adult human tissues. Mutations Somatic MYST4 fusion genes in neoplasia t(10;16)(q22;p13) (see below) 5' MYST4-CREBBP 3' (previously known as MORF-CBP, MORF- CREBBP, or MYST4-CBP) fusion was first described in a 4-year-old girl with AML M5a without signs of erythrophagocytosis and several chromosome abnormalities. It was also described in an 84-year-old male without erythrophagocytosis and with this sole cytogenetic aberration. This suggested that the recurrent fusion gene could contribute directly to the development of the AML. This fusion gene was also described with a variant breakpoint in a 52-year-old japanese woman with a therapy-related myelodysplastic syndrome (t-MDS) and this sole translocation. A novel fusion variant was also described in an AML-M4 female patient with the t(10;16) (q22;p13) and a t(11;17)(q23;q21). t(10;17)(q22;q21-q24). It has been observed that 5% of chromosomally abnormal uterine leiomyomata had rearrangements of 10q22, most of them with balanced translocations with a variety of partners in chromosomes 4, 6, or 12 in leiomyomata and chromosomes 7, 11, 17, or 18 in leiomyosarcomas. Previously the t(10;17) had been reported as the sole cytogenetic abnormality in one leiomyosarcoma and as part of a complex karyotype in another leiomyosarcoma. FISH analysis of four uterine leiomyomata has revealed a breakpoint in the third intron of MYST4 after the H15 domain and before the PHD zinc finger domain. This disruption of MYST4 seems to be more 5' to the breakpoints reported in hematopoietic malignancies. In addition, in three of the four uterine leiomyomata, the10q22 rearrangement also involves a locus on 17q with probably the same breakpoint. This could suggest a cytogenetically distinct subgroup of uterine leiomyomata that could be also defined by a common phenotype.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 477 Implicated in Entity t(10;16)(q22;p13) Note The t(10;16)(q22;p13) fusing MYST4 and CREBBP to generate a chimeric protein MYST4-CREBBP (previously known as MORF-CBP, MORF-CREBBP, or MYST4-CBP) is a very rare cytogenetic abnormality only described in 4 cases to date with AML M4/M5a and therapy-related MDS without signs of erythrophagocytosis; most of them with bad prognosis. This translocation is related to t(8;16)(p11;p13) that fuses MYST3 to CREBBP (previously also known as MOZ-CREBBP or MOZ-CBP) also described in cases with AML/M4-M5 and therapy-related AML with a poor response to chemotherapy and frequently displaying erythrophagocytosis. Disease Described in two cases with AML M5, one case with AML M4 and one case with therapy-related MDS, all of them without signs of erythrophagocytosis (showed in the t(8;16), MYST3-CREBBP fusion). Prognosis poor. Cytogenetics t(10;16)(q22;p13), rarely as sole anomaly. Hybrid/Mutated 5' MYST4-CREBBP 3' Gene Abnormal MYST4-CREBBP The putative MYST4-CREBBP fusion protein Protein retains the zinc fingers, two nuclear localization signals, the HAT domain, and a portion of the acidic domain from MYST4, and most of the CREBBP protein, including its HAT domain.

Entity Rearrangements of 10q22 in uterine leiomyomata Note Some of the chromosomally abnormal uterine leiomyomata had rearrangements of 10q22, most of them with balanced translocations with a variety of partners in chromosomes 4, 6, or 12 in leiomyomata and chromosomes 7, 11, 17, or 18 in leiomyosarcomas. FISH analysis of some uterine leiomyomata has revealed a disruption of MYST4 between the H15 domain and the PHD zinc finger domain. In three cases the partner gene was a locus on 17q with probably the same breakpoint. This could delimit a distinct subgroup of uterine leiomyomata. Prognosis Unknown. Cytogenetics Rearrangements of 10q22, most of them with balanced translocations with chromosomes 4, 6, or 12 in leiomyomata and chromosomes 7, 11, 17, or 18 in leiomyosarcomas. Hybrid/Mutated Several cases has shown disruption of MYST4, some of them with Gene an unknown partner in 17q21-q24. Abnormal Unknown. Protein

Atlas Genet Cytogenet Oncol Haematol 2006; 4 478

External links Nomenclature Hugo MYST4 GDB MYST4 MYST4 23522 MYST histone acetyltransferase (monocytic Entrez_Gene leukemia) 4 Cards Atlas MYST4ID41488ch10q22 GeneCards MYST4 Ensembl MYST4 Genatlas MYST4 GeneLynx MYST4 eGenome MYST4 euGene 23522 Genomic and cartography MYST4 - 10q22.2 chr10:76256385-76462645 + 10q22.2 (hg18- GoldenPath Mar_2006) Ensembl MYST4 - 10q22.2 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MYST4 Gene and transcription Genbank AA416904 [ ENTREZ ] Genbank AB002381 [ ENTREZ ] Genbank AF113514 [ ENTREZ ] Genbank AF119230 [ ENTREZ ] Genbank AF119231 [ ENTREZ ] RefSeq NM_012330 [ SRS ] NM_012330 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_008583 [ SRS ] NT_008583 [ ENTREZ ] RefSeq NW_924796 [ SRS ] NW_924796 [ ENTREZ ] AceView MYST4 AceView - NCBI TRASER MYST4 Traser - Stanford Unigene Hs.599543 [ SRS ] Hs.599543 [ NCBI ] HS599543 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q69YR9 [ SRS] Q69YR9 [ EXPASY ] Q69YR9 [ INTERPRO ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 479 Interpro IPR002717 MOZ_SAS [ SRS ] IPR002717 MOZ_SAS [ EBI ] CluSTr Q69YR9 PF01853 MOZ_SAS [ SRS ] PF01853 MOZ_SAS [ Sanger Pfam ] pfam01853 [ NCBI-CDD ] Blocks Q69YR9 HPRD Q69YR9 Protein Interaction databases DIP Q69YR9 IntAct Q69YR9 Polymorphism : SNP, mutations, diseases OMIM 605880 [ map ] GENECLINICS 605880 SNP MYST4 [dbSNP-NCBI] SNP NM_012330 [SNP-NCI] SNP MYST4 [GeneSNPs - Utah] MYST4] [HGBASE - SRS] HAPMAP MYST4 [HAPMAP] General knowledge Family MYST4 [UCSC Family Browser] Browser SOURCE NM_012330 SMD Hs.599543 SAGE Hs.599543 Amigo nucleosome[Amigo] nucleosome[EGO-EBI] Amigo DNA binding[Amigo] DNA binding[EGO-EBI] histone acetyltransferase activity[Amigo] histone acetyltransferase Amigo activity[EGO-EBI] histone acetyltransferase activity[Amigo] histone acetyltransferase Amigo activity[EGO-EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI] Amigo nucleosome assembly[Amigo] nucleosome assembly[EGO-EBI] Amigo transcription[Amigo] transcription[EGO-EBI] regulation of transcription, DNA-dependent[Amigo] regulation of Amigo transcription, DNA-dependent[EGO-EBI] transcription factor binding[Amigo] transcription factor binding[EGO- Amigo EBI] Amigo zinc ion binding[Amigo] zinc ion binding[EGO-EBI] Amigo acetyltransferase activity[Amigo] acetyltransferase activity[EGO-EBI] negative regulation of transcription[Amigo] negative regulation of Amigo transcription[EGO-EBI]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 480 transcriptional activator activity[Amigo] transcriptional activator Amigo activity[EGO-EBI] transcriptional repressor activity[Amigo] transcriptional repressor Amigo activity[EGO-EBI] Amigo chromatin modification[Amigo] chromatin modification[EGO-EBI] Amigo histone acetylation[Amigo] histone acetylation[EGO-EBI] Amigo histone acetylation[Amigo] histone acetylation[EGO-EBI] Amigo transferase activity[Amigo] transferase activity[EGO-EBI] positive regulation of transcription[Amigo] positive regulation of Amigo transcription[EGO-EBI] positive regulation of transcription[Amigo] positive regulation of Amigo transcription[EGO-EBI] Amigo metal ion binding[Amigo] metal ion binding[EGO-EBI] PubGene MYST4 Other databases Probes Probe MYST4 Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography t(10;17) as the sole chromosome change in a uterine leiomyosarcoma. Dal Cin P, Boghosian L, Crickard K, Sandberg AA. Cancer Genet Cytogenet 1988; 32:263-266. Medline 2354458

Chromosome aberrations in uterine smooth muscle tumors: potential diagnostic relevance of cytogenetic instability. Fletcher JA, Morton CC, Pavelka K, Lage JM. Cancer Res 1990; 50: 4092-4097. Medline 3163264

Identification of a human histone acetyltransferase related to monocytic leukemia zinc finger protein. Champagne N, Bertos NR, Pelletier N, Wang AH, Vezmar M, Yang Y, Heng HH, Yang XJ. J Biol Chem 1999; 274: 28528-28536. Medline 10497217

Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Panagopoulos I, Fioretos T, Isaksson M, Samuelsson U, Billstrom R, Strombeck B, Mitelman F, Johansson B. Hum Mol Genet 2001; 10: 395-404.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 481 Medline 11157802

Expression, purification, and analysis of MOZ and MORF histone acetyltransferases. Pelletier N, Champagne N, Lim H, Yang XJ. Methods 2003; 31: 24-32. Medline 12893170

The MYST family of histone acetyltransferases. REVIEW. Utley RT, Cote J. Curr Top Microbiol Immunol 2003; 274: 203-236. Medline 12596909 t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukaemia. Vizmanos JL, Larrayoz MJ, Lahortiga I, Floristan F, Alvarez C, Odero MD, Novo FJ, Calasanz MJ. Genes Chromosomes Cancer 2003; 36: 402-405. Medline 12619164

Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Moore SD, Herrick SR, Ince TA, Kleinman MS, Cin PD, Morton CC, Quade BJ. Cancer Res 2004; 64: 5570-5577. Medline 15313893

Variant MYST4-CBP gene fusion in a t(10;16) acute myeloid leukaemia. Murati A, Adelaide J, Mozziconacci MJ, Popovici C, Carbuccia N, Letessier A, Birg F, Birnbaum D, Chaffanet M. Br J Haematol 2004; 125: 601-604. Medline 15147375

Querkopf, a histone acetyltransferase, is essential for embryonic neurogenesis. Thomas T, Voss AK. Front Biosci 2004; 9: 24-31. Medline 14766340

MOZ fusion proteins in acute myeloid leukaemia. REVIEW. Troke PJ, Kindle KB, Collins HM, Heery DM.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 482 Biochem Soc Symp 2006; 73: 23-39. Medline 16626284

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- José Luis Vizmanos 2006 Citation This paper should be referenced as such : Vizmanos JL . MYST4 (MYST histone acetyltransferase (monocytic leukemia) 4). Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Genes/MYST4ID41488ch10q22.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 483 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CRTC1 (CREB regulated transcription coactivator 1) Identity Other KIAA0616 names FLJ14027 WAMTP1 MECT1 TORC1 Hugo CRTC1 Location 19p13.11 DNA/RNA Description Spans about 94 kb and includes 14 to 16 exons Transcription two RNA variants of 2505 and 2342 bp, respectively. Protein

Note 634 amino acids; 67300 Da Description Transcriptional coactivator for CREB1. Expression Expressed in a restricted number of tissues including fetal brain and liver and adult heart, skeletal muscle, liver and salivary gland. Localisation Nucleus. Function Interacts through its N-terminal CREB-binding domain with the bZIP domain of CREB1; Binds to CREB1 as a homotetramer. Transcriptional coactivator for CREB1, which activates transcription through both consensus and variant cAMP response element (CRE) sites, leading to activation of CREB1 target genes. Does not appear to modulate CREB1 DNA-binding activity but enhances the interaction of CREB1 with TAF4/TAFII-130. Implicated in Entity Mucoepidermoid carcinoma (most common type of malignant salivary gland tumor; second most frequent lung tumor of bronchial gland origin); benign Warthin¹s tumor; clear cell hidradenoma of the skin (CCH; a.k.a. nodular hidradenomas or eccrine acrospiromas). all sharing a t(11; 19) (q21; p13) Cytogenetics t(11;19)(q21;p13).

Atlas Genet Cytogenet Oncol Haematol 2006; 4 484

Fig1a (a) Partial G-banded and SKY karyotypes showing the t(11;19) in a mucoepidermoid carcinoma (MEC) case. (b) Dual-color FISH experiment of the MEC using BAC 697H10 (MAML2, red signal) and cosmid LLNLR 255A4 (CRTC1, green signal) as probes. Note the presence of the CRTC1- MAML2 fusion gene on the der(11) (fused redgreen signals marked by an arrowhead). Reprinted partially from Publication ³Exp Cell Res 292, Enlund F., Behboudi A., Andren Y., Oberg C., Lendahl U., Mark J., Stenman G., Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors, 21-28, Copyright (2004), with permission from Elsevier.²

Hybrid/Mutated CRTC1-MAML2. Exon 1 of MECT1 fused to exons 2-5 of MAML2. Gene Abnormal MECT1-MAML2; in the fusion protein the first 171 aa including the basic Protein domain of MAML2 are replaced by 42 aa of MECT1; there are no sequence similarities in the N-terminal domains of MAML2 and MECT1; the fusion protein activates transcription of the Notch target gene HES1 independently of both Notch ligand and CSL.

Top: Nucleotide and deduced amino acid sequences of the CRTC1-MAML2 breakpoint junction. Bottom: Schematic representation of the MAML2 protein and the CRTC1- MAML2 fusion protein. In the fusion protein the N-terminal Notch-binding domain of MAML2 is replaced by the CREB-binding domain of CRTC1. Reprinted partially from publication above mentioned

External links Nomenclature Hugo CRTC1 GDB CRTC1 Entrez_Gene CRTC1 23373 CREB regulated transcription coactivator 1

Atlas Genet Cytogenet Oncol Haematol 2006; 4 485 Cards Atlas CRTC1ID471ch19p13 GeneCards CRTC1 Ensembl CRTC1 Genatlas CRTC1 GeneLynx CRTC1 eGenome CRTC1 euGene 23373 Genomic and cartography CRTC1 - 19p13.11 chr19:18655504-18749757 + 19p13.11 GoldenPath (hg18-Mar_2006) Ensembl CRTC1 - 19p13.11 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CRTC1 Gene and transcription Genbank AB014516 [ ENTREZ ] Genbank AK024089 [ ENTREZ ] Genbank AY040323 [ ENTREZ ] Genbank AY360171 [ ENTREZ ] Genbank BC017075 [ ENTREZ ] RefSeq NM_015321 [ SRS ] NM_015321 [ ENTREZ ] RefSeq NM_025021 [ SRS ] NM_025021 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011295 [ SRS ] NT_011295 [ ENTREZ ] RefSeq NW_927195 [ SRS ] NW_927195 [ ENTREZ ] AceView CRTC1 AceView - NCBI TRASER CRTC1 Traser - Stanford Unigene Hs.371096 [ SRS ] Hs.371096 [ NCBI ] HS371096 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q6UUV9 [ SRS] Q6UUV9 [ EXPASY ] Q6UUV9 [ INTERPRO ] CluSTr Q6UUV9 Blocks Q6UUV9 HPRD Q6UUV9 Protein Interaction databases DIP Q6UUV9 IntAct Q6UUV9

Atlas Genet Cytogenet Oncol Haematol 2006; 4 486 Polymorphism : SNP, mutations, diseases OMIM 607536 [ map ] GENECLINICS 607536 SNP CRTC1 [dbSNP-NCBI] SNP NM_015321 [SNP-NCI] SNP NM_025021 [SNP-NCI] SNP CRTC1 [GeneSNPs - Utah] CRTC1] [HGBASE - SRS] HAPMAP CRTC1 [HAPMAP] General knowledge Family CRTC1 [UCSC Family Browser] Browser SOURCE NM_015321 SOURCE NM_025021 SMD Hs.371096 SAGE Hs.371096 Amigo protein binding[Amigo] protein binding[EGO-EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI] Amigo transcription[Amigo] transcription[EGO-EBI] regulation of transcription, DNA-dependent[Amigo] regulation of Amigo transcription, DNA-dependent[EGO-EBI] cAMP response element binding protein binding[Amigo] cAMP Amigo response element binding protein binding[EGO-EBI] positive regulation of transcription from RNA polymerase II Amigo promoter[Amigo] positive regulation of transcription from RNA polymerase II promoter[EGO-EBI] PubGene CRTC1 Other databases Probes Probe CRTC1 Related clones (RZPD - Berlin) PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography TORCs: transducers of regulated CREB activity. Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia L, Hogenesch JB, Montminy M. Mol Cell 2003; 12(2): 413-423. Medline 14536081

Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Iourgenko V, Zhang W, Mickanin C, Daly I, Jiang C, Hexham JM, Orth AP, Miraglia L,

Atlas Genet Cytogenet Oncol Haematol 2006; 4 487 Meltzer J, Garza D, Chirn GW, McWhinnie E, Cohen D, Skelton J, Terry R, Yu Y, Bodian D, Buxton FP, Zhu J, Song C, Labow MA. Proc Natl Acad Sci USA 2003; 100(21): 12147-12152. Medline 14506290 t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, O'Neil K, Stover K, El-Naggar A, Griffin JD, Kirsch IR, Kaye FJ. Nat Genet 2003; 33(2): 208-213. Erratum in: Nat Genet 2003 Mar; 33(3): 430. Medline 12539049

Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. Enlund F, Behboudi A, Andren Y, Oberg C, Lendahl U, Mark J, Stenman G. Exp Cell Res 2004; 292(1): 21-28. Medline 14720503

Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)-- associated TORC1-MAML2 gene fusion. Behboudi A, Winnes M, Gorunova L, van den Oord JJ, Mertens F, Enlund F, Stenman G. Genes Chromosomes Cancer 2005; 43(2): 202-205. Medline 15729701

Fusion oncogenes and tumor type specificity--insights from salivary gland tumors. Stenman G. Semin Cancer Biol 2005; 15(3): 224-235. (Review) Medline 15826837

Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation. Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, Griffin JD. EMBO J 2005; 24(13): 2391-402. Medline 15961999

Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. Behboudi A, Enlund F, Winnes M, Andren Y, Nordkvist A, Leivo I, Flaberg E, Szekely L, Makitie A, Grenman R, Mark J, Stenman G. Genes Chromosomes Cancer 2006; 45(5): 470-481. Medline 16444749

REVIEW articles automatic search in PubMed Last year automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2006; 4 488 publications BiblioGene - INIST Contributor(s) Written 07- Goran Stenman 2003 Updated 05- Afrouz Behboudi, Göran Stenman 2006 Citation This paper should be referenced as such : Stenman G . CRTC1 (CREB regulated transcription coactivator 1). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://AtlasGeneticsOncology.org/Genes/CRTC1ID471ch19p13.html Behboudi A, Stenman G . CRTC1 (CREB regulated transcription coactivator 1). Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Genes/CRTC1ID471ch19p13.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 489 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CEBPA (CCAAT enhancer binding protein alpha) Identity Other C/EBPa names Hugo CEBPA Location 19q13.1 DNA/RNA Description CEBPA is a single exon gene located on the minus strand of chromosome 19q. Transcription The mRNA produced consists of a short 5'UTR containing a small 5'ORF, the coding region and a large 3'UTR. Protein

C/EBPa protein domains The basic region leucine zipper domain mediates DNA binding, homodimerization of C/EBPa and heterodimerization with other members of the C/EBP family. This region is also involved in mediating protein-protein interactions with other transcription factors involved in lineage determination and growth proliferation. N-terminal region transactivating domains mediate interactions with transcriptional machinery and proteins important in cell cycle control. The CEBPA mRNA gives rise to two different translational isoforms by using different start codons within the same open reading frame by means of leaky ribosome scanning; the full length 42kDa protein and a 30kDa truncated form. These isoforms display contrasting functions in regards to gene activation and cell proliferation. Both isoforms can be detected within the cell and it is likely that the ratio of isoforms is important in mediating proliferation and differentiation control.

Expression C/EBPa is expressed in many cell types and plays crucial roles in hepatocyte and adipocyte development, with highest concentrations in terminally differentiated cells. In hematopoiesis, C/EBPa is expressed in myeloid cells and drives granulocytic differentiation. C/EBPa is also found expressed in intestine, lung, adrenal gland, breast, ovary and

Atlas Genet Cytogenet Oncol Haematol 2006; 4 490 placenta tissues. Localisation C/EBPa localises to the nucleus Function C/EBPa and its isoforms play important roles in lineage determination and gene activation in a variety of cell types by activating transcription from lineage-specific promoters. In hematopoiesis, C/EBPa is a key factor in driving the development of myeloid cells interacting with a variety of factors, including c-Myc, PU.1, and microRNAs. The truncated form of C/EBPa has been seen to act in a dominant negative regulatory manner in mice, abolishing normal C/EBPa function and causing a block in differentiation. In humans, the truncated protein selectively inhibits C/EBPa DNA binding but due to variable DNA affinity has a greater range of effects on differentiation. Several pathways have been implicated as the means by which C/EBPa mediates cell cycle arrest and proliferation, including p21, cyclin- dependent kinases and the E2F complex via c-Myc. The 30kDa isoform of C/EBPa lacks the domains required to mediate cell growth. Homology C/EBPa belongs to the family of C/EBP proteins and is conserved across a variety of vertebrate species Mutations Note Mutations in CEBPA occur in approximately 10% of all acute myeloid leukemias (AMLs)

N-terminal mutations abolish expression of full length 42kDa protein, upregulating production of the 30kDa isoform. C-terminal mutations result in C/EBPa proteins with decreased DNA binding or dimerization activity.

Germinal Germline mutations in CEBPA have been described in 2 familial cases of AML. The first family contained a heterozygous germline mutation of del (C) at nucleotide 212 which causes the premature termination of the protein at codon 158. The 30kDa isoform is produced. Somatic mutation causing in frame duplication was also found in the C-terminal region of one patient on the other allele, which was not present in remission samples. The second family contained a heterozygous germline

Atlas Genet Cytogenet Oncol Haematol 2006; 4 491 mutation of ins (C) at nucleotide 217 which causes the premature termination of the protein. The 30kDa isoform is produced. Somatic mutations in the C-terminal region were found in two of the affected family members. Somatic Mutations in CEBPA tend to cluster to two regions. The first group affect the N-terminal region of C/EBPa. These mutations are often insertions or deletions which cause frameshifts which cause premature truncation of the protein. In this case, translation is reinitiated at an internal ATG and the 30kDa protein, which lacks the first transactivating domain, is produced. Secondly, in-frame or missense mutations occur within the C-terminal region of C/EBPa, disrupting the basic zipper region and thus affecting DNA binding, protein interactions as well as homo and heterodimerization with other C/EBP family members. Multiple mutations in CEBPA are common and often biallelic, although the allelic frequency of the mutations can change over the course of the disease. Mutations are generally maintained between presentation and replapse and therefore may be useful for monitoring minimal residual disease. Implicated in Entity Acute myeloid leukemias Disease Mutations in CEBPA have been implicated in acute myeloid leukaemia, most often in association with FAB types M1 and M2, although it has also been found in M4 and M5 types. Mutations in CEBPA occur in approximately 10% of all AMLs and are associated with normal karyotype AML. Prognosis Mutations in CEBPA tend to confer favourable prognosis. Low levels of RNA expression of CEBPA have been noted in AML where it may reflect adverse prognosis. Oncogenesis CEBPA expression is downregulated in the presence of fusion protein AML1-ETO via inhibition of the CEBPA promoter. Translation of the C/EBPa protein is suppressed by the fusion gene AML1-MDS1-EVI1 via the activation of calreticulin. Pericentric inversion of chromosome 16, inv(16)(p13q22), which fuses the CBFB and MYH11 genes, with the latter encoding the smooth muscle myosin heavy chain (SMMHC) suppresses translation of the C/EBPa protein via calreticulin. BCR-ABL fusion is able to suppress CEBPA protein translation via inhibitory action of the poly(rC)-binding protein hnRNP E2. The involvement of CEBPA mutations in familial cases of AML, along with evidence of mutations persisting between presentation and relapse indicate that mutations in CEBPA are an early event in leukaemogenesis.

Entity Although mutated CEBPA is primarily observed in AML, in rare cases it has been found to be mutated in myelodysplasic syndromes (MDS), lung tumours and prostate tumours. Down-regulation of CEBPA has

Atlas Genet Cytogenet Oncol Haematol 2006; 4 492 also been observed in blast crisis chronic myeloid leukaemia, lung cancer, breast cancer and liver cancer.

Entity t(14;19)(q32;q13) --> IGH / CEBPA Disease CEBPA is rarely involved in translocations with other genes. However, in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) the 3'UTR of CEBPA has been found to be translocated to the immunoglobulin heavy chain locus

External links Nomenclature Hugo CEBPA GDB CEBPA Entrez_Gene CEBPA 1050 CCAAT/enhancer binding protein (C/EBP), alpha Cards Atlas CEBPAID40050ch19q13 GeneCards CEBPA Ensembl CEBPA Genatlas CEBPA GeneLynx CEBPA eGenome CEBPA euGene 1050 Genomic and cartography CEBPA - 19q13.1 chr19:38482776-38485160 - 19q13.11 (hg18- GoldenPath Mar_2006) Ensembl CEBPA - 19q13.11 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CEBPA Gene and transcription Genbank BC027902 [ ENTREZ ] Genbank BC063874 [ ENTREZ ] Genbank X87248 [ ENTREZ ] Genbank Y11525 [ ENTREZ ] RefSeq NM_004364 [ SRS ] NM_004364 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011109 [ SRS ] NT_011109 [ ENTREZ ] RefSeq NW_927206 [ SRS ] NW_927206 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 493 AceView CEBPA AceView - NCBI TRASER CEBPA Traser - Stanford Unigene Hs.76171 [ SRS ] Hs.76171 [ NCBI ] HS76171 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P49715 [ SRS] P49715 [ EXPASY ] P49715 [ INTERPRO ] Prosite PS50217 BZIP [ SRS ] PS50217 BZIP [ Expasy ] Prosite PS00036 BZIP_BASIC [ SRS ] PS00036 BZIP_BASIC [ Expasy ] Interpro IPR011700 bZIP_2 [ SRS ] IPR011700 bZIP_2 [ EBI ] Interpro IPR004827 TF_bZIP [ SRS ] IPR004827 TF_bZIP [ EBI ] CluSTr P49715 PF07716 bZIP_2 [ SRS ] PF07716 bZIP_2 [ Sanger ] pfam07716 Pfam [ NCBI-CDD ] Smart SM00338 BRLZ [EMBL] Blocks P49715 HPRD P49715 Protein Interaction databases DIP P49715 IntAct P49715 Polymorphism : SNP, mutations, diseases OMIM 116897;601626 [ map ] GENECLINICS 116897;601626 SNP CEBPA [dbSNP-NCBI] SNP NM_004364 [SNP-NCI] SNP CEBPA [GeneSNPs - Utah] CEBPA] [HGBASE - SRS] HAPMAP CEBPA [HAPMAP] General knowledge Family CEBPA [UCSC Family Browser] Browser SOURCE NM_004364 SMD Hs.76171 SAGE Hs.76171 transcription factor activity[Amigo] transcription factor activity[EGO- Amigo EBI] RNA polymerase II transcription factor activity, enhancer Amigo binding[Amigo] RNA polymerase II transcription factor activity, enhancer binding[EGO-EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI]

Amigo nucleus[Amigo] nucleus[EGO-EBI]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 494 generation of precursor metabolites and energy[Amigo] generation Amigo of precursor metabolites and energy[EGO-EBI] Amigo transcription[Amigo] transcription[EGO-EBI] Amigo transcription[Amigo] transcription[EGO-EBI] regulation of transcription, DNA-dependent[Amigo] regulation of Amigo transcription, DNA-dependent[EGO-EBI] transcription from RNA polymerase II promoter[Amigo] transcription Amigo from RNA polymerase II promoter[EGO-EBI] transcription factor binding[Amigo] transcription factor binding[EGO- Amigo EBI] cytokine and chemokine mediated signaling Amigo pathway[Amigo] cytokine and chemokine mediated signaling pathway[EGO-EBI] myeloid cell differentiation[Amigo] myeloid cell differentiation[EGO- Amigo EBI] sequence-specific DNA binding[Amigo] sequence-specific DNA Amigo binding[EGO-EBI] protein dimerization activity[Amigo] protein dimerization Amigo activity[EGO-EBI] BIOCARTA Keratinocyte Differentiation [Genes] BIOCARTA MAPKinase Signaling Pathway [Genes] PubGene CEBPA Other databases Probes Probe CEBPA Related clones (RZPD - Berlin) PubMed PubMed 82 Pubmed reference(s) in LocusLink Bibliography The CCAAT/enhancer binding protein (C/EBP alpha) gene (CEBPA) maps to human chromosome 19q13.1 and the related nuclear factor NF-IL6 (C/EBP beta) gene (CEBPB) maps to human chromosome 20q13.1. Hendricks-Taylor LR, Bachinski LL, Siciliano MJ, Fertitta A, Trask B, de Jong PJ, Ledbetter DH, Darlington GJ. Genomics 1992; 14:12-7. Medline 1427819

PU.1 (Spi-1) and C/EBP alpha regulate expression of the granulocyte- macrophage colony-stimulating factor receptor alpha gene. Hohaus S, Petrovick MS, Voso MT, Sun Z, Zhang DE, Tenen DG. Mol Cell Biol 1995; 15:5830-45. Medline 7565736

C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase

Atlas Genet Cytogenet Oncol Haematol 2006; 4 495 promoter. Oelgeschlager M, Nuchprayoon I, Luscher B, Friedman AD. Mol Cell Biol 1996; 16:4717-25. Medline 8756629

PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Smith LT, Hohaus S, Gonzalez DA, Dziennis SE, Tenen DG. Blood 1996; 88:1234-47. Medline 8695841

Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG. Proc Natl Acad Sci USA 1997; 94:569-74. Medline 9012825

Multiple functional domains of AML1: PU.1 and C/EBPalpha synergize with different regions of AML1. Petrovick MS, Hiebert SW, Friedman AD, Hetherington CJ, Tenen DG, Zhang DE. Mol Cell Biol 1998; 18:3915-25. Medline 9632776

C/EBPalpha bypasses granulocyte colony-stimulating factor signals to rapidly induce PU.1 gene expression, stimulate granulocytic differentiation, and limit proliferation in 32D cl3 myeloblasts. Wang X, Scott E, Sawyers CL, Friedman AD. Blood 1999; 94:560-71. Medline 10397723

Translational control of C/EBPalpha and C/EBPbeta isoform expression. Calkhoven CF, Muller C, Leutz A. Genes Dev 2000; 14:1920-32. Medline 10921906

AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG. Nat Med 2001; 7:444-51. Medline 1283671

Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, Behre G, Hiddemann W, Tenen DG.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 496 Nat Genet 2001; 27:263-70. Medline 11242107

Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH, Larsen RJ, Asou H, Miller CW, Hoelzer D, Koeffler HP. Blood 2002; 99(4):1332-40. Medline 11830484

BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K, Iervolino A, Condorelli F, Gambacorti-Passerini C, Caligiuri MA, Calabretta B. Nat Genet 2002; 30:48-58. Medline 11753385

Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S, Thomas X, Raffoux E, Lamandin C, Castaigne S, Fenaux P, Dombret H; ALFA Group. Blood 2002; 100:2717-23. Medline 12351377

CCAAT/enhancer-binding proteins: structure, function and regulation. Ramji DP, Foka P. Biochem J 2002; 365:561-75. (REVIEW) Medline 12006103

Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, Meijer J, van Oosterhoud S, van Putten WL, Valk PJ, Berna Beverloo H, Tenen DG, Lowenberg B, Delwel R. Hematol J 2003; 4:31-40. Medline 12692518

The amino terminal and E2F interaction domains are critical for C/EBPa mediated induction of granulopoietic development of hematopoietic cells. D¹Alo F, Johansen LM, Nelson EA, Radomska HS, Evans EK, Zhang P, Nerlov C, Tenen D. Blood 2003; 102:3163-3171. Medline 12869508

Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 497 Snaddon J, Smith ML, Neat M, Cambal-Parrales M, Dixon-McIver A, Arch R, Amess JA, Rohatiner AZ, Lister TA, Fitzgibbon J. Genes Chromosomes Cancer 2003; 37:72-8. Medline 12661007

Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia. Tiesmeier J, Czwalinna A, Muller-Tidow C, Krauter J, Serve H, Heil G, Ganser A, Verbeek W. Br J Haematol 2003; 123:413-9. Medline 14616999

C/EBPalphap30, a myeloid leukemia oncoprotein, limits G-CSF receptor expression but not terminal granulopoiesis via site-selective inhibition of C/EBP DNA binding. Cleaves R, Wang QF, Friedman AD. Oncogene 2004; 23:716-25. Medline 14737106

CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K. J Clin Oncol 2004; 22:624-33. Medline 14726504

Disruption of C/EBPalpha function in acute myeloid leukemia. Frohling S, Dohner H. N Engl J Med 2004; 351:2370-2. (perspective) Medline 15575052

The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin. Helbling D, Mueller BU, Timchenko NA, Hagemeijer A, Jotterand M, Meyer-Monard S, Lister A, Rowley JD, Huegli B, Fey MF, Pabst T. Proc Natl Acad Sci USA 2004; 101:13312-7. Medline 15326310

The CCAAT Enhancer-binding protein a (C/EBPa) requires a SWI/SNF complex for proliferation arrest. Muller C, Calkhoven CF, Sha X, Leutz A. J Biol Chem 2004; 279:7353-7358. Medline 14660596

C/EBPa mutations in acute myeloid leukaemias. Nerlov C.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 498 Nat Rev Cancer 2004; 4:394-400. (REVIEW) Medline 15122210

A dominant-negative mutant of C/EBPalpha, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse. Schwieger M, Lohler J, Fischer M, Herwig U, Tenen DG, Stocking C. Blood 2004; 103:2744-52. Medline 14656889

Mutation of CEBPA in familial acute myeloid leukemia. Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. N Engl J Med 2004; 351:2403-7. Medline 15575056

Enhancement of hematopoietic stem cell repopulating capacity and self- renewal in the absence of the transcription factor C/EBP alpha. Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM, Shigematsu H, Levantini E, Huettner CS, Lekstrom-Himes JA, Akashi K, Tenen DG. Immunity 2004; 21:853-63. Medline 15589173

A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, Bozzoni I. Cell 2005; 123:819-31. Medline 16325577

Down-regulation and growth inhibitory role of C/EBPalpha in breast cancer. Gery S, Tanosaki S, Bose S, Bose N, Vadgama J, Koeffler HP. Clin Cancer Res 2005; 11:3184-90. Medline 15867211

Role of transcription factors C/EBPalpha and PU.1 in normal hematopoiesis and leukemia. Koschmieder S, Rosenbauer F, Steidl U, Owens BM, Tenen DG. Int J Hematol 2005; 81:368-77. (REVIEW) Medline 16158816

CEBPA point mutations in hematological malignancies. Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C. Leukemia 2005; 19:329-34. (REVIEW) Medline 15674366

Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct

Atlas Genet Cytogenet Oncol Haematol 2006; 4 499 immunophenotype of the leukemic cells. Lin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC, Shen HL, Su FH, Yao M, Huang SY, Tien HF. Clin Cancer Res 2005; 11(4):1372-9. Medline 15746035

CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Helbling D, Mueller BU, Timchenko NA, Schardt J, Eyer M, Betts DR, Jotterand M, Meyer-Monard S, Fey MF, Pabst T. Blood 2005; 106:1369-75. Medline 15855281

CEBPalpha mutations in childhood acute myeloid leukemia. Liang DC, Shih LY, Huang CF, Hung IJ, Yang CP, Liu HC, Jaing TH, Wang LY, Chang WH. Leukemia 2005; 19:410-4. Medline 15618961

C/EBPa and the pathophysiology of acute myeloid leukaemia. Mueller BU, Pabst T. Curr Opin Hematol 2005; 13:7-14. (REVIEW) Medline 16319681

CCAAT/enhancer binding protein alpha (C/EBPalpha) and C/EBPalpha myeloid oncoproteins induce bcl-2 via interaction of their basic regions with nuclear factor-kappaB p50. Paz-Priel I, Cai DH, Wang D, Kowalski J, Blackford A, Liu H, Heckman CA, Gombart AF, Koeffler HP, Boxer LM, Friedman AD. Mol Cancer Res 2005; 3:585-96. Medline 16254192

Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. Porse BT, Bryder D, Theilgaard-Monch K, Hasemann MS, Anderson K, Damgaard I, Jacobsen SE, Nerlov C. J Exp Med 2005; 202:85-96. Medline 15983063

Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia. Sellick GS, Spendlove HE, Catovsky D, Pritchard-Jones K, Houlston RS. Leukemia 2005; 19:1276-1278. Medline 15902292

Heterogeneous patterns of CEBPalpha mutation status in the progression of

Atlas Genet Cytogenet Oncol Haematol 2006; 4 500 myelodysplastic syndrome and chronic myelomonocytic leukemia to acute myelogenous leukemia. Shih LY, Huang CF, Lin TL, Wu JH, Wang PN, Dunn P, Kuo MC, Tang TC. Clin Cancer Res 2005; 11:1821-6. Medline 15756005

AML patients with CEBP_ mutations mostly retain identical mutation patterns but frequently change in allelic distribution at relapse: a comparative analysis on paired diagnosis and relapse samples. Shih LY, Liang DC, Huang CF, Wu JH, Lin TL, Wang PN, Dunn P, Kuo MC, Tang TC. Leukemia 2006; 20: 604-609. Medline 16453003

Development of a quantitative real-time polymerase chain reaction method for monitoring CEBPA mutations in normal karyotype acute myeloid meukemia. Smith LL, Pearce D, Smith ML, Jenner M, Lister TA, Bonnet D, Goff L, Fitzgibbon J. Br J Haematol 2006; 133: 103-105. Medline 16512836

Involvement of the CEBP gene family in four IGH@ chromosomal translocations in B-Cell precursor acute lymphoblastic leukemia (BCP-ALL). Dyer MJS, Akasaka T, Balasas T, Russell L, Sugimoto K, Majid A, Brown DG, Cain K, Strefford JC, Harrison CJ, Siebert R. Abstract# 2842 at American Society of Hematology annual meeting, 2005

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Lan-Lan Smith 2006 Citation This paper should be referenced as such : Smith LL . CEBPA (CCAAT enhancer binding protein alpha). Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Genes/CEBPAID40050ch19q13.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 501 Atlas of Genetics and Cytogenetics in Oncology and Haematology

TRIM37 (tripartite motif-containing 37) Identity Other MUL names KIAA0898 POB1 TEF3 Hugo TRIM37 Location 17q23.2 Genes flanking TRIM37 oriented from centromere to telomere on 17q23 are: RAD51C, 17q22-q23, D51 homolog C (S. Cerevisiae) Local_order PPM1E, 17q23.2, protein phosphatase 1E (PP2C domain containing) TRIM37, 17q22-q23, tripartite motif-containing 37 FAM33A 17q23.2, family with sequence similarity 33, member A PRR11(FLJ11029) 17q23.2, proline rich 11 DNA/RNA Description The TRIM37 gene spans 106.9 kb. Promoter prediction and reporter constructs suggest the presence of elements sufficient for strong basal activity between -591 and -246 relative to the translation initiation site. This region is GC rich (70%) and TATA-less. Transcription RIM37 has two major well-described transcript variants: TRIM37a (4488 bp, 24 exons) and TRIM37b (3588 bp, 25 exons). The cDNA and genomic DNA alignments and boundaries of exons are determined by the mRNA-to-genomic alignment tool Spidey. Both of these variants encode an identical protein product but they use different termination codons and have different 3¹ untranslated sequences. In the first transcript, all of the exon 24 sequence is included, whereas in the second one, only the first 79 nucleotides of exon 24 are included followed by nucleotides of exon 25, resulting in a shorter transcript. A third ³TRIM37adel23² transcript is detected as an alternatively spliced transcript of TRIM37a. This transcript lacks exon 23 (only 117 bp) with an in frame deletion of 39 amino acids that span the evolutionarily conserved DES (aspartate-glutamate-serine) rich motif at the C- terminus. A 4.4 kb band representing the full-length transcript of TRIM37 is detected in RNA representing brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, ovary, small intestine, colon and leukocyte samples by hybridization of several PCR-generated TRIM37 cDNA probes on a multi-tissue Northern blot. In addition, a strong signal of 3.9 kb is detected in the testis sample

Atlas Genet Cytogenet Oncol Haematol 2006; 4 502 and a 2.6 kb band is noted in the heart sample. In situ hybridization suggests TRIM37 expression patterns in multiple tissues during mouse and human embryogenesis. No Trim37 expression is detected up to E9.5. At E11.5, Trim37 expression is detected in cells lining the esophagus and bronchias well as the innermost cells of the optic cup adjacent to the lens. Between E12.5 and E14.5, TRIM37 is detected in different parts of ganglia and throughout liver. Intense expression is seen in gut epithelium of the midgut, stomach, esophagus and in the primitive seminiferous tubules of the developing testis at E14.5. Expression is also evident in the olfactory epithelium, epithelial lining of the bronchioles, surface ectoderm and in the developing eye lens epithelium, neural layer of the retina (but not in the optic nerve), epithelium of developing nephron, mesonephric duct, and epithelial pancreas cells. Similar to the E14.5 mouse, in 7 week old human embryos, TRIM37 expression can be detected in similar tissues including dorsal root ganglia, liver, submandibular gland and epithelial lining of the gut lumen. At 10 weeks, intense TRIM37 expression can be detected in dorsal root and trigeminal ganglia, epithelia in multiple tissues and liver. However, no TRIM37 transcript can be detected in migrating neural crest cells. In another study, TaqMan PCR results suggest expression of TRIM37a and TRIM37b to be the highest in testis. In the brain, TRIM37a expression is 15-fold higher in adult and 20-fold higher in fetal tissue compared to the expression in heart as a reference. The lowest TRIM37a expression is detected in skeletal muscle with 0.3 and 0.8 times the expression of heart in adult and in fetal tissues. Pseudogene There are no reported pseudogenes of TRIM37. Protein

RING (14th-58th aa) : RING-finger (Really Interesting New Gene) domain that has the 'cross-brace' motif C-X2-C-X(9-39)-C-X(1-3)- H-X(2-3)- (N/C/H)-X2-C-X(4-48) C-X2-C. This domain is believed to be involved in mediating protein-protein interactions and also found in ubiquitin ligases. Ubiquitin ligases attach ubiquitin to target proteins during a cascade of enzymatic reactions. RING finger domains are present in a variety of proteins (e.g. Anaphase promoting complex, APC, Cbl family proteins, MDM2) implicated in cancer. Zf-B Box (90th-132th aa) : B-box zinc finger. Function is largely unknown.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 503 BBC (132th-254th aa) : B-Box C-terminal domain; Coiled coil region C- terminal to (some) B-Box domains. MATH (278th-403th aa) : Meprin and TRAF-C homology domains. Meprins are extracellular membrane metalloproteases that can cleave biologically active peptides, growth factors, extracellular matrix proteins, etc. Math domains can form hetero- and homo-oligomeric enzymes formed from dimers of disulfide-linked dimers. TRAFs are adapter proteins that link cell surface receptors (Tumor Necrosis Factor like) to downstream kinases during activation of transcription factors and regulation of cell survival, growth and stress response in the immune and inflammatory systems. In addition, a nuclear coil localization signal (NLS) and two aspartate- glutamate serine (DES) rich sequences at the C terminus are found.

Description TRIM37 has 964 amino acids with a predicted molecular weight of 108kDa. TRIM37 antibodies (against an internal (490-513) region and a C terminal (942-964) region) recognize a 130 kDa band in TRIM37 transfected COS-1 cells. TRIM37 has the following domains 5. See above. Expression In mouse embryonic tissues, Trim37 protein is detected in epithelia of ducts of developing pancreas, of the midgut and in nasal epithelium. In adult mice, Trim37 immunoreactivity is detected in central and peripheral nervous systems, including retina, enteric ganglia and the adrenal medulla and in subset of cells in the adenohypophysis (endocrine part of the pituitary gland). In post-pubertal testis, a stage-specific cytoplasmic Trim37 staining of germ cells can be detected. Developing sperm from type B spermatogonia to early round spermatids show immunoreactivity. In post-pubertal ovary, intense Trim37 staining is observed in maturing oocytes as well as in the granulosa cells, luteal gland, and in the epithelium of the fallopian tubes. Localisation peroxisome Function Evidence suggest that TRIM37 can auto ubiquitinate itself and therefore is believed to function as an E3 ubiquitin ligase due to its RING domain that is found in ubiquitin ligases. Homology H.sapiens , TRIM37 tripartite motif-containing 37, 964 aa. P.troglodytes , LOC455163 similar to POB1, 705 aa. C.familiaris , LOC480575 similar to tripartite motif protein 37, 962 aa. M.musculus , Trim37 tripartite motif protein 37, 961 aa. R.norvegicus , Trim37_predicted, 1075 aa. G.gallus , TRIM37, 983 aa. A.gambiae , ENSANGG00000009789, 153 aa. Mutations Germinal 1. c.493-497 : This ³Finmajor² mutation co-segregates with the Finnish ancestral MUL haplotype. Finmajor mutation is found in 98 of 100 Finnish MUL chromosomes. This mutation is a 5-bp deletion at nucleotides 493-497 of the TRIM37 cDNA. Sequencing of genomic DNA

Atlas Genet Cytogenet Oncol Haematol 2006; 4 504 suggets an A-to-G transition altering the consensus dinucleotide sequence of the 3' splice site (AG) at position c.493_2 and this results in aberrant splicing at the next AG site. The cDNA deletion causes a frameshift and predicts a stop codon ten codons downstream. This mutation is predicted to generate a truncated 174 aa protein. 2. c.2212delG : This ³Finminor² mutation is a 1-bp deletion of a G at nucleotide c.2212 and results in a frameshift that predicts a stop codon 30 codons downstream. Finminor is found to be associated with a distinct haplotype that is found in 2 of 100 Finnish MUL chromosomes. This mutation is predicted to generate a truncated 767 aa protein. Two patients were found to be compound heterozygotes for the Finmajor and Finminor mutations. 3. c.838delACTTT : This homozygous ³Czech² mutation found in a Czech patient is a 5-bp deletion of ACTTT at nucleotides c.838_842 leading to a frameshift that results in a stop codon 55 codons downstream. This mutation is predicted to generate a truncated 334 aa protein. 4. c.134insA : this ³American² mutation is a homozygous 1-bp insertion of an A nucleotide after c.1346 in an American patient. The mutation disrupts the reading frame and results in a stop codon eight codons downstream. This mutation is predicted to generate a truncated 334 aa protein. 5. c.855_862delTGAATTAG : This mutation detected in a Turkish family is an 8-bp deletion. On the genomic level, aberrant splicing was implicated due to a transition at the splice acceptor (AG) at position c.8551G>A. A cryptic splice site (AG, c.860) 8-bp downstream is activated, which leads to disruption of the open reading frame (ORF) through a premature stop codon (PTC, TGA) at position c.10451047 that translates into a truncated protein. 6. c.745C>T : This mutation detected in a Canadian patient is predicted to generate a truncated 249 aa protein. 7. c.965G>T : This mutation detected in a Canadian patient is predicted to generate a missense amino acid at the 322th position (Gly322Val). 8. c.1037_1040dupAGAT : This mutation detected in a Canadian patient is a four base-pair duplication in exon 13. It is predicted to generate a frame-shift at amino acid position 347, and truncation of the protein product after seven code-shifted amino acids. 9. c.1411C>T : This mutation detected in Tunusian-German and Canadian patients is predicted to generate a truncated 471 aa protein. 10. c.1314+507_1668-207del : This mutation detected in a Sicilian patient is predicted to generate a genomic deletion of 8603 bp with break points in introns 14 and 16 (c.1314+507_1668-207del), thus deleting exons 15 and 16. At the protein level this mutation leads to a frame-shift at 439th aa and truncation of the protein product after four

Atlas Genet Cytogenet Oncol Haematol 2006; 4 505 code-shifted amino acids. 11. c.2056C>T : This mutation detected in a Saudi-Arabian patient is predicted to generate a truncated 686 aa protein.

Implicated in Entity Mulibrey nanism(MUL) Disease Mutations of TRIM37 have been linked to Mulibrey nanism (MUL): muscle-liver-brain-eye nanism. MUL is a rare autosomal recessively inherited disorder that is characterized by severe growth failure with prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features. Four percent of MUL patients develop Wilm¹s tumors. Oncogenesis The role(s) of TRIM37 has not been established for oncogenesis. Evidence suggests amplification and overexpression of TRIM37 in breast cancer cells as part of the 17q23 amplicon. The fact that 4% of the MUL patients develop Wilm¹s tumor also suggests that this gene is involved in oncogeneisis

External links Nomenclature Hugo TRIM37 GDB TRIM37 Entrez_Gene TRIM37 4591 tripartite motif-containing 37 Cards Atlas TRIM37ID42703ch17q23 GeneCards TRIM37 Ensembl TRIM37 Genatlas TRIM37 GeneLynx TRIM37 eGenome TRIM37 euGene 4591 Genomic and cartography TRIM37 - 17q23.2 chr17:54414793-54539011 - 17q22 (hg18- GoldenPath Mar_2006) Ensembl TRIM37 - 17q22 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TRIM37 Gene and transcription Genbank AB020705 [ ENTREZ ] Genbank AF213365 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 506 Genbank AK022701 [ ENTREZ ] Genbank AK025648 [ ENTREZ ] Genbank BC036012 [ ENTREZ ] RefSeq NM_001005207 [ SRS ] NM_001005207 [ ENTREZ ] RefSeq NM_015294 [ SRS ] NM_015294 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010783 [ SRS ] NT_010783 [ ENTREZ ] RefSeq NW_926894 [ SRS ] NW_926894 [ ENTREZ ] AceView TRIM37 AceView - NCBI TRASER TRIM37 Traser - Stanford Unigene Hs.579079 [ SRS ] Hs.579079 [ NCBI ] HS579079 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O94972 [ SRS] O94972 [ EXPASY ] O94972 [ INTERPRO ] Prosite PS50144 MATH [ SRS ] PS50144 MATH [ Expasy ] Prosite PS50119 ZF_BBOX [ SRS ] PS50119 ZF_BBOX [ Expasy ] Prosite PS00518 ZF_RING_1 [ SRS ] PS00518 ZF_RING_1 [ Expasy ] Prosite PS50089 ZF_RING_2 [ SRS ] PS50089 ZF_RING_2 [ Expasy ] Interpro IPR003649 Bbox_C [ SRS ] IPR003649 Bbox_C [ EBI ] Interpro IPR002083 MATH [ SRS ] IPR002083 MATH [ EBI ] Interpro IPR013322 TRAF-type [ SRS ] IPR013322 TRAF-type [ EBI ] Interpro IPR008974 Traf_like [ SRS ] IPR008974 Traf_like [ EBI ] Interpro IPR000315 Znf_Bbox [ SRS ] IPR000315 Znf_Bbox [ EBI ] Interpro IPR001841 Znf_RING [ SRS ] IPR001841 Znf_RING [ EBI ] CluSTr O94972 PF00917 MATH [ SRS ] PF00917 MATH [ Sanger ] pfam00917 [ Pfam NCBI-CDD ] PF00643 zf-B_box [ SRS ] PF00643 zf-B_box [ Sanger Pfam ] pfam00643 [ NCBI-CDD ] Smart SM00502 BBC [EMBL] Smart SM00336 BBOX [EMBL] Smart SM00061 MATH [EMBL] Blocks O94972 HPRD O94972 Protein Interaction databases DIP O94972 IntAct O94972 Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2006; 4 507 OMIM 253250;605073 [ map ] GENECLINICS 253250;605073 SNP TRIM37 [dbSNP-NCBI] SNP NM_001005207 [SNP-NCI] SNP NM_015294 [SNP-NCI] SNP TRIM37 [GeneSNPs - Utah] TRIM37] [HGBASE - SRS] HAPMAP TRIM37 [HAPMAP] General knowledge Family TRIM37 [UCSC Family Browser] Browser SOURCE NM_001005207 SOURCE NM_015294 SMD Hs.579079 SAGE Hs.579079 Amigo protein binding[Amigo] protein binding[EGO-EBI] Amigo intracellular[Amigo] intracellular[EGO-EBI] Amigo peroxisome[Amigo] peroxisome[EGO-EBI] Amigo zinc ion binding[Amigo] zinc ion binding[EGO-EBI] Amigo metal ion binding[Amigo] metal ion binding[EGO-EBI] PubGene TRIM37 Other databases Probes Probe TRIM37 Related clones (RZPD - Berlin) PubMed PubMed 16 Pubmed reference(s) in LocusLink Bibliography Blast 2 sequences - a new tool for comparing protein and nucleotide sequences. Tatiana AT, Thomas LM. FEMS Microbiol Lett 1999; 174: 247-250. Medline 10339815

Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism. Avela K, Lipsanen-Nyman M, Idanheimo N, Seemanova E, Rosengren S, Makela TP, Perheentupa J, Chapelle AD, Lehesjoki AE. Nat Genet 2000; 25(3): 298-301. Medline 10888877

Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 508 Barlund M, Mousses S, Kononen J, Sauter G, Heiskanen M, Paavola P, Avela K, Chen Y, Bittner ML, Kallioniemi Proc Natl Acad Sci U S A 2001; 98(10): 5711-5716. Medline 11331760

Overexpressed genes/ESTs and characterization of distinct amplicons on 17q23 in breast cancer cells. Erson AE, Niell BL, DeMers SK, Rouillard JM, Hanash SM, Petty EM. Neoplasia 2001; 3(6): 521-526. Medline 11774034

PML protein isoforms and the RBCC/TRIM motif. Jensen K, Shiels C, Freemont PS. Oncogene 2001; 20(49): 7223-7233. Review. Medline 11704850

Expression of MUL: a gene encoding a novel RBCC family ring-finger protein in human and mouse embryogenesis. Lehesjoki AE, Reed VA, Mark Gardiner R, Greene ND. Mech Dev. 2001; 108(1-2): 221-225. Medline 11578880

A diverse family of proteins containing tumor necrosis factor receptor- associated factor domains. Zapata JM, Pawlowski K, Haas E, Ware CF, Godzik A, Reed JC. J Biol Chem 2001; 276(26): 24242-24252. Medline 11279055

The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder. Kallijarvi J, Avela K, Lipsanen-Nyman M, Ulmanen I, Lehesjoki AE. Am J Hum Genet 2002; 70(5): 1215-1228. Medline 11938494

A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity. Jagiello P, Hammans C, Wieczorek S, Arning L, Stefanski A, Strehl H, Epplen JT, Gencik M. Hum Mutat 2003; 21(6): 630-635. Medline 12754710

Novel mutations in the TRIM37 gene in Mulibrey Nanism. Hamalainen RH, Avela K, Lambert JA, Kallijarvi J, Eyaid W, Gronau J, Ignaszewski AP, McFadden D, Sorge G, Lipsanen-Nyman M, Lehesjoki AE. Hum Mutat 2004; 23(5): 522. Medline 15108285

Atlas Genet Cytogenet Oncol Haematol 2006; 4 509

Mulibrey nanism: clinical features and diagnostic crite Karlberg N, Jalanko H, Perheentupa J, Lipsanen-Nyman M. J Med Genet 2004; 41(2): 92-98. Medline 14757854

TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase. Kallijarvi J, Lahtinen U, Hamalainen R, Lipsanen-Nyman M, Palvimo JJ, Lehesjoki AE Exp Cell Res 2005; 308(1): 146-155. Medline 15885686

Insulin Resistance Syndrome in Subjects With Mutated RING Finger Protein TRIM37. Karlberg N, Jalanko H, Kallijarvi J, Lehesjoki AE, Lipsanen-Nyman M. Diabetes 2005; 54(12): 3577-3581. Medline 16306379

Characterisation of the mulibrey nanism-associated TRIM37 gene: transcription initiation, promoter region and alternative splicing. Hamalainen RH, Joensuu T, Kallijarvi J, Lehesjoki AE Gene 2006; 366(1): 180-188. Medline 16310976

Tissue expression of the mulibrey nanism-associated Trim37 protein in embryonic and adult mouse tissues. Kallijarvi J, Hamalainen RH, Karlberg N, Sainio K, Lehesjoki AE. Histochem Cell Biol 2006; 126(3): 325-334. Medline 16514549 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Elif Ayse Erson,.M Elizabeth Petty 2006 Citation This paper should be referenced as such : Erson EA, Petty ME . TRIM37 (tripartite motif-containing 37). Atlas Genet Cytogenet Oncol Haematol. June 2006 . URL : http://AtlasGeneticsOncology.org/Genes/TRIM37ID42703ch17q23.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 510 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MUTYH (mutY homolog (E. coli)) Identity Other MYH names MYHbeta MutY homolog (hMYH) mutY (E. coli) homolog mutY homolog Hugo MUTYH Location 1p34.3-p32.1 DNA/RNA

Mutyh AUG 1, 2 and 3 are alternative codons for translation initiation; cDNA not drawn to scale (adapted from Parker et al., 2003).

Description The MUTYH gene contains 16 exons spanning a region of 11147 bp. Transcription The transcribed mRNA is 1854 bp long. There are three major classes of human MUTYH mRNAs: a, b and g. Each of these undergoes alternative splicing, suggesting a total of 10 possible mature transcripts. However, their distribution and abundance in different normal tissues

Atlas Genet Cytogenet Oncol Haematol 2006; 4 511 have yet to be determined. The reference isoform is MutYa3. Protein

Diagram of the MUTYH protein in scale. Filled boxes represent known functional domains (adapted from Sampson et al, 2005).

Description Aminoacids: 535. Molecular Weight: 52 kDa. MUTYH is a protein involved in base excision repair (BER). It contains a DNA binding domain, an adenine binding motif and several interaction domains for APE1, PCNA, RPA and MSH6, located in different regions of the gene. Expression Ubiquitous. Localisation Nuclear and mithocondrial. Function MUTYH is involved in oxidative DNA damage repair. Human MutY is responsible for recognition and removal of inappropriately inserted adenine in Ao8-oxoG mispairs. If unrepaired, the Ao8-oxoG mispairs can result in C:G to A:T transversions. MUTYH functions in a postreplication repair pathway and is targeted to the newly synthesized daughter strand of DNA for removal of the adenine base. Homology MUTYH is homologous to the bacterial MutY gene, and MUTYH homologues are also present in eukaryote. Mutations Germinal Biallelic germline mutations of MUTYH are associated with colorectal polyposis. The most common mutations in Caucasians are the missense substitutions Y165C (494A>G) and G382D (1145G>A). Functional analysis of C165 and D382 proteins has shown a severe decrease of catalytic activity. E466X and Y90X are the common mutations reported in Indian and Pakistani cases. Several other missense, nonsense, in-frame, frameshift and splicing mutations have been found in patients with colorectal polyposis.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 512 Somatic To date, no MUTYH somatic mutation has been described. Implicated in Entity MAP (MUTYH-associated polyposis). Disease Biallelic MUTYH mutations are responsible for the autosomal recessive form of intestinal adenomatous polyposis. Oncogenesis Defective BER function associated with MUTYH mutations determines an increase in the somatic mutation rate, namely of G>T transversions at guanine residues that are potential targets of oxidative damage. Tumors from biallelic MUTYH mutation carriers display an excess of somatic G>T mutations in the APC and KRAS genes

External links Nomenclature Hugo MUTYH GDB MUTYH Entrez_Gene MUTYH 4595 mutY homolog (E. coli) Cards Atlas MUTYHID41464ch1p34 GeneCards MUTYH Ensembl MUTYH Genatlas MUTYH GeneLynx MUTYH eGenome MUTYH euGene 4595 Genomic and cartography GoldenPath MUTYH - chr1:45567501-45578729 - 1p34.1 (hg18-Mar_2006) Ensembl MUTYH - 1p34.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MUTYH Gene and transcription Genbank AB025227 [ ENTREZ ] Genbank AB032920 [ ENTREZ ] Genbank AB032921 [ ENTREZ ] Genbank AB032922 [ ENTREZ ] Genbank AB032923 [ ENTREZ ] RefSeq NM_001048171 [ SRS ] NM_001048171 [ ENTREZ ] RefSeq NM_001048172 [ SRS ] NM_001048172 [ ENTREZ ] RefSeq NM_001048173 [ SRS ] NM_001048173 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 513 RefSeq NM_001048174 [ SRS ] NM_001048174 [ ENTREZ ] RefSeq NM_012222 [ SRS ] NM_012222 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_032977 [ SRS ] NT_032977 [ ENTREZ ] RefSeq NW_921351 [ SRS ] NW_921351 [ ENTREZ ] AceView MUTYH AceView - NCBI TRASER MUTYH Traser - Stanford Unigene Hs.271353 [ SRS ] Hs.271353 [ NCBI ] HS271353 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q5T411 [ SRS] Q5T411 [ EXPASY ] Q5T411 [ INTERPRO ] PS00764 ENDONUCLEASE_III_1 [ SRS ] PS00764 Prosite ENDONUCLEASE_III_1 [ Expasy ] PS01155 ENDONUCLEASE_III_2 [ SRS ] PS01155 Prosite ENDONUCLEASE_III_2 [ Expasy ] IPR011257 DNA_glycsylse [ SRS ] IPR011257 DNA_glycsylse [ Interpro EBI ] Interpro IPR003265 Endo_3c [ SRS ] IPR003265 Endo_3c [ EBI ] Interpro IPR004035 EndoIII_FCL [ SRS ] IPR004035 EndoIII_FCL [ EBI ] Interpro IPR004036 EndoIII_HhH [ SRS ] IPR004036 EndoIII_HhH [ EBI ] Interpro IPR003651 FeS_bind [ SRS ] IPR003651 FeS_bind [ EBI ] Interpro IPR000445 HhH [ SRS ] IPR000445 HhH [ EBI ] IPR000086 NUDIX_hydrolase [ SRS ] IPR000086 Interpro NUDIX_hydrolase [ EBI ] CluSTr Q5T411 PF00633 HHH [ SRS ] PF00633 HHH [ Sanger ] pfam00633 [ Pfam NCBI-CDD ] PF00730 HhH-GPD [ SRS ] PF00730 HhH-GPD [ Sanger Pfam ] pfam00730 [ NCBI-CDD ] PF00293 NUDIX [ SRS ] PF00293 NUDIX [ Sanger ] pfam00293 Pfam [ NCBI-CDD ] Smart SM00478 ENDO3c [EMBL] Smart SM00525 FES [EMBL] Blocks Q5T411 HPRD Q5T411 Protein Interaction databases DIP Q5T411 IntAct Q5T411 Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2006; 4 514 OMIM 132600;137215;604933;608456 [ map ] GENECLINICS 132600;137215;604933;608456 SNP MUTYH [dbSNP-NCBI] SNP NM_001048171 [SNP-NCI] SNP NM_001048172 [SNP-NCI] SNP NM_001048173 [SNP-NCI] SNP NM_001048174 [SNP-NCI] SNP NM_012222 [SNP-NCI] SNP MUTYH [GeneSNPs - Utah] MUTYH] [HGBASE - SRS] HAPMAP MUTYH [HAPMAP] General knowledge Family MUTYH [UCSC Family Browser] Browser SOURCE NM_001048171 SOURCE NM_001048172 SOURCE NM_001048173 SOURCE NM_001048174 SOURCE NM_012222 SMD Hs.271353 SAGE Hs.271353 Amigo DNA binding[Amigo] DNA binding[EGO-EBI] Amigo endonuclease activity[Amigo] endonuclease activity[EGO-EBI] Amigo iron ion binding[Amigo] iron ion binding[EGO-EBI] Amigo intracellular[Amigo] intracellular[EGO-EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI] Amigo base-excision repair[Amigo] base-excision repair[EGO-EBI] Amigo mismatch repair[Amigo] mismatch repair[EGO-EBI] Amigo cell cycle[Amigo] cell cycle[EGO-EBI] Amigo metabolism[Amigo] metabolism[EGO-EBI] hydrolase activity, acting on glycosyl bonds[Amigo] hydrolase Amigo activity, acting on glycosyl bonds[EGO-EBI] DNA N-glycosylase activity[Amigo] DNA N-glycosylase Amigo activity[EGO-EBI] negative regulation of progression through cell Amigo cycle[Amigo] negative regulation of progression through cell cycle[EGO-EBI] Amigo metal ion binding[Amigo] metal ion binding[EGO-EBI] 4 iron, 4 sulfur cluster binding[Amigo] 4 iron, 4 sulfur cluster Amigo binding[EGO-EBI]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 515 PubGene MUTYH Other databases Probes Probe MUTYH Related clones (RZPD - Berlin) PubMed PubMed 40 Pubmed reference(s) in LocusLink Bibliography Characterization of a mammalian homolog of the Escherichia coli MutY mismatch repair protein. McGoldrick JP, Yeh YC, Solomon M, Essigmann JM, Lu AL. Mol Cell Biol 1995; 15(2): 989-996. Medline 7823963

Identification of human MutY homolog (hMYH) as a repair enzyme for 2- hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria. Ohtsubo T, Nishioka K, Imaiso Y, Iwai S, Shimokawa H, Oda H, Fujiwara T, Nakabeppu Y. Nucleic Acids Res 2000; 28(6): 1355-1364. Medline 1068493

Inherited variants of MYH associated with somatic G:C --> T:A mutations in colorectal tumors. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, Hodges AK, Davies DR, David SS, Sampson JR, Cheadle JP. Nat Genet 2002; 30: 227-232. Medline 11818965

Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6. Gu Y, Parker A, Wilson TM, Bai H, Chang DY, Lu AL. J Biol Chem 2002; 277(13): 11135-11142. Medline 1801590

Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations. Jones S, Emmerson P, Maynard J, Best JM, Jordan S, Williams GT, Sampson JR, Cheadle JP. Hum Mol Genet 2002; 11(23): 2961-2967. Medline 12393807

Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers. Halford SE, Rowan AJ, Lipton L, Sieber OM, Pack K, Thomas HJ, Hodgson SV,

Atlas Genet Cytogenet Oncol Haematol 2006; 4 516 Bodmer WF, Tomlinson IP. Am J Pathol 2003; 162: 1545-1548. Medline 12707038

Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Lipton L, Halford SE, Johnson V, Novelli MR, Jones A, Cummings C, Barclay E, Sieber O, Sadat A, Bisgaard ML, Hodgson SV, Aaltonen LA, Thomas HJ, Tomlinson IP. Cancer Res 2003; 63: 7595-7599. Medline 14633673

Human MutY: gene structure, protein functions and interactions, and role in carcinogenesis. Parker AR, Eshleman JR. Cell Mol Life Sci 2003; 60(10): 2064-2083. Medline 14618256

Defective human MutY phosphorylation exists in colorectal cancer cell lines with wild-type MutY alleles. Parker AR, O'Meally RN, Sahin F, Su GH, Racke FK, Nelson WG, DeWeese TL, Eshleman JR. J Biol Chem 2003; 278(48): 47937-47945. Medline 12966098

Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Sampson JR, Dolwani S, Jones S, Eccles D, Ellis A, Evans DG, Frayling I, Jordan S, Maher ER, Mak T, Maynard J, Pigatto F, Shaw J, Cheadle JP. Lancet 2003; 362: 39-41. Medline 12853198

Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RKS, Bisgaard M- L, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJW, Tomlinson IPM. New Eng J Med 2003; 348: 791-779. Medline 12606733

Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. Croitoru ME, Cleary SP, Di Nicola N, Manno M, Selander T, Aronson M, Redston M, Cotterchio M, Knight J, Gryfe R, Gallinger S. J Natl Cancer Inst 2004; 96: 1631-1634. Medline 15523092

Atlas Genet Cytogenet Oncol Haematol 2006; 4 517 Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Gismondi V, Meta M, Bonelli L, Radice P, Sala P, Bertario L, Viel A, Fornasarig M, Arrigoni A, Gentile M, Ponz de Leon M, Anselmi L, Mareni C, Bruzzi P, Varesco L. Int J Cancer 2004; 109: 680-684. Medline 14999774

The multiple colorectal adenoma phenotype and MYH, a base excision repair gene. Lipton L, Tomlinson I. Clin Gastroenterol Hepatol 2004; 2(8): 633-638. Medline 15290654

Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas. Jones S, Lambert S, Williams GT, Best JM, Sampson JR, Cheadle JP. Br J Cancer 2004; 90(8): 1591-1593. Medline 15083190

High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis. Venesio T, Molatore S, Cattaneo F, Arrigoni A, Risio M, Ranzani GN. Gastroenterology 2004; 126: 1681-1685. Medline 15188161

The multiple colorectal adenoma phenotype and MYH, a base excision repair gene. Lipton L, Tomlinson I. Clin Gastroenterol Hepatol 2004; 2(8): 633-638. Medline 15290654

.Functional characterization of two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis. .Bai H, Jones S, Guan X, Wilson TM, Sampson JR, Cheadle JP, Lu AL. Nucleic Acids Res 2005; 33(2): 597-604. Medline 15673720

Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair. Parker AR, Sieber OM, Shi C, Hua L, Takao M, Tomlinson IP, Eshleman JR. Carcinogenesis 2005; 26(11): 2010-2018. Medline 5987719

Insight into the functional consequences of hMYH variants associated with

Atlas Genet Cytogenet Oncol Haematol 2006; 4 518 colorectal cancer: distinct differences in the adenine glycosylase activity and the response to AP endonucleases of Y150C and G365D murine MYH. Pope MA, Chmiel NH, David SS. DNA Repair (Amst) 2005; 4(3): 315-325. Medline 15661655

MutYH (MYH) and colorectal cancer. Sampson JR, Jones S, Dolwani S, Cheadle JP. Biochem Soc Trans 2005; 33: 679-683. Medline 16042573

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Maurizio Genuardi, Rossella Tricarico 2006 Citation This paper should be referenced as such : Genuardi M, Tricarico R. . MUTYH (mutY homolog (E. coli)). Atlas Genet Cytogenet Oncol Haematol. June 2006 . URL : http://AtlasGeneticsOncology.org/Genes/MUTYHID41464ch1p34.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 519 Atlas of Genetics and Cytogenetics in Oncology and Haematology

HOXA11 (homeobox A11) Identity Other HOX1I (HOMEOBOX 1I) names Hugo HOXA11 Location 7p15-7p14.2 DNA/RNA

Description spans a 3,7 kb genomic region containing 2 exons Transcription mRNA 2295 bp Protein

homeobox containing protein with C terminal localisation of the homedomain. N terminal several repeat regions: 1: Poly-Ser; 2: Poly-Arg; 3 :Poly-Ala; 4: Poly- Gly; 5: Poly-Ala.

Description 313 amino acids, 34.5 kDa, contains a homeodomain with helix-turn- helix (HTH) motif. The HTH motif consists of approximately 20 residues and is characterised by 2 alpha-helices, which make intimate contacts with the DNA and are joined by a short turn. The second helix of the HTH motif binds to DNA via a number of hydrogen bonds and hydrophobic interactions, which occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA. The first helix helps to stabilise the structure. Expression in lung, bone, uterus, placenta, testis, prostate, liver, hematopoietic precursor cells, endometrium Localisation nucleus Function Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. HOXA11 is involved in the regulation of

Atlas Genet Cytogenet Oncol Haematol 2006; 4 520 uterine development and is required for female fertility. Expression of HOXA11 is detected at all differentiation stages of normal T cells in the thymus, suggesting a role in normal T cell development. Homology homolog to murine Hox-1.9; ABD-B homeobox family Mutations Germinal Mutation of HOXA11 in radio-ulnar synostosis with amegakaryotic thrombocytopenia; autosomal dominant inheritance; 1-bp deletion in exon 2 of the HOXA11 gene. Deletion of an adenine converted AAC (asparagine) to ACA (threonine), resulting in a premature termination codon and truncation of the remaining 22 amino acids of the HOXA11 protein. Implicated in Entity inv(7)(p15q34), t(7;7)(p15;q34) Disease T-cell acute lymphoblastic leukemia Cytogenetics inv(7)(p15q34) or t(7;7)(p15;q34) places 5'HOXA cluster genes (7p15) under the influence of strong enhancers within the TCRB locus (7q34) resulting in ectopic expression of especially HOXA10 and HOXA11 Abnormal no fusion protein but ectopic expression of HOXA10 and HOXA11 Protein

Entity t(7;11)(p15;p15) Disease CML, only once reported Prognosis unknown Cytogenetics this rearrangement fuses the 5' NUP98 gene in frame to the 3' HOXA11 gene generation a chimeric fusion transcript Hybrid/Mutated 5' NUP98-3'HOXA11 Gene

External links Nomenclature Hugo HOXA11 GDB HOXA11 Entrez_Gene HOXA11 3207 homeobox A11 Cards Atlas HOXA11ID40847ch7p15 GeneCards HOXA11 Ensembl HOXA11 Genatlas HOXA11 GeneLynx HOXA11

Atlas Genet Cytogenet Oncol Haematol 2006; 4 521 eGenome HOXA11 euGene 3207 Genomic and cartography HOXA11 - chr7:27187302-27191360 - 7p15.2 (hg18- GoldenPath Mar_2006) Ensembl HOXA11 - 7p15.2 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene HOXA11 Gene and transcription Genbank AL551705 [ ENTREZ ] Genbank BC033706 [ ENTREZ ] Genbank BC040948 [ ENTREZ ] Genbank CR611111 [ ENTREZ ] Genbank CR612696 [ ENTREZ ] RefSeq NM_005523 [ SRS ] NM_005523 [ ENTREZ ] RefSeq AC_000050 [ SRS ] AC_000050 [ ENTREZ ] RefSeq AC_000068 [ SRS ] AC_000068 [ ENTREZ ] RefSeq NC_000007 [ SRS ] NC_000007 [ ENTREZ ] RefSeq NT_007819 [ SRS ] NT_007819 [ ENTREZ ] RefSeq NT_079592 [ SRS ] NT_079592 [ ENTREZ ] RefSeq NW_923240 [ SRS ] NW_923240 [ ENTREZ ] AceView HOXA11 AceView - NCBI TRASER HOXA11 Traser - Stanford Unigene Hs.249171 [ SRS ] Hs.249171 [ NCBI ] HS249171 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P31270 [ SRS] P31270 [ EXPASY ] P31270 [ INTERPRO ] PS00027 HOMEOBOX_1 [ SRS ] PS00027 HOMEOBOX_1 [ Prosite Expasy ] PS50071 HOMEOBOX_2 [ SRS ] PS50071 HOMEOBOX_2 [ Prosite Expasy ] Interpro IPR001356 Homeobox [ SRS ] IPR001356 Homeobox [ EBI ] IPR012287 Homeodomain-rel [ SRS ] IPR012287 Homeodomain- Interpro rel [ EBI ] IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ] CluSTr P31270 PF00046 Homeobox [ SRS ] PF00046 Homeobox [ Sanger Pfam ] pfam00046 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 522 Smart SM00389 HOX [EMBL] Prodom PD000010 Homeobox[INRA-Toulouse] P31270 HXA11_HUMAN [ Domain structure ] P31270 Prodom HXA11_HUMAN [ sequences sharing at least 1 domain ] Blocks P31270 HPRD P31270 Protein Interaction databases DIP P31270 IntAct P31270 Polymorphism : SNP, mutations, diseases OMIM 142958;605432 [ map ] GENECLINICS 142958;605432 SNP HOXA11 [dbSNP-NCBI] SNP NM_005523 [SNP-NCI] SNP HOXA11 [GeneSNPs - Utah] HOXA11] [HGBASE - SRS] HAPMAP HOXA11 [HAPMAP] General knowledge Family HOXA11 [UCSC Family Browser] Browser SOURCE NM_005523 SMD Hs.249171 SAGE Hs.249171 transcription factor activity[Amigo] transcription factor activity[EGO- Amigo EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI] regulation of transcription, DNA-dependent[Amigo] regulation of Amigo transcription, DNA-dependent[EGO-EBI] Amigo morphogenesis[Amigo] morphogenesis[EGO-EBI] sequence-specific DNA binding[Amigo] sequence-specific DNA Amigo binding[EGO-EBI] PubGene HOXA11 Other databases Probes Probe HOXA11 Related clones (RZPD - Berlin) PubMed PubMed 23 Pubmed reference(s) in LocusLink Bibliography Homeotic transformations and limb defects in HOXA11 mutant mice. Small KM, Potter SS.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 523 Genes Dev 1993; 7(12A): 2318-2328. Medline 7902826

Absence of radius and ulna in mice lacking Hoxa-11 and Hoxd-11. Davis AP, Witte DP, Hsieh-Li HM, Potter SS, Capecchi MR. Nature 1995; 375(6534): 791-795. Medline 7596412

HOXA11 structure, extensive antisense transcription, and function in male and female fertility. Hsieh-Li HM, Witte DP, Weinstein M, Branford W, Li H, Small K, Potter SS, Development 1995; 121(5): 1373-1385. Medline 7789268

Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Gendron RL, Paradis H, Hsieh-Li HM, Lee DW, Potter SS, Markoff E. Biol Reprod 1997; 56(5): 1097-1105. Medline 9160706

Characterization of HOXA10/HOXA11 transheterozygotes reveals functional redundancy and regulatory interactions. Branford WW, Benson GV, Ma L, Maas RL, Potter SS. Dev Biol 2000; 224(2): 373-387. Medline 10926774

Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Thompson AA, Nguyen LT. Nat Genet 2000; 26(4): 397-398. Medline 11101832

Single-translocation and double-chimeric transcripts: detection of NUP98- HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15). Fujino T, Suzuki A, Ito Y, Ohyashiki K, Hatano Y, Miura I, Nakamura T. Blood 2002; 99(4): 1428-1433. Medline 11830496

Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: implications for human T-cell. Taghon T, Thys K, De Smedt M, Weerkamp F, Staal FJ, Plum J, Leclercq G. Leukemia 2003; 17(6): 1157-1163. Medline 12764384

HOX10 and HOX11 genes are required to globally pattern the mammalian

Atlas Genet Cytogenet Oncol Haematol 2006; 4 524 skeleton. Wellik DM, Capecchi MR. Science 2003; 301(5631): 363-367. Medline 12869760

HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Soulier J, Clappier E, Cayuela JM, Regnault A, Garcia-Peydro M, Dombret H, Baruchel A, Toribio ML, Sigaux F. Blood 2005; 106(1): 274-286. Medline 15774621

A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias. Speleman F, Cauwelier B, Dastugue N, Cools J, Verhasselt B, Poppe B, Van Roy N, Vandesompele J, Graux C, Uyttebroeck A, Boogaerts M, De Moerloose B, Benoit Y, Selleslag D, Billiet J, Robert A, Huguet F, Vandenberghe P, De Paepe A, Marynen P, Hagemeijer A. Leukemia 2005; 19(3): 358-366 Medline 15674412

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Barbara Cauwelier, Frank Speleman 2006 Citation This paper should be referenced as such : Cauwelier B, Speleman F . HOXA11 (homeobox A11). Atlas Genet Cytogenet Oncol Haematol. June 2006 . URL : http://AtlasGeneticsOncology.org/Genes/HOXA11ID40847ch7p15.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 525 Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALOX15 (Arachidonate 15-Lipoxygenase) Identity Note Arachidonate 15-Lipoxygenase (15-LOX-1) is one of several LOX isoforms that oxygenates polyunsaturated fatty acids as well as complex substrates such as biomembranes. Its expression is associated with the development of inflammatory diseases such as atherosclerosis, asthma, cancer and osteoporosis. Other 15-LOX names EC 1.13.11.33 arachidonate omega 6-lipoxygenase LOG15 Hugo ALOX15 Location 17p13.3 Genes flanking ALOX15 in centromere to telomere direction on 17p13 are: MYBBP1A 17p13.3 MYB binding protein (P160) 1a. GGT6 17p13.2 homolog of gamma-glutamyltransferase 6 Local_order LOC124974 17p13.2, thioredoxin 1 pseudogene 4. SMTNL2 17p13.2 smoothelin-like 2 ALOX15 17p13.2 arachidonate 15-lipoxygenase (Homo sapiens) PELP1 17p13.2 proline, glutamic acid and leucine rich protein 1. ARRB2 17p13 arrestin, beta 2. Note Arachidonate 15-Lipoxygenase (15-LOX-1) is one of several LOX isoforms that oxygenates polyunsaturated fatty acids as well as complex substrates such as biomembranes. Its expression is associated with the development of inflammatory diseases such as atherosclerosis, asthma, cancer and osteoporosis. DNA/RNA Note With the exception of ALOX5, all human LOX genes, including ALOX15, are clustered on the short arm of chromosome 17 within a few megabases of each other. ALOX12, which has 86% sequence homology to ALOX15 is in closest proximity (17p13.1). Since chromosome 17 is known for gene duplications, the multiple LOX genes on the same chromosome may be as a result of such duplications.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 526

ALOX15Fig. Diagram of the ALOX15 gene. Exons are represented by red boxes (in scale) untranscribed sequences in black, with exon numbers on the bottom. The arrows show the ATG and the stop codons respectively.

Description ALOX15 gene spans a region of 10.7 kilo bases. and has 14 exons, the sizes being 149, 202, 82, 123, 104, 161, 144, 210, 87, 170, 122, 101, 108 and 859 bps. Transcription ALOX15 mRNA has 2702 bps. TH2 cytokines IL-4 ID: 40960 and IL-13 have been shown to transcriptionally upregulate 15-LOX-1 expression via phosphorylation of Signal Transducer and Activator of transcription (STAT) proteins, particularly STAT-1, STAT-3 and STAT-6 and their translocation to the nucleus. Acetylation of histones, which block STAT6 binding at the 15- LOX-1 promoter if they are present as nonacetylated proteins, enables promoter binding of phosphorylated and acetylated STAT6, which in turn may lead to transcriptional activation of the 15-LOX gene. TRANSCRIPTION NSAIDS have been reported to upregulate 15-LOX- 1 expression through GATA-6. Ku70/ ALOX15 mRNA is expressed in bone marrow, spleen, thymus, spinal cord, heart, skeletal muscle, liver, prostate, kidney and lung. Pseudogene The arachidonate 15-lipoxygenase pseudogene (ALOX15P) is located on 17p13.1. Protein

Note Two different 15-Lipoxygenases exist, 15-LOX-1 (reticulocyte type) and 15-LOX-2 (epidermis type), differentiated by their tissue expression and a 40% homology at the amino acid level. 15-LOX-1 preferentially oxygenates linoleic acid into 13(S)-hydroxyoctadecadienoic acid (13(S)- HPODE) whereas 15-LOX-2 preferentially metabolizes arachidonic acid (AA) to 15S- hydroperoxyeicosatetraenoic acid (15-HETE) with poor activity with linoleic acid (LA). Description 15-LOX-1 protein consists of 661 amino acids and is 74.7 kDa. It contains 1 gram atom of non-haem non-sulphur bound iron per mole of the enzyme. Conserved domain search, the presence of a polycystin/lipoxygenase/alpha-toxin (PLAT) domain in the 15-LOX-1 protein allows it access and enables it to catalyze enzymatic lipid peroxidation in complex biological structures via direct dioxygenation of

Atlas Genet Cytogenet Oncol Haematol 2006; 4 527 phospholipids and cholesterol esters of biomembranes and plasma lipoproteins. The membrane binding domain of the rabbit reticulocyte 15-LOX are determined by a concerted action of the N-terminal beta- barrel and the C-terminal catalytic domain. Expression 15-LOX-1 was first purified in rabbit reticulocytes and was subsequently found to be specifically expressed or induced in mast cells, eosinophils, activated monocytes or dendritic cells, and bronchial epithelial cells. Localisation Located in the cytoplasm. Function 15-LOX-1 is a member of the inflammatory leukotriene biosynthesis pathway where, in presence of molecular oxygen, it converts arachidonic acid to(15-HETE). Also acts on C-12 of arachidonate forming products (12-HETE) at a ratio of 12:1 (15-HETE:12-HETE). Preferentially converts linoleic acid to 13(S)-HODE. Homology C. familiaris LOC4894581 similar to Arachidonate 15-lipoxygenase; R. norvegicus: Alox15 arachidonate 12-lipoxygenase; M. musculus: Alox15 arachidonate 15-lipoxygenase (12/15LOX); A. thaliana: F12B7.11, F12B7_111 iron ion binding / lipoxygenase; Mutations Note No mutations have been reported for ALOX15 that cause congenital anomalies. Single nucleotide polymorphism (SNP) studies have revealed that a C-to-T base exchange (-292C/T) enhances the transcriptional activity of the ALOX15 promoter in macrophages through the generation of a novel SPI1 transcription factor binding site. In addition, a G to A base exchange (-5229G/A) in the ALOX15 promoter region has been associated with low bone mineral density. Implicated in Entity Prostate cancer Note Genechip study of the mRNA levels of key enzymes involved in the LA and AA pathways in 18 human donor (normal) prostates compared to 60 prostate tumours showed a lower level of 15-LOX-1 expression (the key enzyme in the LA pathway) in contrast to a higher 15-lipoxygenase- 2 expression in donor (normal) prostates. On the other hand, significantly high levels of 15-LOX-1 and low levels of 15-LOX- 2/ALOX15B were observed in prostate carcinoma tissues.

Entity Colorectal cancer Note The role of 15-LOX-1 in colorectal cancer is controversial with some researchers claiming a mitogenic role through up-regulation of the EGF signaling pathway as well as activation of ERK and down regulation of anti-inflammatory PPAR-gamma transcriptional activity. Its upregulation by mutant TP53 has been reported. On the other hand, in recent years others have shown that 15-LOX-1 expression is reduced in colorectal cancer and implicated 13(S)-HPODE in the pro-apoptotic functions of 15-LOX-1. 15-LOX-1 expression was shown to be down-regulated in colorectal adenomas (compared with non neoplastic epithelial mucosa) in 87% (13 of 15) of patients with familial adenomatous polyposis

Atlas Genet Cytogenet Oncol Haematol 2006; 4 528 resulting in an escape from apoptosis. Ectopic restoration of 15-LOX-1 expression re-established apoptosis in Caco-2 colon cancer cells. A proapoptotic function ascribed to 15-LOX-1 and 15-LOX-2 in colon cancer is said to be through the activation of the anti-tumorigenic PPAR- gamma and down-regulation of the pro-tumorigenic PPAR-delta/beta. In addition, the apoptotic functions of NSAIDS are reported to be via an upregulation of 15-LOX-1.

Entity Breast cancer Note An immunoblot analysis of metastatic human breast carcinoma cells with antibodies to 15-LOX-1 and 15-LOX-2 indicated that it is the 15(S)- LOX-2 isoform that generates 15-HETE and activates specific growth factor receptor-related signalling pathways, thereby initiating signal transduction events resulting in enhanced cell adhesion to the extracellular matrix. However, a second study indicated that both 15- LOX-2 and 15-LOX-1 were expressed at significantly lower levels in metastatic tumours and in patients who died of breast cancer related causes. This reduction is correlated with the disease progression of breast cancer and a poor clinical outcome.

Entity Atherosclerosis Disease Atherosclerosis is a chronic proliferative disease of the arterial wall that is associated with aberrant immune reactions. A proatherogenic activity of 12/15LOX via oxidation of low density lipoproteins and formation of foam cells in various rodent atherosclerosis models has been shown. A similar extrapolation to humans has not been convincingly proven, particularly since significantly lower expression of 15-LOX-1 was detected in diseased and normal human arteries when compared to 5- LOX.

Entity Asthma Disease Patients with severe asthma with persistent airway eosinophils have been shown to manifest high levels of 15(S)-HETE in bronchoalveolar lavage (BALF), which may be associated with airway fibrosis. In addition, IL-4-induced apoptosis via upregulation of 15-LOX-1 and PPAR-gamma may contribute to severe loss of alveolar structures and infiltration of eosinophils, mononuclear phagocytes, etc., into the lung tissue of chronic asthma patients.

External links Nomenclature Hugo ALOX15 GDB ALOX15 Entrez_Gene ALOX15 246 arachidonate 15-lipoxygenase

Atlas Genet Cytogenet Oncol Haematol 2006; 4 529 Cards Atlas ALOX15ID42986ch17p13 GeneCards ALOX15 Ensembl ALOX15 Genatlas ALOX15 GeneLynx ALOX15 eGenome ALOX15 euGene 246 Genomic and cartography ALOX15 - 17p13.3 chr17:4480970-4491709 - 17p13.2 (hg18- GoldenPath Mar_2006) Ensembl ALOX15 - 17p13.2 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ALOX15 Gene and transcription Genbank BC029032 [ ENTREZ ] Genbank M23892 [ ENTREZ ] Genbank M95923 [ ENTREZ ] Genbank XM_001131480 [ ENTREZ ] Genbank XM_001131480 [ ENTREZ ] RefSeq NM_001140 [ SRS ] NM_001140 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010718 [ SRS ] NT_010718 [ ENTREZ ] AceView ALOX15 AceView - NCBI TRASER ALOX15 Traser - Stanford Unigene Hs.73809 [ SRS ] Hs.73809 [ NCBI ] HS73809 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P16050 [ SRS] P16050 [ EXPASY ] P16050 [ INTERPRO ] PS00711 LIPOXYGENASE_1 [ SRS ] PS00711 Prosite LIPOXYGENASE_1 [ Expasy ] PS00081 LIPOXYGENASE_2 [ SRS ] PS00081 Prosite LIPOXYGENASE_2 [ Expasy ] Prosite PS50095 PLAT [ SRS ] PS50095 PLAT [ Expasy ] IPR008976 Lipase_LipOase [ SRS ] IPR008976 Lipase_LipOase [ Interpro EBI ] Interpro IPR000907 LipOase [ SRS ] IPR000907 LipOase [ EBI ] Interpro IPR001024 LipOase_LH2 [ SRS ] IPR001024 LipOase_LH2 [ EBI ] Interpro IPR001885 Mammal lipOase [ SRS ] IPR001885

Atlas Genet Cytogenet Oncol Haematol 2006; 4 530 Mammal_lipOase [ EBI ] CluSTr P16050 PF00305 Lipoxygenase [ SRS ] PF00305 Lipoxygenase [ Sanger Pfam ] pfam00305 [ NCBI-CDD ] PF01477 PLAT [ SRS ] PF01477 PLAT [ Sanger ] pfam01477 [ Pfam NCBI-CDD ] Smart SM00308 LH2 [EMBL] Blocks P16050 HPRD P16050 Protein Interaction databases DIP P16050 IntAct P16050 Polymorphism : SNP, mutations, diseases OMIM 152392 [ map ] GENECLINICS 152392 SNP ALOX15 [dbSNP-NCBI] SNP NM_001140 [SNP-NCI] SNP ALOX15 [GeneSNPs - Utah] ALOX15] [HGBASE - SRS] HAPMAP ALOX15 [HAPMAP] General knowledge Family ALOX15 [UCSC Family Browser] Browser SOURCE NM_001140 SMD Hs.73809 SAGE Hs.73809 1.13.11.33 [ Enzyme-SRS ] 1.13.11.33 [ Brenda-SRS ] 1.13.11.33 Enzyme [ KEGG ] 1.13.11.33 [ WIT ] Amigo iron ion binding[Amigo] iron ion binding[EGO-EBI] Amigo plasma membrane[Amigo] plasma membrane[EGO-EBI] Amigo electron transport[Amigo] electron transport[EGO-EBI] Amigo lipid metabolism[Amigo] lipid metabolism[EGO-EBI] Amigo inflammatory response[Amigo] inflammatory response[EGO-EBI] Amigo lipoxygenase activity[Amigo] lipoxygenase activity[EGO-EBI] Amigo lipoxygenase activity[Amigo] lipoxygenase activity[EGO-EBI] Amigo oxidoreductase activity[Amigo] oxidoreductase activity[EGO-EBI] Amigo leukotriene biosynthesis[Amigo] leukotriene biosynthesis[EGO-EBI] Amigo metal ion binding[Amigo] metal ion binding[EGO-EBI] arachidonate 15-lipoxygenase activity[Amigo] arachidonate 15- Amigo lipoxygenase activity[EGO-EBI]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 531 KEGG Prostaglandin and Leukotriene Metabolism PubGene ALOX15 Other databases Probes Probe ALOX15 Related clones (RZPD - Berlin) PubMed PubMed 44 Pubmed reference(s) in LocusLink Bibliography Discovery of a second 15S-lipoxygenase in humans. Brash AR, Boeglin WE, Chang MS. Proc Natl Acad Sci USA 1997; 94: 6148-6152. Medline 9177185

Expression of 15-lipoxygenase-1 in human colorectal cancer. Ikawa H, Kamitani H, Calvo BF, Foley JF, Eling TE. Cancer Res 1999; 59: 360-366. Medline 9927047

Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: evidence that 15- lipoxygenase is a mutator gene. Kelavkar UP, Badr KF. Proc Natl Acad Sci USA 1999; 96: 4378-4383. Medline 10200270

Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. Shankaranarayanan P, Chaitidis P, Kuhn H, Nigam S. J Biol Chem 2001; 276: 42753-42760. Medline 11509556

Nonsteroidal anti-inflammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression. Shureiqi I, Xu X, Chen D, Lotan R, Morris JS, Fischer SM, Lippman SM. Cancer Res 2001; 61: 4879-4884. Medline 11406566

15-lipoxygenase: a Janus enzyme? Chanez P, Bonnans C, Chavis C, Vachier I. Am J Respir Cell Mol Biol 2002; 27: 655-658. Medline 12444024

15-lipoxygenase-1 overexpression in prostate adenocarcinoma. Kelavkar U, Cohen C, Eling T, Badr K.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 532 Adv Exp Med Biol 2002; 507: 133-145. Medline 12664577

KU 70/80 lupus autoantigen is the transcription factor induced by interleukins (IL)-13 and -4 leading to induction of 15-lipoxygenase (15-LO) in human cells. Kelavkar U, Wang S, Badr K. Adv Exp Med Biol 2002; 507: 469-481. Medline 12664628

GATA-6 transcriptional regulation of 15-lipoxygenase-1 during NSAID-induced apoptosis in colorectal cancer cells. Shureiqi I, Jiang W, Fischer SM, Xu X, Chen D, Lee JJ, Lotan R, Lippman SM. Cancer Res 2002; 62: 1178-1183. Medline 11861401

The N-terminal domain of the reticulocyte-type 15-lipoxygenase is not essential for enzymatic activity but contains determinants for membrane binding. Walther M, Anton M, Wiedmann M, Fletterick R, Kuhn H. J Biol Chem 2002; 277: 27360-27366. Medline 12004065

15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway. Chen GG, Xu H, Lee JF, Subramaniam M, Leung KL, Wang SH, Chan UP, Spelsberg TC. Int J Cancer 2003; 107: 837-843. Medline 14566836

IL-4 induces apoptosis in A549 lung adenocarcinoma cells: evidence for the pivotal role of 15-hydroxyeicosatetraenoic acid binding to activated peroxisome proliferator-activated receptor gamma transcription factor. Shankaranarayanan P, Nigam S. J Immunol 2003; 170: 887-894. Medline 12517954

Interleukin-13 induction of 15-lipoxygenase gene expression requires p38 Xu B, Bhattacharjee A, Roy B, Xu HM, Anthony D, Frank DA, Feldman GM, Cathcart MK. Mol Cell Biol.2003; 23: 3918-3928. Medline 11861401

Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. Liu C, Xu D, Sjoberg J, Forsell P, Bjorkholm M, Claesson HE. Exp Cell Res 2004; 297: 61-67. Medline 15194425

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15-Lipoxygenase-1 has anti-tumorigenic effects in colorectal cancer. Nixon JB, Kim KS, Lamb PW, Bottone FG, Eling TE. Prostaglandins Leukot Essent Fatty Acids 2004; 70: 7-15. Medline 14643174

15-LOX-1 inhibits p21 (Cip/WAF 1) expression by enhancing MEK-ERK 1/2 signaling in colon carcinoma cells. Yoshinaga M, Buchanan FG, DuBois RN. Prostaglandins Other Lipid Mediat 2004; 73: 111-122. Medline 15165036

15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. Nony PA, Kennett SB, Glasgow WC, Olden K, Roberts JD. REFERENCE J Biol Chem 2005; 280: 31413-31419. Medline 16000313

The role of lipoxygenase-isoforms in atherogenesis. Kuhn H, Romisch I, Belkner J. Mol Nutr Food Res 2005; 49: 1014-1029. Medline 16270276

The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis. Shureiqi I, Wu Y, Chen D, Yang XL, Guan B, Morris JS, Yang P, Newman RA, Broaddus R, Hamilton SR, Lynch P, Levin B, Fischer SM, Lippman SM. Cancer Res 2005; 65: 11486-11492. Medline 16357157

Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5'-flanking region (-5229G/A) with bone mineral density. Urano T, Shiraki M, Fujita M, Hosoi T, Orimo H, Ouchi Y, Inoue S. J Bone Miner Metab 2005; 23: 226-230. Medline 15838625

Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Jiang WG, Watkins G, Douglas-Jones A, Mansel RE. Prostaglandins Leukot Essent Fatty Acids 2006; 74: 235-245. Medline 16556493

The yin and yang of 15-lipoxygenase-1 and delta-desaturases: Dietary omega-6 linoleic acid metabolic pathway in prostate. Kelavkar U, Lin Y, Landsittel D, Chandran U, Dhir R. J Carcinog 2006; 5: 9.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 534 Medline 16566819

Inflammation and immune regulation by 12/15-lipoxygenases. Kuhn H, O'Donnell VB. Prog Lipid Res 2006; 45: 334-56. Medline 16678271

Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Zuo X, Wu Y, Morris JS, Stimmel JB, Leesnitzer LM, Fischer SM, Lippman SM, Shureiqi I. Oncogene 2006; 25: 1225-1241. Medline 16288226

Functional polymorphism in ALOX15 results in increased allele-specific transcription in macrophages through binding of the transcription factor SPI1. Wittwer J, Marti-Jaun J, Hersberger M. Hum Mutat 2006; 27: 78-87. Medline 16320347

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Sreeparna Banerjee 2006 Citation This paper should be referenced as such : Banerjee S . ALOX15 (Arachidonate 15-Lipoxygenase). Atlas Genet Cytogenet Oncol Haematol. June 2006 . URL : http://AtlasGeneticsOncology.org/Genes/ALOX15ID42986ch17p13.html

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PAX3 (paired box gene 3 (Waardenburg syndrome 1)) Identity Other CDHS names HUP2 MGC120381 MGC120382 MGC120383 MGC120384 MGC134778 WS1 WS3 HGNC8617 Hugo PAX3 Location 2q35-2q36.1 DNA/RNA Description The PAX3 gene extends approximately 100 kb and consists of 10 exons. Transcription In human tissues and tumors, seven alternatively spliced transcripts have been described. The abundant transcripts, which have been studied in neural-related tumor specimens and cell lines, appear to consist of the first eight or nine exons (PAX3c and PAX3d). In addition, there is also frequent alternative splicing at the 5¹ end of exon 3 in human tissues and tumors that results in inclusion or exclusion of a single codon encoding a glutamine residue. Protein

Description 479 amino acids, 53.0 kDa (8 exon form, PAX3c) or 484 amino acids, 53.5 kDa (9 exon form, PAX3d). The isoform containing the variable glutamine residue at the exon 3/4 junction is referred to as Q+, while the isoform lacking the Q is designated as Q-. Expression Based on experiments in the mouse, Pax3 is expressed in the spinal cord and selected regions of the brain. Pax3 is expressed in the neural crest and is involved in development of neural crest derivatives including spinal ganglia, melanocytes and Schwann cells. Pax3 expression is also detected in somite compartments that give rise to embryonic skeletal muscle progenitors, and in cells that give rise to

Atlas Genet Cytogenet Oncol Haematol 2006; 4 536 skeletal muscle compartments of the developing limb buds. In addition, Pax3 (as well as Pax7 ) is also expressed in a proliferating population without skeletal muscle specific markers that reside within limb and trunk muscles throughout later development; and a subset of adult muscles subsequently contain Pax3-expressing satellite cells. Localisation Nucleus. Function PAX3 is a transcription factor characterized by three highly converved motifs in the N-terminal region: a paired box DNA binding domain, an intervening octapeptide of unclear function, and a homeobox DNA binding domain. The C-terminal region contains a proline-, serine- and threonine-rich transactivation domain. Based on the studies of the mutant Pax3 alleles in the mouse (Splotch phenotype) as well as studies of patients with mutant PAX3 genes (see below), Pax3 is postulated to have a crucial role in the development of the early neural structures, derivatives of the neural crest, and skeletal musculature. In these developmental processes, there is evidence that the transcriptional function of Pax3 impacts at four biological activities: 1. proliferation 2. apoptosis 3. differentiation 4. motility Homology PAX3 shares homology through the conserved paired box with eight other members of the PAX gene family. In particular, within the PAX gene family, PAX3 and PAX7 constitute a subfamily characterized by a paired box, intervening octapeptide and complete homeobox as well as homology between the C-terminal transcriptional activation domains. Mutations Germinal Germ-line sequence changes involving the PAX3 gene are found in Waardenburg syndrome type I and type III, a non-neoplastic autosomal dominant disorder characterized by hearing loss and pigmentary abnormalities. The majority of these alterations are nucleotide substitutions resulting in missense mutations, usually in the regions encoding the paired box or homeobox. A smaller number of base substitutions at splicing sites and small deletions and insertions, which usually alter the reading frame, have also been reported. Finally, there have also been several cases of large deletions and other rearrangements of chromosome 2. Somatic The PAX3 gene is rearranged by the characteristic and recurrent acquired chromosomal translocation - t(2;13)(q35;q14) - in the myogenic soft tissue cancer alveolar rhabdomyosarcoma. As a result of this 2;13 translocation, portions of the PAX3 gene are juxtaposed with portions of the FKHR (also called FOXO1A) gene on chromosome 13. In particular, the 5' region of PAX3 including the first seven exons is joined to the 3' region of FKHR including its last two exons. Though the reciprocal chimeric gene is also generated, this PAX3-FKHR chimeric gene is more consistent and highly expressed, and results in expression of a fusion protein consisting of the intact PAX3 N-terminal DNA binding domain fused in-framed to the intact FKHR C-terminal transcriptional

Atlas Genet Cytogenet Oncol Haematol 2006; 4 537 activation domain. This fusion protein functions as an aberrant transcription factor. In rare cases of alveolar rhabdomyosarcoma, PAX3 is fused to alternative C-terminal partners - MLLT7 (AFX, FOXO4) and EPIGENETICS Implicated in Entity Alveolar Rhabdomyosarcoma (ARMS) Disease ARMS is one subtype of a family of pediatric soft tissue tumors that is related to the skeletal muscle lineage. In contrast to the embryonal rhabdomyosarcoma (ERMS), the other major subtype in this family, ARMS often occurs in adolescents and young adults, with primary tumors located in the vicinity of skeletal muscle, such as in the extremities and trunk. Prognosis In contrast to the favorable outcome in most cases of ERMS, ARMS is associated with an unfavorable prognosis. In the IRS-IV clinical trial, the three year failure-free survival rate was 66% for patients presenting without metastatic disease and 16% for patients presenting with metastatic disease (compared to 83% and 37% for non-metastatic and metastatic ERMS, respectively). This unfavorable prognosis in ARMS is related to the propensity for early and wide dissemination, often involving bone marrow, and to poor response to chemotherapy. Cytogenetics Chromosomal studies identified nonrandom chromosomal translocations that distinguish the majority of ARMS tumors from ERMS and other pediatric solid tumors. The t(2;13)(q35;q14) translocation is the most prevalent and the t(1;13)(p36;q14) is identified in a smaller subset of cases.

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a) Diagram of t(2;13)(q35;q14) and t(1;13)(p36;q14) chromosomal translocations generating PAX3-FKHR and PAX7-FKHR fusions b) Generation of chimeric genes by the t(2;13)(q35;q14) translocation in ARMS. The exons of the wild-type and fusion genes are shown as boxes above each map and the translocation breakpoint distributions are shown as line segments below the map of the wild-type genes. c) Comparison of wild-type and fusion products associated with the 2;13 and 1;13 translocations. The paired box, octapeptide, homeobox and fork head domain are indicated as open boxes, and transcriptional domains (DNA binding domain, DBD; transcriptional activiation domain, TAD; transcriptional inhibitory domain, TID) are shown as solid bars. The sites phosphorylated by Akt are indicated by stars, and the alternative splice in the paired box is shown by an arrowhead. The vertical dash line indicates the translocation fusion point. {Reproduced from: Barr (2001) Oncogene 20: 5736- 5746}

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Hybrid/Mutated The 2;13 or 1;13 chromosome translocation juxtapose the PAX3 Gene gene on chromosome 2 or the PAX7 gene on chromosome 1 with the FKHR (FOXO1A) gene on chromosome 13 to generate two chimeric genes. These chimeric genes are transcribed to generate chimeric transcripts, of which the PAX3-FKHR and PAX7-FKHR transcripts are the most highly and consistently expressed of the pair of potential products. Based on RT-PCR assays for these chimeric transcripts, approximately 60% of ARMS cases express PAX3-FKHR and thus contain the t(2;13), 20% express PAX7-FKHR and thus contain the t(1;13), and 20% are fusion-negative. Oncogenesis The PAX3-FKHR and PAX7-FKHR chimeric genes encode fusion proteins that contain the intact DNA binding domain of PAX3 or PAX7 in the N-terminal region fused in frame with a C-terminal FKHR (FOXO1A) segment containing the transactivation domain. The chromosomal changes in ARMS result in high level expression, potent transcriptional activity, and constitutive nuclear localization of the PAX3-FKHR or PAX7-FKHR fusion products. The end result is exaggerated activity at multiple biological levels that converges to inappropriate activation of PAX3/PAX7 target genes and ultimately contributes to tumourigenic behavior.

Entity Waardenburg syndrome (type I et III) Disease Waardenburg syndrome (WS) is an inherited autosomal-dominant disorder characterized by sensorineural hearing loss (of varying severity), dystopia canthorum (lateral displacement of inner corners of eye), and pigmentary disturbances of the eye, skin and hair. It is a common cause of inherited deafness in infants. Depending on additional symptoms, WS is classified into four types, WS1, WS2, WS3, and WS4, with only WS1 and WS3 being associated with PAX3 mutations. Deletions, insertion, base pair substitution, or dominant point mutations of PAX3 cause WS1 and WS3. WS3 (Klein-Waardenburg syndrome) is similar to WS1 but WS3 is also characterized by musculoskeletal abnormalities, usually involving the upper limbs. It should be noted that WS3 is often associated with deletions of the long arm of chromosome 2 involving multiples genes including PAX3 whereas WS1 is generally is associated with mutations within the PAX3 gene. WS2 is heterogenous, being caused by mutations in the MITF gene in some but not all affected families. WS4 is caused by mutations in the EDN3, EDNRB, or SOX10 ID genes.

Entity Craniofacial-deafness-hand syndrome (CDHS) Disease Craniofacial-deafness-hand syndrome is inherited as an autosomal dominant mutation. CDHS shows clinical characteristics of the absence or hypoplasia of the nasal bones, profound sensorineural deafness, a small and short nose with slitlike nares, hypertelorism,

Atlas Genet Cytogenet Oncol Haematol 2006; 4 540 short palpebral fissures, and limited movement at the wrist and ulnar deviations of the fingers. A missense mutation (Asn47Lys) in the paired domain (exon 2) of PAX3 was detected in a family of three (a mother and two children) first reported with this syndrome.

External links Nomenclature Hugo PAX3 GDB PAX3 Entrez_Gene PAX3 5077 paired box gene 3 (Waardenburg syndrome 1) Cards Atlas PAX3ID70ch2q35 GeneCards PAX3 Ensembl PAX3 Genatlas PAX3 GeneLynx PAX3 eGenome PAX3 euGene 5077 Genomic and cartography GoldenPath PAX3 - chr2:222866593-222871944 - 2q36.1 (hg18-Mar_2006) Ensembl PAX3 - 2q36.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PAX3 Gene and transcription Genbank AY251279 [ ENTREZ ] Genbank AY251280 [ ENTREZ ] Genbank BC063547 [ ENTREZ ] Genbank BC101299 [ ENTREZ ] Genbank BC101300 [ ENTREZ ] RefSeq NM_000438 [ SRS ] NM_000438 [ ENTREZ ] RefSeq NM_013942 [ SRS ] NM_013942 [ ENTREZ ] RefSeq NM_181457 [ SRS ] NM_181457 [ ENTREZ ] RefSeq NM_181458 [ SRS ] NM_181458 [ ENTREZ ] RefSeq NM_181459 [ SRS ] NM_181459 [ ENTREZ ] RefSeq NM_181460 [ SRS ] NM_181460 [ ENTREZ ] RefSeq NM_181461 [ SRS ] NM_181461 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 541 RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_005403 [ SRS ] NT_005403 [ ENTREZ ] RefSeq NW_921618 [ SRS ] NW_921618 [ ENTREZ ] AceView PAX3 AceView - NCBI TRASER PAX3 Traser - Stanford Unigene Hs.42146 [ SRS ] Hs.42146 [ NCBI ] HS42146 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P23760 [ SRS] P23760 [ EXPASY ] P23760 [ INTERPRO ] PS00027 HOMEOBOX_1 [ SRS ] PS00027 HOMEOBOX_1 [ Prosite Expasy ] PS50071 HOMEOBOX_2 [ SRS ] PS50071 HOMEOBOX_2 [ Prosite Expasy ] Prosite PS00034 PAIRED_1 [ SRS ] PS00034 PAIRED_1 [ Expasy ] Prosite PS51057 PAIRED_2 [ SRS ] PS51057 PAIRED_2 [ Expasy ] Interpro IPR001356 Homeobox [ SRS ] IPR001356 Homeobox [ EBI ] IPR012287 Homeodomain-rel [ SRS ] IPR012287 Homeodomain- Interpro rel [ EBI ] IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ] IPR001523 Paired_box_N [ SRS ] IPR001523 Paired_box_N [ EBI Interpro ] IPR007104 Paired_homeo [ SRS ] IPR007104 Paired_homeo [ EBI Interpro ] IPR011991 Wing_hlx_DNA_bd [ SRS ] IPR011991 Interpro Wing_hlx_DNA_bd [ EBI ] CluSTr P23760 PF00046 Homeobox [ SRS ] PF00046 Homeobox [ Sanger Pfam ] pfam00046 [ NCBI-CDD ] PF00292 PAX [ SRS ] PF00292 PAX [ Sanger ] pfam00292 [ Pfam NCBI-CDD ] Smart SM00389 HOX [EMBL] Smart SM00351 PAX [EMBL] Prodom PD000010 Homeobox[INRA-Toulouse] P23760 PAX3_HUMAN [ Domain structure ] P23760 Prodom PAX3_HUMAN [ sequences sharing at least 1 domain ] Blocks P23760 HPRD P23760 Protein Interaction databases DIP P23760 IntAct P23760

Atlas Genet Cytogenet Oncol Haematol 2006; 4 542 Polymorphism : SNP, mutations, diseases OMIM 122880;148820;193500;268220;606597 [ map ] GENECLINICS 122880;148820;193500;268220;606597 SNP PAX3 [dbSNP-NCBI] SNP NM_000438 [SNP-NCI] SNP NM_013942 [SNP-NCI] SNP NM_181457 [SNP-NCI] SNP NM_181458 [SNP-NCI] SNP NM_181459 [SNP-NCI] SNP NM_181460 [SNP-NCI] SNP NM_181461 [SNP-NCI] SNP PAX3 [GeneSNPs - Utah] PAX3] [HGBASE - SRS] HAPMAP PAX3 [HAPMAP] General knowledge Family PAX3 [UCSC Family Browser] Browser SOURCE NM_000438 SOURCE NM_013942 SOURCE NM_181457 SOURCE NM_181458 SOURCE NM_181459 SOURCE NM_181460 SOURCE NM_181461 SMD Hs.42146 SAGE Hs.42146 transcription factor activity[Amigo] transcription factor activity[EGO- Amigo EBI] transcription factor activity[Amigo] transcription factor activity[EGO- Amigo EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI] regulation of transcription, DNA-dependent[Amigo] regulation of Amigo transcription, DNA-dependent[EGO-EBI] transcription from RNA polymerase II promoter[Amigo] transcription Amigo from RNA polymerase II promoter[EGO-EBI] Amigo apoptosis[Amigo] apoptosis[EGO-EBI] Amigo development[Amigo] development[EGO-EBI] segment polarity determination[Amigo] segment polarity Amigo determination[EGO-EBI] Amigo nervous system development[Amigo] nervous system

Atlas Genet Cytogenet Oncol Haematol 2006; 4 543 development[EGO-EBI] sensory perception of sound[Amigo] sensory perception of Amigo sound[EGO-EBI] Amigo organ morphogenesis[Amigo] organ morphogenesis[EGO-EBI] sequence-specific DNA binding[Amigo] sequence-specific DNA Amigo binding[EGO-EBI] BIOCARTA Regulation of transcriptional activity by PML [Genes] PubGene PAX3 Other databases Probes Probe PAX3 Related clones (RZPD - Berlin) PubMed PubMed 59 Pubmed reference(s) in LocusLink Bibliography Previously undescribed syndrome of craniofacial, hand anomalies, and sensorineural deafness. Sommer A, Young-Wee T, Frye T. Am J Med Genet 1983; 15: 71-77. Medline 6859126

Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. Goulding MD, Chalepakis G, Deutsch U, Erselius JR, Gruss P. EMBO J 1991; 10: 1135-1147. Medline 2022185

An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Baldwin CT, Hoth CF, Amos JA, da-Silva EO, Milunsky A. Nature 1992; 355: 637-638. Medline 1347149

Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Tassabehji M, Read AP, Newton VE, Harris R, Balling R, Gruss P, Strachan T. Nature 1992; 355: 635-636. Medline 1347148

Rearrangement of the PAX3 paired box gene in the pediatric solid tumour alveolar rhabdomyosarcoma. Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS. Nat Genet 1993; 3: 113-117. Medline 8098985

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Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ III, Emanuel BS, Rovera G, Barr FG Nat Genet 1993; 5: 230-235. Medline 8275086

Pax-3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells. Bober E, Franz T, Arnold HH, Gruss P, Tremblay P. Development 1994; 120: 603-612. Medline 8162858

Pax3: a paired domain gene as a regulator in PNS myelination. Kioussi C, Gross MK, Gruss P. Neuron 1995; 15: 553-562. Medline 7546735

The mutational spectrum in Waardenburg syndrome. Tassabehji M, Newton VE, Liu Xz, Brady A, Donnai D, Krajewskawalasek M, Murday V, Norman A, Obersztyn E, Reardon W, Rice JC, Trembath R, Wieacker P, Whiteford M, Winter R, Read AP. Hum Mol Genet 1995; 4: 2131-2137. Medline 8589691

Missense mutation in the paired domain of PAX 3 causes craniofacial- deafness-hand syndrome. Asher JH, Sommer A, Morell R, Friedman TB. Hum Mutat 1996; 7: 30-35. Medline 8664898

Induction of apoptosis in rhabdomyosarcoma cells through down-regulation of PAX proteins. Bernasconi M, Remppis A, Fredericks WJ, Rauscher FJ 3rd, Schafer BW. Proc Natl Acad Sci USA 1996; 93: 13164-13169. Medline 8917562

An alternative splicing event in the Pax-3 paired domain identifies the linker region as a key determinant of paired domain DNA-binding activity. Vogan KJ, Underhill DA, Gros P. Mol Cell Biol 1996; 16: 6677-6686. Medline 8943322

Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 545 Davis RJ, Barr FG. Proc Natl Acad Sci USA 1997; 94: 8047-8051. Medline 9223312

Waardenburg syndrome. Read AP, Newton VE. J Med Genet 1997; 34: 656-665. (Review). Medline 9279758

PAX3 gene structure, alternative splicing and evolution. Barber TD, Barber MC, Cloutier TE, Friedman TB. Gene 1999; 237: 311-319. Medline 10521655

Predominant expression of alternative PAX3 and PAX7 forms in myogenic and neural tumor cell lines. Barr FG, Fitzgerald JC, Ginsberg JP, Vanella ML, Davis RJ, Bennicelli JL. Cancer Res 1999; 59: 5443-5448. Medline 10554014

PAX3 and PAX7 exhibit conserved cis-acting transcription repression domains and utilize a common gain of function mechanism in alveolar rhabdomyosarcoma. Bennicelli JL, Advani S, Schafer BW, Barr FG. Oncogene 1999; 18: 4348-4356. Medline 10439042

The oncogenic potential of the Pax3-FKHR fusion protein requires the Pax3 homeodomain recognition helix but not the Pax3 paired-box DNA binding domain. Lam PY, Sublett JE, Hollenbach AD, Roussel MF. Mol Cell Biol 1999; 19: 594-601. Medline 9858583

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Barr FG. Oncogene 2001; 20: 5736-5746. (Review). Medline 11607823

Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, Breneman J, J Clin Oncol 2001; 19: 3091-3102. Medline 11408506

Atlas Genet Cytogenet Oncol Haematol 2006; 4 546 Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Barr FG, Qualman SJ, Macris MH, Melnyk N, Lawlor ER, Strzelecki DM, Triche Cancer Res 2002; 62: 4704-4710. Medline 12183429

PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, Bridge JA, Crist WM, Triche TJ, Barr FG. J Clin Oncol 2002; 20: 2672-2679. Medline 12039929

Prognostic factors and clinical outcomes in children and adolescents with Breneman JC, Lyden E, Pappo AS, Link MP, Anderson JR, Parham DM, Qualman SJ, J Clin Oncol 2003; 21: 78-84. Medline 12506174

Craniofacial-deafness-hand syndrome revisited. Sommer A, Bartholomew DW. Am J Med Genet A 2003; 123: 91-94. Medline 14556253

Expression of PAX 3 alternatively spliced transcripts and identification of two new isoforms in human tumors of neural crest origin. Parker CJ, Shawcross SG, Li H, Wang QY, Herrington CS, Kumar S, MacKie RM, Prime W, Rennie IG, Sisley K, Kumar P. Int J Cancer 2004; 108: 314-320. Medline 14639621

Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1. Wachtel M, Dettling M, Koscielniak E, Stegmaier S, Treuner J, Simon-Klingenstein K, Buhlmann P, Niggli FK, Schafer BW. Cancer Res 2004; 64: 5539-5545. Medline 15313887

Co-expression of alternatively spliced forms of PAX3, PAX7, PAX3-FKHR and PAX7-FKHR with distinct DNA binding and transactivation properties in Du S, Lawrence EJ, Strzelecki D, Rajput P, Xia SJ, Gottesman DM, Barr FG. Int J Cancer 2005; 115: 85-92. Medline 15688409

Pax3 functions at a nodal point in melanocyte stem cell differentiation. Lang D, Lu MM, Huang L, Engleka KA, Zhang M, Chu EY, Lipner S, Skoultchi A,

Atlas Genet Cytogenet Oncol Haematol 2006; 4 547 Millar SE, Epstein JA. Nature 2005; 433: 884-887. Medline 15729346

A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Relaix F, Rocancourt D, Mansouri A, Buckingham M. Nature 2005; 435: 948-953. Medline 15843801

Pax3 and Pax7 have distinct and overlapping functions in adult muscle Relaix F, Montarras D, Zaffran S, Gayraud-Morel B, Rocancourt D, Tajbakhsh S, Mansouri A, Cumano A, Buckingham M. J Cell Biol 2006; 172: 91-102. Medline 16380438

A PANorama of PAX genes in cancer and development. Robson EJ, He SJ, Eccles MR. Nat Rev Cancer 2006; 6: 52-62. (Review). Medline 16397527

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Eun Hyun AHN, Frederic G. BARR 2006 Citation This paper should be referenced as such : AHN EH, BARR FG . PAX3 (paired box gene 3 (Waardenburg syndrome 1)). Atlas Genet Cytogenet Oncol Haematol. July 2006 . URL : http://AtlasGeneticsOncology.org/Genes/PAX3ID70ch2q35.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 548 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MSH3 (mutS homolog 3 (E coli)) Identity Other DUP names hMSH3 MRP1 Hugo MSH3 Location 5q11-q12 Local_order Between the DHFR and RASGRF2 genes. DNA/RNA Description The MSH3 gene is composed of 24 exons spanning in a region of 222 Kb. Transcription There are two major transcripts of 5 kb and 3,8 kb under the control of two different polyadenilation sites. Protein Description Amino acids: 1137. Molecular Weight: 127 KDa. MSH3 is a protein involved in the mismatch repair process after DNA replication. Expression Expression of MSH3 together with the dihydrofolate reductase (DHFR) gene appear to be regulated by a bidirectional promoter composed of multiple GC boxes and two initiator elements. MSH3 is expressed in all human tissues at low levels but with variable intensities, with higher expression in testis and pancreas and lower in small intestine and colon. Function MSH3 binds to MSH2 to form the MutSb heterodimer, which binds to insertion-deletion mismatches of two or more base pairs. Thereafter the MutS complex associates with the MutL complex and recruits the proteins needed for DNA excision and repair. Homology MSH3 is homologue to the bacterial MutS gene and to the Msh3 gene in S. cerevisiae. Homology is higher in the C-terminal region. Mutations Somatic MSH3 has insertions/deletions in a A(8) repeat in tumours showing microsatellite instability (MSI). As MSH3 is a mismatch repair gene and is mutated in a microsatellite only in MSI tumours is considered to be a secondary mutator that enhances a more severe MSI. Implicated in Entity MSI (MicroSatellite Instability). Note Tumours in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 549 Disease This phenotype is present in 15% of colorectal cancer, gastric cancer and endometrial cancer, and with lower incidence in some other tissues. Oncogenesis The average frequencies of the microsatellite mutation reported in sporadic MSI from colorectal, gastric and endometrial cancer are 38%, 39% and 25% respectively. In hereditary MSI (or HNPCC) is 51%. Entity Hematological malignancies. Oncogenesis It has been reported loss of expression of MSH3 at the mRNA level in some hematological malignancies including chronic myelogenous leukemia and acute myelogenous leukemia, acute lymphocytic leukemia and myelodysplastic syndrome. External links Nomenclature Hugo MSH3 GDB MSH3 Entrez_Gene MSH3 4437 mutS homolog 3 (E. coli) Cards Atlas MSH3ID341ch5q11 GeneCards MSH3 Ensembl MSH3 Genatlas MSH3 GeneLynx MSH3 eGenome MSH3 euGene 4437 Genomic and cartography GoldenPath MSH3 - chr5:79986050-80208389 + 5q14.1 (hg18-Mar_2006) Ensembl MSH3 - 5q14.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MSH3 Gene and transcription Genbank AA601983 [ ENTREZ ] Genbank AI817671 [ ENTREZ ] Genbank BC004177 [ ENTREZ ] Genbank BC011817 [ ENTREZ ] Genbank BC017273 [ ENTREZ ] RefSeq NM_002439 [ SRS ] NM_002439 [ ENTREZ ] RefSeq AC_000048 [ SRS ] AC_000048 [ ENTREZ ] RefSeq NC_000005 [ SRS ] NC_000005 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 550 RefSeq NT_006713 [ SRS ] NT_006713 [ ENTREZ ] RefSeq NW_922729 [ SRS ] NW_922729 [ ENTREZ ] AceView MSH3 AceView - NCBI TRASER MSH3 Traser - Stanford Unigene Hs.280987 [ SRS ] Hs.280987 [ NCBI ] HS280987 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P20585 [ SRS] P20585 [ EXPASY ] P20585 [ INTERPRO ] PS00486 DNA_MISMATCH_REPAIR_2 [ SRS ] PS00486 Prosite DNA_MISMATCH_REPAIR_2 [ Expasy ] Interpro IPR000432 MutS_C [ SRS ] IPR000432 MutS_C [ EBI ] Interpro IPR007860 MutS_II [ SRS ] IPR007860 MutS_II [ EBI ] Interpro IPR007696 MutS_III [ SRS ] IPR007696 MutS_III [ EBI ] Interpro IPR007695 MutS_N [ SRS ] IPR007695 MutS_N [ EBI ] CluSTr P20585 PF01624 MutS_I [ SRS ] PF01624 MutS_I [ Sanger ] pfam01624 Pfam [ NCBI-CDD ] PF05188 MutS_II [ SRS ] PF05188 MutS_II [ Sanger Pfam ] pfam05188 [ NCBI-CDD ] PF05192 MutS_III [ SRS ] PF05192 MutS_III [ Sanger Pfam ] pfam05192 [ NCBI-CDD ] PF00488 MutS_V [ SRS ] PF00488 MutS_V [ Sanger Pfam ] pfam00488 [ NCBI-CDD ] Smart SM00534 MUTSac [EMBL] Smart SM00533 MUTSd [EMBL] Prodom PD001263 MutS_C[INRA-Toulouse] P20585 MSH3_HUMAN [ Domain structure ] P20585 Prodom MSH3_HUMAN [ sequences sharing at least 1 domain ] Blocks P20585 HPRD P20585 Protein Interaction databases DIP P20585 IntAct P20585 Polymorphism : SNP, mutations, diseases OMIM 600887 [ map ] GENECLINICS 600887 SNP MSH3 [dbSNP-NCBI] SNP NM_002439 [SNP-NCI] SNP MSH3 [GeneSNPs - Utah] MSH3] [HGBASE - SRS] HAPMAP MSH3 [HAPMAP]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 551 General knowledge Family MSH3 [UCSC Family Browser] Browser SOURCE NM_002439 SMD Hs.280987 SAGE Hs.280987 Amigo nucleotide binding[Amigo] nucleotide binding[EGO-EBI] purine-specific mismatch base pair DNA N-glycosylase Amigo activity[Amigo] purine-specific mismatch base pair DNA N- glycosylase activity[EGO-EBI] Amigo damaged DNA binding[Amigo] damaged DNA binding[EGO-EBI] Amigo protein binding[Amigo] protein binding[EGO-EBI] Amigo ATP binding[Amigo] ATP binding[EGO-EBI] Amigo nucleus[Amigo] nucleus[EGO-EBI] Amigo base-excision repair[Amigo] base-excision repair[EGO-EBI] Amigo mismatch repair[Amigo] mismatch repair[EGO-EBI] mismatched DNA binding[Amigo] mismatched DNA binding[EGO- Amigo EBI] single guanine insertion binding[Amigo] single guanine insertion Amigo binding[EGO-EBI] dinucleotide repeat insertion binding[Amigo] dinucleotide repeat Amigo insertion binding[EGO-EBI] protein homodimerization activity[Amigo] protein homodimerization Amigo activity[EGO-EBI] PubGene MSH3 Other databases Probes Probe MSH3 Related clones (RZPD - Berlin) PubMed PubMed 16 Pubmed reference(s) in LocusLink Bibliography Isolation and characterization of cDNA clones derived from the divergently transcribed gene in the region upstream from the human dihydrofolate reductase gene. Fujii H, Shimada T. J Biol Chem 1989; 264: 10057-10064. Medline 2722860

Loss of expression of the human MSH3 gene in hematological malignancies. Inokuchi K, Ikejima M, Watanabe A, Nakajima E, Orimo H, Nomura T, Shimada T. Biophys Res Commun 1995; 214: 171-179.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 552 Medline 7669036

Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Risinger JI, Umar A, Boyd J, Berchuck A, Kunkel TA, Barrett JC. Nature Genet 1996; 14: 102-109. Medline 8782829

Genomic organization and expression of the human MSH3 gene. Watanabe A, Ikejima M, Suzuki N, Shimada T. Genomics 1996; 31: 311-318. Medline 8838312

HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. de Wind N, Dekker M, Claij N, Jansen L, van Klink Y, Radman M, Riggins G, van der Valk M, van't Wout K, te Riele H. Nature Genet 1999; 23: 359-362. Medline 10545954

Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Duval A, Hamelin R. Cancer Res 2002; 62: 2447-2454. (REVIEW). Medline 11980631

DNA mismatch repair defects: role in colorectal carcinogenesis. Jacob S, Praz F. Biochimie 2002; 84: 27-47. (REVIEW). Medline 11900875 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Enric Domingo, Simo Schwartz Jr. 2006 Citation This paper should be referenced as such : Domingo E, Schwartz S Jr . MSH3. Atlas Genet Cytogenet Oncol Haematol. July 2006 . URL : http://AtlasGeneticsOncology.org/Genes/MSH3ID341ch5q11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 4 553 Atlas of Genetics and Cytogenetics in Oncology and Haematology

FH (fumarate hydratase). Identity Hugo FH Location 1q42.1 Local_order Telomeric to RGS7, centromeric to KMO DNA/RNA

Fig1. Genomic structure of FH. Exons are represented by purple boxes with base pair number above and exon number below. Image is not drawn to scale.

Description 10 exons; 22,152 base pairs. Transcription 1,1790 bp. Multiple RNA transcripts encode two FH gene products- one with a mitochondrial signal protein and the other lacking the signal sequence. Protein

Atlas Genet Cytogenet Oncol Haematol 2006; 4 554

Description FH encodes the homotetrameric enzyme, fumarase, composed of 510 amino acids (molecular weight 54,637 Da); four identical subunits (50 kDa each); three active DNA binding sites (site A) and one lower affinity substrate (site B). Isoenzyme products have nearly identical amino acid sequences, but vary at the amino terminus. Expression Widespread in both fetal and adult tissues; most abundantly expressed in the skin, parathyroid, lymph and colon (four highest NCBI expression profiles). Tumors: expression in benign mesenchymal tissue (e.g., uterine, cutaneous); malignant tumors: leiomyosarcoma and papillary

Atlas Genet Cytogenet Oncol Haematol 2006; 4 555 (type II) renal cell carcinoma. Localisation Mitochondrial and cytosolic. Subcellular localization is determined by presence or absence of a signal sequence at the amino terminus. Presence of the signal generates the mitochondrial-targeted form while absence of the signal results in the cytosolic form. Function Fumarase plays a key enzymatic role in fundamental metabolic pathways. The mitochondrial isoenzyme catalyzes conversion of fumarate to malate in the Krebs, or tricarboxylic acid (TCA) cycle, in which acetyl-CoA produces CO2, reduced electron carriers (FADH2 and NADH) and ATP. The cytosolic isoenzyme is involved with amino acid metabolism. Mutations Germinal Germline mutations in FH are associated with two distinct conditions: Homozygous and compound heterozygous mutations (e.g., missense and in-frame deletions) of the 3' end result in fumarate hydratase deficiency (FHD). Heterozygous 5' mutations (e.g., nonsense, missense and deletions ranging from one base pair to whole gene) predispose individuals to somatic mutations in the normal allele leading to Hereditary leiomyomatosis and renal cell carcinoma / multiple cutaneous and uterine leiomyomatosis (HLRCC/MCUL1). Somatic Loss-of-heterozygosity of the wild type allele results in functional nullizygosity for fumarate hydratase. Malignant uterine and kidney tumors characteristic of HLRCC can subsequently develop. Implicated in Entity (UL) NOTE Synonyms include uterine fibroids, fibromas, myofibromas and myomas. Disease Benign mesenchymal tumors of the uterus. Prognosis Excellent, but may require surgical intervention as one- third of hysterectomies performed in the United States have a primary indication of UL. Cytogenetics UL rarely associated with cytologically visible 1q42 deletions. Hybrid/Mutated Deletions of FH from structural rearrangements of 1q42.1. Gene Abnormal Presumed haploinsufficiency or functional null if mutation in other FH Protein allele occurs.

Entity Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)/ multiple cutaneous and uterine leiomyomatosis (MCUL1). Note Also known as Reed¹s syndrome. Disease HLRCC is an autosomal dominant disorder, characterized by smooth muscle tumors of the skin and uterus and/or kidney. Prognosis Good, if early diagnosis. Abnormal Inherited mutations can predispose to somatic deletions resulting in

Atlas Genet Cytogenet Oncol Haematol 2006; 4 556 Protein truncated, non-functional or absent proteins. Oncogenesis FH acts as classic tumor suppressor gene in HLRCC/MCUL1. Genetic or epigenetic alterations in FH resulting from substitution, deletion or methylation follow the Knudson ³two hit² mechanism. The resulting functionally null state for fumarase can lead to subsequent oxidative tissue damage and tumorigenesis.

Entity Fumarate hydratase deficiency (FHD). Note Synonymous with fumarase deficiency and fumaric aciduria. Disease Autosomal recessive condition characterized by delayed development, diminished muscle tone, and encephalopathy likely due to limited energy generation during development. Prognosis Poor. FHD is a rare condition, but reported cases indicate most affected individuals survive only several months while very few survive into their third decade. Hybrid/Mutated The most common allelic abnormality is a 3 base pair- AAA insertion. Gene Abnormal Mutations near fumarase active site result in absent or truncated Protein protein.

External links Nomenclature Hugo FH GDB FH Entrez_Gene FH 2271 fumarate hydratase Cards Atlas FHID40573ch1q42 GeneCards FH Ensembl FH Genatlas FH GeneLynx FH eGenome FH euGene 2271 Genomic and cartography FH - 1q42.1 chr1:239727528-239749677 - 1q43 (hg18- GoldenPath Mar_2006) Ensembl FH - 1q43 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene FH

Atlas Genet Cytogenet Oncol Haematol 2006; 4 557 Gene and transcription Genbank BC003108 [ ENTREZ ] Genbank BC017444 [ ENTREZ ] Genbank BT009839 [ ENTREZ ] Genbank CR590170 [ ENTREZ ] Genbank CR594789 [ ENTREZ ] RefSeq NM_000143 [ SRS ] NM_000143 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004836 [ SRS ] NT_004836 [ ENTREZ ] RefSeq NW_927128 [ SRS ] NW_927128 [ ENTREZ ] AceView FH AceView - NCBI TRASER FH Traser - Stanford Unigene Hs.592490 [ SRS ] Hs.592490 [ NCBI ] HS592490 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P07954 [ SRS] P07954 [ EXPASY ] P07954 [ INTERPRO ] PS00163 FUMARATE_LYASES [ SRS ] PS00163 Prosite FUMARATE_LYASES [ Expasy ] Interpro IPR003031 D_crystallin [ SRS ] IPR003031 D_crystallin [ EBI ] Interpro IPR005677 Fum_hydII [ SRS ] IPR005677 Fum_hydII [ EBI ] IPR000362 Fumarate_lyase [ SRS ] IPR000362 Fumarate_lyase [ Interpro EBI ] IPR008948 L-Aspartase-like [ SRS ] IPR008948 L-Aspartase-like [ Interpro EBI ] CluSTr P07954 PF00206 Lyase_1 [ SRS ] PF00206 Lyase_1 [ Sanger Pfam ] pfam00206 [ NCBI-CDD ] Blocks P07954 HPRD P07954 Protein Interaction databases DIP P07954 IntAct P07954 Polymorphism : SNP, mutations, diseases OMIM 136850;150800;605839;606812 [ map ] GENECLINICS 136850;150800;605839;606812 SNP FH [dbSNP-NCBI] SNP NM_000143 [SNP-NCI] SNP FH [GeneSNPs - Utah] FH] [HGBASE - SRS] HAPMAP FH [HAPMAP]

Atlas Genet Cytogenet Oncol Haematol 2006; 4 558 General knowledge Family FH [UCSC Family Browser] Browser SOURCE NM_000143 SMD Hs.592490 SAGE Hs.592490 4.2.1.2 [ Enzyme-SRS ] 4.2.1.2 [ Brenda-SRS ] 4.2.1.2 [ KEGG Enzyme ] 4.2.1.2 [ WIT ] fumarate hydratase activity[Amigo] fumarate hydratase Amigo activity[EGO-EBI] Amigo cytoplasm[Amigo] cytoplasm[EGO-EBI] Amigo mitochondrion[Amigo] mitochondrion[EGO-EBI] Amigo tricarboxylic acid cycle[Amigo] tricarboxylic acid cycle[EGO-EBI] Amigo fumarate metabolism[Amigo] fumarate metabolism[EGO-EBI] Amigo cell cycle[Amigo] cell cycle[EGO-EBI] Amigo lyase activity[Amigo] lyase activity[EGO-EBI] tricarboxylic acid cycle enzyme complex[Amigo] tricarboxylic acid Amigo cycle enzyme complex[EGO-EBI] negative regulation of progression through cell Amigo cycle[Amigo] negative regulation of progression through cell cycle[EGO-EBI] KEGG Citrate Cycle (TCA Cycle) PubGene FH Other databases Probes Probe FH Related clones (RZPD - Berlin) PubMed PubMed 23 Pubmed reference(s) in LocusLink Bibliography Mitochondrial and cytoplasmic fumarases in Saccharomyces cerevisiae are encoded by a single nuclear gene FUM1. Wu M, Tzagoloff A. J Biol Chem 1987; 262: 12275-12282. Medline 3040736

Crystallographic studies of the catalytic a second site in fumarase C from Escherichia coli. Weaver T, Banaszak L. Biochemistry 1996; 35: 13955-13965. Medline 8909293

Atlas Genet Cytogenet Oncol Haematol 2006; 4 559 Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Kiuru M, Launonen V, Hietala M, Aittomaki K, Vierimaa O, Salovaara R, Arola J, Pukkala E, Sistonen P, Herva R, Aaltonen LA. Am J Path 2001; 159: 825-829. Medline 11549574

Inherited susceptibility to uterine leiomyomas and renal cell cancer. Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA. Proc Natl Acad Sci USA 2001; 98: 3387-3392. Medline 11248088

Low frequency of somatic mutations in FH/ multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas. Barker KT, Bevan S, Wang R, Lu Y-J, Flanagan AM, Bridge JA, Fisher C, Finlayson CJ, Shipley J, Houlston RS. Brit J Cancer 2002; 87: 446-448. Medline 12177782

Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Kiuru M, Lehtonen R, Arola J, Salovaara R, Jarvinen H, Aittomaki K, Sjoberg J, Visakorpi T, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, Karhu A, Aaltonen LA. Cancer Res 2002; 62: 4554-4557. Medline 12183404

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Tomlinson IPM, Alam NA, Rowan AJ, Barclay E, Jaeger EEM, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Bevan S, Barker K, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA. Nature Genet 2002; 30: 406-410. Medline 11865300

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, Potts EDA, Crone M, Wilkinson S, Camacho-Martinez F, Jablonska S, Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S, Tomlinson IPM.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 560 Hum Molec Genet 2003; 12: 1241-1252. Medline 12761039

Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyoke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B. Am J Hum Genet 2003; 73: 95-106. Medline 12772087

Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies. Gross KL, Panhuysen CIM, Kleinman MS, Goldhammer H, Jones ES, Nassery N, Stewart EA, Morton CC. Genes Chromosomes Cancer 2004; 41: 183-190. Medline 15334541

The genetics of uterine leiomyomata. Stewart EA and Morton CC. Obstet Gynecol 2006; 107: 917-921. (Review) Medline 16582132

Distinct expression profile in fumarate-hydratase-deficient uterine fibroids Vanharanta S, Pollard PJ, Lehtonen HJ, Laiho P, Sjoberg J, Leminen A, Aittomaki K, Arola J, Kruhoffer M, Orntoft TF, Tomlinson IP, Kiuru M, Arango D, Aaltonen LA. Hum Mol Genet 2006; 15: 97-103. Medline 16319128

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Allison M Lynch, Cynthia C Morton. 2006 Citation This paper should be referenced as such : Lynch AM, Morton CC. . FH (fumarate hydratase).. Atlas Genet Cytogenet Oncol Haematol. July 2006 . URL : http://AtlasGeneticsOncology.org/Genes/FHID40573ch1q42.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 561 Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALOX5 (Arachidonate 5-Lipoxygenase). Identity Other 5-LO names EC 1.13.11.34 leukotriene A4 synthase 5LPG LOG5 Hugo ALOX5 Location 10q11.2 Genes flanking ALOX5, in centromere to telomere direction on 10q11, are: OR6D1P 10q11.21 olfactory receptor, family 6, subfamily D, member 1 pseudogene. LOC643413 10q11.21 hypothetical protein LOC643413. Local_order ALOX5 10q11.2 arachidonate 5-lipoxygenase. MARCH8 10q11.21 membrane-associated ring finger (C3HC4) 8. LOC653306 10q11.21 similar to membrane-associated ring finger (C3HC4) 8. ANUBL1 10q11.21 AN1, ubiquitin-like, homolog (Xenopus laevis). DNA/RNA

Diagram of the ALOX5 gene. Exons are represented by purple boxes (in scale). Exons 1 to 14 are from the 5' to 3¹ direction.

Description ALOX5 gene spans a region of 71,88 kb and has 14 exons, the sizes being 192, 199, 82, 123, 107, 173, 147, 204, 87, 179, 122, 101, 171 and 606 bps. ALOX5 gene has 5 CpG islands and 3' end of the gene for cellular modulator of immune recognition (c-MIR). Transcription ALOX5 gene promoter (H. sapiens) lacks the TATA box and has eight GC- boxes within 180 bp from the major transcription initiation site (at-65 in relation to ATG), five of which are in tandem (-176 to - 147). Consensus-binding sites for the transcription factor serum protein 1 (SP1), and early growth-response protein 1(EGR-1) exists in this region. A Vitamin D receptor binding site has been located in a positive regulatory region (-779 to -229) of the ALOX5 promoter. Several other consensus-binding sites for transcription factors such as GATA, glucocorticoid receptors and NFKB also exist. DNA methylation and histone deacetylase are also strongly involved in ALOX5 expression.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 562 Pseudogene No pseudogenes have been reported for ALOX5. Protein

Note The ALOX5 gene encodes a member of the lipoxygenase gene family, 5-LOX, which catalyzes the synthesis of leukotrienes (LT) from arachidonic acid. Leukotrienes are responsible for a series of inflammatory and allergic conditions. 5-LOX is also unique in requiring the 5-LOX activating protein (FLAP), a nuclear trans-membrane protein that plays an essential role in the transfer of arachidonic acid to 5-LOX. FLAP can also bind to MK-886, a compound that blocks LT biosynthesis. Description 5-LOX is a 77.9 kDa protein consisting of 673 amino acids. The enzyme requires calcium, iron and ATP as cofactors. The enzyme activity is also stimulated by the presence of microsomal membranes and trace amounts of lipid hydroperoxides. The protein has a catalytic domain and a regulatory domain. The regulatory domain, which controls leukotriene synthesis and binds calcium, nucleotides and phospholipids also has a PLAT (Polycystin-1, Lipoxygenase, alpha-Toxin) domain. Expression 5-LOX protein is expressed in bone marrow derived cells such as monocytes/macrophages, mast cells, B-lymphocytes, polymorphonuclear leukocytes, dendritic cells and foam cells of human atherosclerotic tissues, as well as spleen, thymus brain, spinal cord, skeletal muscle, pancreas, prostate, kidney and lung in humans. Localisation Subcellular location of 5-LOX protein is the cytoplasm or nucleoplasm. 5-LOX is largely cytosolic in resting peritoneal macrophages, monocytes, neutrophils, monocytes and eosinophils. By contrast, alveolar macrophages and mast cells contain cytosolic and intranuclear fractions of the enzyme. Leukotriene synthesis capacity is determined by a calcium independent nuclear import of 5-lipoxygenase. Three nuclear localization sequence (NLS) exist, Leu-111 to Asp-121; Asp-156 to Asp-166 and Val-514 to Leu-535. Function 5-LOX, a monomeric enzyme, catalyzes the conversion of arachidonic acid to 5(S)-hydroperoxy-6-trans-8, 11, 14-cis-eicosatetraenoic acid (5(S)-HETE), and further dehydration to the allylic epoxide 5(S)-trans- 7,9-trans-11,14-cis-eicosatetrenoic acid (leukotriene A4). The LTA4 intermediate is then converted to LTB4 by LTA4 hydrolase. LTB4 attracts leukocytes and are important for the inflammatory response. 5-LOX migrates to the nuclear membrane upon cellular activation leading to LTB4 biosynthesis. This function depends on calcium dependent binding of the N-terminal C2 domain of 5-LOX to phospholipids resulting in the release of fatty acid substrates for enzyme action. Phosphorylation of 5-LOX on Ser-271 by MAPK-activating protein (MAPKAP) kinase 2, Ser-663 by extracellular signal-regulated kinases (ERK-2) and Ser-523 by protein kinase A (PKA) catalytic subunit has been shown to stimulate 5-LOX activity.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 563 In addition, overexpression of 5-LOX was shown to promote senescence-like growth arrest in human and mouse embryo fibroblasts via a p53/p21-dependent pathway, by regulating reactive oxygen species production, independent of telomerase activity. Thus, a senescence-like growth arrest may be of significance in the pathogenesis of 5-LOX-associated disorders. Homology C. familiaris: LOC477753, similar to Arachidonate 5-lipoxygenase R. norvegicus: ALOX5, arachidonate 5-lipoxygenase M. musculus: ALOX5, arachidonate 5-lipoxygenase A. thaliana: AT3G22400 iron ion binding / lipoxygenase O. sativa: OSJNBb0017F17.2, putative lipoxygenase Mutations Note A family of mutations in the G+C-rich transcription factor binding region of ALOX5 has been identified in which several Sp1 and Egr-1 binding motifs are altered in the region of 176 to 147 bp upstream from the ATG translation start site. These mutations alter transcription factor binding and may play a role in 5-LOX gene expression in vivo. A haplotype containing polymorphisms in a negative regulatory region of the ALOX5 promoter (G-1752A and G-1699A) may influence colon cancer risk in Caucasians. In addition, the genetic variant of tandem repeat (GGGCGG; Sp1-binding motif) in ALOX5 promoter in group of Korean aspirin intolerant asthma patients has been associated with the severity of airway hyper-responsiveness. Implicated in Entity Esophageal cancer Disease Immunohistochemistry analyses of 5-LOX expression in 161 esophageal tissue indicated that the enzyme was expressed in 79% (127/161) of cancer tissues but in only 13% (4/32) of normal esophageal mucosa. 5-LOX was also expressed in 8 esophageal cancer cell lines examined. In addition, 5-LOX inhibitors AA861 and REV5901 increased cell viability and apoptosis in the esophageal cancer cell lines.

Entity Pancreatic cancer Disease 5-LOX expression is upregulated human pancreatic cancer cells. The 5-LOX metabolite 5(S)-HETE was shown to stimulate proliferation, as well as the proliferation of the mitogenic intracellular tyrosine kinases, MEK/ERK and PI3 kinase/AKT.

Entity Colorectal cancer Disease Exposure to cigarette smoke extract (CSE) was shown to enhance 5- LOX protein expression in the inflammation-associated colonic adenomas. The effects of CSE on colon cancer cells were mediated by 5-LOX DNA demethylation. In addition, an up-regulation of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor

Atlas Genet Cytogenet Oncol Haematol 2006; 4 564 (VEGF), key angiogenic factors for tumorigenesis, were also observed. These effects were reversed by treating the colon cancer cells with dual 5-LOX and COX-2 inhibitors.

Entity Atherosclerosis Disease 5-LOX, known to generate proinflammatory LTs, is highly expressed in the arterial walls of atherosclerotic patients, with the number of enzyme expressing lesion leukocytes increasing during disease progression. All constituents of the 5-LOX pathway are significantly expressed in human diseased arteries, thereby supporting a model of atherogenesis, whereby 5-LOX pathway dependent inflammatory circuits composed of leukocytes, smooth muscle cells and endothelial cells evolve within blood vessels during late stages of lesion development.

Entity Asthma Disease LTs and their receptors play an important role in the pathogenesis of asthma. Th2 cytokines, interleukins-4 and -13 can upregulate cysteinyl leukotriene 1 receptor expression. In addition, cysteinyl LTs favour an allergic phenotype by upregulating type 2 cytokine expression and decreasing type 1 cytokine expression. Polymorphisms of the 5-LOX promoter have also been associated with the development of asthma.

Entity Immune response and tissue homeostasis Note The products of the ALOX5 pathway, particularly LTs, are lipid messengers that act on the immune response system and tissue homeostasis. Their abnormal production can induce several diseases such as asthma, inflammation, atherosclerosis, basophilic leukaemia, oedema, exercise-induced asthma, anaphylaxis, psoriasis, bronchial spasms and allergic rhinitis. Oncogenesis Alterations in the 5-LOX pathway can result in the aberrant formation of its products, hydroxyeicosatetraenoic acids or leukotrienes. This can, in turn, increase cellular proliferation and survival and suppress apoptosis of human cells and thereby play a significant role in human carcinogenesis.

External links Nomenclature Hugo ALOX5 GDB ALOX5 Entrez_Gene ALOX5 240 arachidonate 5-lipoxygenase Cards Atlas ALOX5ID42985ch10q11 GeneCards ALOX5

Atlas Genet Cytogenet Oncol Haematol 2006; 4 565 Ensembl ALOX5 Genatlas ALOX5 GeneLynx ALOX5 eGenome ALOX5 euGene 240 Genomic and cartography ALOX5 - 10q11.2 chr10:45189635-45261567 + 10q11.21 GoldenPath (hg18-Mar_2006) Ensembl ALOX5 - 10q11.21 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ALOX5 Gene and transcription Genbank AB208946 [ ENTREZ ] Genbank AK225603 [ ENTREZ ] Genbank BC034464 [ ENTREZ ] Genbank BC040450 [ ENTREZ ] Genbank BQ003253 [ ENTREZ ] RefSeq NM_000698 [ SRS ] NM_000698 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_033985 [ SRS ] NT_033985 [ ENTREZ ] AceView ALOX5 AceView - NCBI TRASER ALOX5 Traser - Stanford Unigene Hs.89499 [ SRS ] Hs.89499 [ NCBI ] HS89499 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P09917 [ SRS] P09917 [ EXPASY ] P09917 [ INTERPRO ] PS00711 LIPOXYGENASE_1 [ SRS ] PS00711 Prosite LIPOXYGENASE_1 [ Expasy ] PS00081 LIPOXYGENASE_2 [ SRS ] PS00081 Prosite LIPOXYGENASE_2 [ Expasy ] Prosite PS50095 PLAT [ SRS ] PS50095 PLAT [ Expasy ] IPR008976 Lipase_LipOase [ SRS ] IPR008976 Lipase_LipOase [ Interpro EBI ] Interpro IPR000907 LipOase [ SRS ] IPR000907 LipOase [ EBI ] Interpro IPR001024 LipOase_LH2 [ SRS ] IPR001024 LipOase_LH2 [ EBI ] IPR001885 Mammal_lipOase [ SRS ] IPR001885 Interpro Mammal_lipOase [ EBI ] CluSTr P09917 Pfam PF00305 Lipoxygenase [ SRS ] PF00305 Lipoxygenase [ Sanger

Atlas Genet Cytogenet Oncol Haematol 2006; 4 566 ] pfam00305 [ NCBI-CDD ] PF01477 PLAT [ SRS ] PF01477 PLAT [ Sanger ] pfam01477 [ Pfam NCBI-CDD ] Smart SM00308 LH2 [EMBL] Blocks P09917 HPRD P09917 Protein Interaction databases DIP P09917 IntAct P09917 Polymorphism : SNP, mutations, diseases OMIM 152390;600807 [ map ] GENECLINICS 152390;600807 SNP ALOX5 [dbSNP-NCBI] SNP NM_000698 [SNP-NCI] SNP ALOX5 [GeneSNPs - Utah] ALOX5] [HGBASE - SRS] HAPMAP ALOX5 [HAPMAP] General knowledge Family ALOX5 [UCSC Family Browser] Browser SOURCE NM_000698 SMD Hs.89499 SAGE Hs.89499 1.13.11.34 [ Enzyme-SRS ] 1.13.11.34 [ Brenda-SRS ] 1.13.11.34 Enzyme [ KEGG ] 1.13.11.34 [ WIT ] arachidonate 5-lipoxygenase activity[Amigo] arachidonate 5- Amigo lipoxygenase activity[EGO-EBI] Amigo iron ion binding[Amigo] iron ion binding[EGO-EBI] Amigo calcium ion binding[Amigo] calcium ion binding[EGO-EBI] Amigo protein binding[Amigo] protein binding[EGO-EBI] Amigo electron transport[Amigo] electron transport[EGO-EBI] Amigo inflammatory response[Amigo] inflammatory response[EGO-EBI] Amigo lipoxygenase activity[Amigo] lipoxygenase activity[EGO-EBI] Amigo oxidoreductase activity[Amigo] oxidoreductase activity[EGO-EBI] Amigo leukotriene biosynthesis[Amigo] leukotriene biosynthesis[EGO-EBI] BIOCARTA Eicosanoid Metabolism [Genes] KEGG Prostaglandin and Leukotriene Metabolism PubGene ALOX5 Other databases Probes

Atlas Genet Cytogenet Oncol Haematol 2006; 4 567 Probe ALOX5 Related clones (RZPD - Berlin) PubMed PubMed 68 Pubmed reference(s) in LocusLink Bibliography Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. In KH, Asano K, Beier D, Grobholz J, Finn PW, Silverman EK, Silverman ES, Collins T, Fischer AR, Keith TP, Serino K, Kim SW, De Sanctis GT, Yandava C, Pillari A, Rubin P, Kemp J, Israel E, Busse W, Ledford D, Murray JJ, Segal A, Tinkleman D, Drazen JM. J Clin Invest 1997; 99(5): 1130-1137. Medline 9062372

Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Silverman ES, Du J, De Sanctis GT, Radmark O, Samuelsson B, Drazen JM, Collins T. Am J Respir Cell Mol Biol 1998; 19(2): 316-323

Mutations in the human 5-lipoxygenase gene. In KH, Silverman ES, Asano K, Beier D, Fischer AR, Keith TP, Serino K, Yandava C, De Sanctis GT, Drazen JM. Clin Rev Allergy Immunol 1999; 17(1-2): 59-69. Medline 10436859

The Discovery of the Leukotrienes. Samuelsson, B. Am J Respir Crit Care Med. 2000; 161 (2 Pt 2): S2-6. Medline 10673217

Extracellular signal-regulated kinases phosphorylate 5-lipoxygenase and stimulate 5-lipoxygenase product formation in leukocytes. Werz O, Burkert E, Fischer L, Szellas D, Dishart D, Samuelsson B, Radmark O, Steinhilber D. FASEB J 2002; 16(11): 1441-1443. Medline 12205041

Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). Werz O, Szellas D, Steinhilber D, Radmark O. J Biol Chem 2002; 277(17): 14793-14800. Medline 11844797

Extending the understanding of leukotrienes in asthma. Coffey M, Peters-Golden M.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 568 Curr Opin Allergy Clin Immunol 2003; 3(1): 57-63. Medline 12582316

Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer. Ding XZ, Tong WG, Adrian TE. Oncology 2003; 65(4): 285-294. Medline 14707447

Trichostatin A and structurally related histone deacetylase inhibitors induce 5- lipoxygenase promoter activity. Klan N, Seuter S, Schnur N, Jung M, Steinhilber D. Biol Chem 2003; 384(5): 777-785. Medline 12817474

Nuclear localization of 5-lipoxygenase as a determinant of leukotriene B4 synthetic capacity. Luo M, Jones SM, Peters-Golden M, Brock TG. Proc Natl Acad Sci U S A 2003; 100(21): 12165-12170. Medline 14530386

5-lipoxygenase and FLAP. Peters-Golden M, Brock TG. Prostaglandins Leukot Essent Fatty Acids 2003; 69(2-3): 99-109. Medline 12895592

Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K, Moos MP, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kuhn H, Radmark O, Samuelsson B, Habenicht AJ. Proc Natl Acad Sci U S A 2003; 100(3): 1238-1243. Medline 12552108

DNA methylation regulates 5-lipoxygenase promoter activity. Uhl J, Klan N, Rose M, Entian KD, Werz O, Steinhilber D. Adv Exp Med Biol 2003; 525: 169-172. Medline 12751760

Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk. Goodman JE, Bowman ED, Chanock SJ, Alberg AJ, Harris CC. Carcinogenesis 2004; 25(12): 2467-2472. Medline 15308583

Protein kinase A inhibits leukotriene synthesis by phosphorylation of 5-

Atlas Genet Cytogenet Oncol Haematol 2006; 4 569 lipoxygenase on serine 523. Luo M, Jones SM, Phare SM, Coffey MJ, Peters-Golden M, Brock TG. J Biol Chem 2004; 279(40): 41512-41520. Medline 15280375

Multiple nuclear localization sequences allow modulation of 5-lipoxygenase nuclear import. Luo M, Pang CW, Gerken AE, Brock TG. Traffic 2004; 5(11): 847-854. Medline 15479450

Contributory role of 5-lipoxygenase and its association with angiogenesis in the promotion of inflammation-associated colonic tumorigenesis by cigarette smoking. Ye YN, Liu ES, Shin VY, Wu WK, Cho CH. Toxicology 2004; 203(1-3): 179-188. Medline 15363593

Structural organization of the regulatory domain of human 5-lipoxygenase. Allard JB, Brock TG. Curr Protein Pept Sci 2005; 6(2): 125-131. Medline 15853649

5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS- dependent p53 activation. Catalano A, Rodilossi S, Caprari P, Coppola V, Procopio A. EMBO J 2005; 24(1): 170-179. Medline 15616590

GC-rich sequences in the 5-lipoxygenase gene promoter are required for expression in Mono Mac 6 cells, characterization of a novel Sp1 binding site. Dishart D, Schnur N, Klan N, Werz O, Steinhilber D, Samuelsson B, Radmark O. Biochim Biophys Acta 2005; 1738(1-3): 37-47. Medline 16413224

Stress-induced nuclear export of 5-lipoxygenase. Hanaka,H., Shimizu,T. and Izumi,T. Biochem. Biophys. Res. Commun 2005; 338(1): 111-116. Medline 16165096

Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention. Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S, Zhang H, Cao L, Ajani JA, Xu XC. Carcinogenesis 2005; 26(4): 785-791. Medline 15661803

Atlas Genet Cytogenet Oncol Haematol 2006; 4 570

Polymorphism of tandem repeat in promoter of 5-lipoxygenase in ASA- intolerant asthma: a positive association with airway hyperresponsiveness. Kim SH, Bae JS, Suh CH, Nahm DH, Holloway JW, Park HS. Allergy 2005; 60(6): 760-765. Medline 15876305

The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis. Lotzer K, Funk CD, Habenicht AJ. Biochim Biophys Acta 2005; 1736(1): 30-37. Medline 16081317

Regulation of 5-lipoxygenase enzyme activity. Radmark O, Samuelsson B. Biochem Biophys Res Commun 2005; 338(1): 102-110. Medline 16122704

Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke. Ye YN, Wu WK, Shin VY, Bruce IC, Wong BC, Cho CH. Carcinogenesis 2005; 26(4): 827-834. Medline 15637091

5-Lipoxygenase-activating protein homodimer in human neutrophils: evidence for a role in leukotriene biosynthesis. Plante H, Picard S, Mancini J, Borgeat P. Biochem J 2006; 393(Pt 1): 211-218. Medline 16144515

Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong CH, Hedin U, Swedenborg J, Hansson GK, Samuelsson B, Paulsson-Berne G, Haeggstrom JZ. Proc Natl Acad Sci U S A 2006; 103(21): 8161-8166. Medline 16698924

Analysis of the 5-lipoxygenase promoter and characterization of a vitamin D receptor binding site. Sorg BL, Klan N, Seuter S, Dishart D, Radmark O, Habenicht A, Carlberg C, Werz O, Steinhilber D. Biochim Biophys Acta 2006; 1761(7): 686-697. Medline 16750418

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications

Atlas Genet Cytogenet Oncol Haematol 2006; 4 571 BiblioGene - INIST Contributor(s) Written 07- Sreeparna Banerjee, Seda Tuncay 2006 Citation This paper should be referenced as such : Banerjee S, Tuncay S . ALOX5 (Arachidonate 5-Lipoxygenase).. Atlas Genet Cytogenet Oncol Haematol. July 2006 . URL : http://AtlasGeneticsOncology.org/Genes/ALOX5ID42985ch10q11.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 572 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(1;5)(q22;q33) Clinics and Pathology Disease Myeloproliferative disorders (MPD) with eosinophilia (or chronic eosinophilic leukemia (CEL)) and B-cell acute lymphoblastic leukaemia (ALL) Epidemiology 4 cases of MPD with eosinophilia, and 1 case of ALL; because the phenotypes are different, it may be that genes involved in this/these disease(s) are not similar; PDE4DIP and PDFRGB were found involved in MPD with eosinophilia (see below). Clinics MPD cases were found in 3 infants (aged 5, 7, and 11 mths), and one young adult, aged 21 yrs; sex ratio was 1/1. The ALL case was a 13 yr old boy. Prognosis One MPD case died 9 mths after diagnosis, another one was alive at 14 mths+, one was alive and well 7 yrs after diagnosis with IFN therapy, and one was found resistant to various treatments, including IFN therapy, until -because PDGFRB was found to be involved in the disease- imatinib was started and remission obtained. The ALL case experienced difficult remission, relapse, BM transplantation, CNS relapse; the parents finally refused further therapy and the patient died. Cytogenetics Additional Sole anomaly in each case. anomalies Genes involved and Proteins Gene PDE4DIP (phosphodiesterase 4D interacting protein). Name Note 1q22 Protein PDE4DIP codes for a protein called myomegalin; interacts with the cyclic nucleotide phosphodiesterase PDE4D; there are at least 2 isoforms of myomegalin: KIAA0454 isoform and KIAA0477 isoform Gene PDGFRB Name Location 5q33 Protein PDGFRB is the receptor for PDGFB (platelet-derived growth factor-b); Ig like, transmembrane and tyrosine kinase domains; membrane tyrosine kinase; can homodimerize Result of the chromosomal anomaly Hybrid gene Description 5' PDE4DIP - 3' PDGFRB; PDE4DIP (KIAA0477 isoform) fuses in frame

Atlas Genet Cytogenet Oncol Haematol 2006; 4 573 PDGFRB exon 11 Transcript The reciprocal PDGFRB-PDE4DIP is not expressed

Fusion Protein Description The first 905 amino acids of PDE4DIP, including the coiled-coil domains are fused to the transmembrane and the tyrosine kinase domains of PDGFRB.

External links Other t(1;5)(q22;q33) Mitelman database (CGAP - NCBI) database Other t(1;5)(q22;q33) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography A myeloproliferative disease in two infants associated with eosinophilia and chromosome t(1;5) translocation. Darbyshire PJ, Shortland D, Swansbury GJ, Sadler J, Lawler SD, Chessells JM. Br J Haematol. 1987; 66: 483-486. Medline 3663504 t(1;5)(q23;q33) in a patient with high-risk B-lineage acute lymphoblastic leukemia. Barriga F, Bertin P, Legues E, Risueno C, Andrade W, Cabrera E, Grebe G. Cancer Genet Cytogenet. 1996; 87: 4-6. Medline 8646739

AlphaIFN-induced hematologic and cytogenetic remission in chronic eosinophilic leukemia with t(1;5). Luciano L, Catalano L, Sarrantonio C, Guerriero A, Califano C, Rotoli B. Haematologica. 1999; 84: 651-653. Medline 10406909

Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, Onuffer J, Jin SL, Conti M. J Biol Chem. 2001; 276: 11189-11198. Medline 11134006

Atlas Genet Cytogenet Oncol Haematol 2006; 4 574 Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Wilkinson K, Velloso ER, Lopes LF, Lee C, Aster JC, Shipp MA, Aguiar RC. Blood. 2003; 102: 4187-4190. Medline 12907457

Contributor(s) Written 04- Jean Loup Huret 2006 Citation This paper should be referenced as such : Huret JL . t(1;5)(q22;q33). Atlas Genet Cytogenet Oncol Haematol. April 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0105q22q33ID1115.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 575 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(12;17)(p13;q11-21) in ALL Clinics and Pathology Disease Acute lymphoblastic leukaemia (ALL) Note Identical or similar translocations have been reported rarely in acute myeloid leukemia (AML) and acute mixed lineage leukaemia ( t(12;17)(p13;q11-21) in AML ). Phenotype / Most reports indicate an early pre-B immunophenotype, frequently cell stem characterised by low CD10 and positivity of the myeloid marker CD33. origin Epidemiology Rare; non-random translocation that predominantly occurs in children and young adults. No definable sex bias. Prognosis Early reports suggested that prognosis may be poor, but there are currently too few reported cases to define a robust association. Cytogenetics Cytogenetics The chromosome 17q breakpoint has been defined in different reports Morphological to be between q11-q21. The chromosome 12 breakpoint has been confirmed to be located in 12p13 telomeric to the ETV6/TEL locus. The translocation occurs as the sole or primary event in approximately 50% of cases Additional No consistent picture and only +21 has been reported in more than anomalies one case. Genes involved and Proteins Note Breakpoint on 12p13 telomeric to TEL. Currently the genes involved on both chromosome 12 and 17 are unidentified.

To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography t(12;17)(p13;q21) in early pre-B acute lymphoid leukemia. Krance RA, Raimondi SC, Dubowy R, Estrada J, Borowitz M, Behm F, Land VJ, Pullen J, Carroll AJ. Leukemia 1992 ;6 :251-255. Medline 1534130

Translocation (12;17)(p11-12;q11-12): a recurrent primary rearrangement in acute leukemia.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 576 Liu HW, Wan SK, Ching LM, Liang R, Chan LC. Cancer Genet Cytogenet 1992; 64: 27-29. (REVIEW) Medline 1458446

Fluorescence in situ hybridization analysis of the cryptic t(12;21) (p13;q22) in childhood B-lineage acute lymphoblastic leukemia. Yehuda-Gafni O, Cividalli G, Abrahmov A, Weintrob M, Neriah SB, Cohen R, Abeliovich D. Cancer Genet Cytogenet 2002; 132: 61-64. Medline 11801311

A t(12;17)(p13;q12) identifies a distinct TEL rearrangement-negative subtype of precursor-B acute lymphoblastic leukemia. Reid AG, Seppa L, von der Weid N, Niggli FK, Betts DR. Cancer Genet Cytogenet 2006; 165: 64-69. Medline 16490598

Contributor(s) Written 04- David Betts 2006 Citation This paper should be referenced as such : Betts D . t(12;17)(p13;q11-21) in ALL. Atlas Genet Cytogenet Oncol Haematol. April 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t1217p13q21ALLID1072.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 577 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(11;12)(p15;p13) Identity Note t(11;12)(p15;p13) should be the recurrent translocation; however, the only known case was in fact a variant/complex t(11;21;12)(p15;p13;p13) Clinics and Pathology Disease Acute megakaryoblastic leukemia (AML -M7) Epidemiology So far only 1 case known, an infant case. However, the translocation might be missed using conventional banding techniques, and therefore additional cases might exist. Prognosis Remains in complete remission for at least 5 years Cytogenetics Cytogenetics Not visible with conventional banding techniques alone: misdiagnosed Morphological as add(11)(p15) and der(21)(t(11;21)(p15;p13). Chromosome 12 was cytogenetically normal by conventional banding techniques and only identified as a partner in this translocation after FISH. Variants t(11;21;12)(p15;p13;p13). A t(11;12)(p15;p13), resulting in the same fusion product, might also exist, but none have been identified so far. Genes involved and Proteins Gene NUP98 Name Location 11p15 Protein 920 amino acids; 97 kDa; contains repeated motifs (GLFG and FG) in N-term and a RNA binding motif in C-term Gene JARID1A Name Location 12p13 Protein 1722 amino acids; 196 kD; retinoblastoma binding protein 2 Result of the chromosomal anomaly Hybrid gene Description In-frame fusion of the first 13 exons of NUP98 to exons 28-31 of JARID1A Transcript 5' NUP98- 3' JARID1A Detection FISH: BAC clones RP11-348A20 (NUP98) and RP11-283I3 (spanning JARID1A exon 11-31) colocalize.

Fusion Protein

Atlas Genet Cytogenet Oncol Haematol 2006; 4 578

Schematic representation of the fusion NUP98-JARID1A. From up to down: NUP98, JARID1A and the putative chimeric NUP98-JARID1A structure. FG-repeats, phenylalanine-glycine repeats; JMJ, Jumonji domains; ARID, AT-rich interaction domain; PHD, plant homeodomain fingers or LAP domains. The arrow indicates the position of the fusion.

Description The NUP98-JARID1A fusion protein contains the Phe-Gly (FG) repeats of the N-terminal part of NUP98. The JARID1A sequence starting with exon 28 still contains the sequence encoding the C-terminal PHD domain

External links Other t(11;12)(p15;p13) Mitelman database (CGAP - NCBI) database Other t(11;12)(p15;p13) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. van Zutven LJ, Onen E, Velthuizen SC, van Drunen E, von Bergh AR, van den Heuvel-Eibrink MM, Veronese A, Mecucci C, Negrini M, de Greef GE, Beverloo HB Genes Chromosomes Cancer 2006; 45: 437-446. Medline 16419055

Atlas Genet Cytogenet Oncol Haematol 2006; 4 579 Contributor(s) Written 04- Laura J.C.M. van Zutven, H. Berna Beverloo 2006 Citation This paper should be referenced as such : van Zutven LJCM, Beverloo H.B . t(11;12)(p15;p13). Atlas Genet Cytogenet Oncol Haematol. April 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t1112p15p13ID1428.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 580 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Trisomy 2 Identity

GTG-banded partial karyotype showing 47,XY,+2

Clinics and Pathology Note Trisomy 2 (+2) is a rare yet recurrent finding in myelodysplastic syndrome (MDS) but occurs more frequently in acute myeloid leukaemia(AML) in combination with other chromosomal abnormalities. It is a recognised chromosomal change in other neoplasms, in particular hepatoblastomas and has been described in fibrous dysplasia, pleuropulmonary blastoma, proliferative myositis, nasopharyngeal carcinoma and proliferative fascitis. As the sole abnormality, it has been associated with post-transplant lymphoproliferative disorders (PTLD). Isolated trisomy 2 has been reported in 4 cases of MDS and in two patients with MDS transforming to AML . These cases account for the following stages of MDS refractory anaemia (RA), RA with excess blasts (RAEB), RA with excess blasts in transformation (RAEB-t) and chronic myelomonocytic leukaemia (CMML). It has been suggested that the presence of trisomy 2 in MDS is an early genetic event that, in combination with other chromosomal changes, may give rise to AML. All of the reported cases appear to be mosaic in nature, and thus its true incidence may be higher. Further case reports are needed to ascertain the effect of trisomy 2 at clinical presentation in both MDS and AML, its association with progression of MDS to AML and prognostic significance. It has also been suggested that the presence of trisomy 2 may be age- related. Trisomy 2 has been observed in in vitro senescent lymphocytes in elderly patients ranging in age from 70-100 years. All the published cases of trisomy 2 as a sole abnormality in MDS fall within this age range and thus the possibility that the presence of trisomy 2 may be an age-related phenomenon cannot be excluded.

Prognosis Trisomy 2 may define a distinct subtype of MDS, which in combination with further clonal chromosomal changes gives rise to AML. Further cases need to be collated to substantiate this. Cytogenetics

Atlas Genet Cytogenet Oncol Haematol 2006; 4 581 Note The patient is a 73-year-old Asian male with rheumatoid arthritis, ischaemic heart disease, benign prostate hyperplasia and b- thalassaemia trait who presented with severe anaemia. Patient's blood film showed erythrocyte anisocytosis and poikilocytosis, platelet anisocytosis and dysplastic neutrophils. Blood counts showed: haemoglobin 9.4 g/dL, white cell count 6.8x109/L and platelet count 98x109/L. Bone marrow aspirate was hypercellular with trilineage dysplasia and 18% myeloblasts, consistent with MDS, WHO category ³refractory anaemia with excess blasts (RAEB-II)². Chromosome analysis on bone marrow cells showed: 47,XY,+2[5]/46,XY[13]. To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Trisomy 2 in proliferative fascitis. Dembinski A, Bridge JA, Berger C, Sandberg AA. Cancer Genet Cytogenet 1992; 60: 27-30. Medline 1591703

Cytogenetic studies in 112 cases of untreated myelodysplastic syndromes Sole F, Prieto F, Badia L, Woessner S, Florensa L, Caballin R, Coll MD, Besses C, Sana-Sabrafen J. Cancer Genet Cytogenet 1992; 64: 12-20. Medline 1458444

Cytogenetic studies in 3 xenografted nasopharyngeal carcinomas. Bernheim A, Rousselet G, Massaud L, Busson P, Tursz T. Cancer Genet Cytogenet 1993; 66: 11-15. Medline 8467469

Trisomy 2 found in proliferative myositis cultured cell. Ohjimi Y, Iwasaki H, Ishiguro M, Isayama T, Kaneko Y. Cancer Genet Cytogenet 1994; 76: 157. Medline 7923069

Cytogenetic analysis in patients with primary myelodysplastic syndromes in leukaemic transformation. Group Francais de Cytogenetique Hematologique (GFCH). Hematol Cell Ther 1996; 38: 177-181. Medline 8931999

Pleuropulmonary blastoma:fluorescence in situ hybridization analysis indicating trisomy 2. Yang P, hasegawa T, Hirose T, Fukomoto T, Uyama T, Monden Y, Sano T.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 582 Am J Surgical Pathol 1997; 21: 854-859. Medline 9236843

Karyotypic analyses of hepatoblastoma. Report of two cases and review of the literature suggesting chromosomal loci responsible for the pathogenesis of this disease. Nagata T, Mugishima H, Shichino H, Suzuki T, Chin M, Koshinaga S, Inoue M, Harada K. Cancer Genet Cytogenet 1999; 114: 42-50. Medline 10526534

Recurrent chromosome aberrations in fibrous dyspplasia of the bone:a report of the CHAMP study group.Chromosomes and MorPHology. Dal Cin P, Sciot R, Brys P, De Wever I, Dorfman H, Fletcher CDM, Jonsson K, Mandahl N, Mertens F, Mitelman F,Rosai J,Rydholm A, Samson I, Tallini G, Van den Berghe H, Vanni R, Willan H. Cancer Genet Cytogenet 2000; 122: 30-32. Medline 11104029

Chromosome studies of in vitro senescent lymphocytes:non-random trisomy 2. Busson-Le Coniat M, Boucher N, Blanche H, Thomas G, Berger R. Ann Genet 2002; 45: 193-196. Medline 12668167

Mosaic trisomy 2 in myelodysplastic syndromes and acute myeloblastic leukaemia. Czepulkowski B, Saunders K, Pocock C, Sadullah S. Cancer Genet Cytogenet 2003;145: 78-81. Medline 12885468

Trisomy 2 as the sole karyotypic abnormality in a lymphoproliferative disorder post-liver transplant. Ferro Delgado MT, Garcia-Miguel P, Sordo MT, Villalon C, Leon A, Garcia-Sagredo JM, San Roman C. Cancer Genet Cytogenet 2005; 163: 184-185. Medline 16337866

Myelodysplastic syndrome associated with trisomy 2. Heller M, Provan D, Amess J, Dixon-McIver A. Clin Lab Haem 2005; 27: 270-273. Medline 16048496

Contributor(s) Written 04- Amanda Dixon-McIver 2006

Atlas Genet Cytogenet Oncol Haematol 2006; 4 583 Citation This paper should be referenced as such : Dixon-McIver A . Trisomy 2. Atlas Genet Cytogenet Oncol Haematol. April 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/Tri2ID1429.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 584 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(10;16)(q22;p13) Identity

G-band analysis. Partial karyotype showing the t(10;16)(q22;p13). Arrows indicate breakpoints in both chromosomes.

Clinics and Pathology Disease Acute myeloid leukaemia (AML) M4/M5a and therapy-related myelodysplastic syndromes (MDS). Epidemiology Very rare, only four cases described. Clinics There is no erythrophagocytosis associated Treatment Bad response to chemotherapy. Prognosis Poor. Cytogenetics

Fig2. FISH analysis. FISH using BACs RPCI-11 461A8 (green) and RPCI-11 95J11 (red) showing that the signal of 95J11, which covers the initial part of the CREBBP gene, is split between der(10) and der(16).

Additional First described in a 4-year-old girl with AML M5a with 47,XX,der(7) anomalies t(7;10)(p13;p11),+8,der(10)t(7;10)(p13;p11)t(10;16)(q22;p13),der(16)t(10;16)(q22;p13)

Atlas Genet Cytogenet Oncol Haematol 2006; 4 585 /46,XX. Later it was also described in an 84-year-old male without erythrophagocytosis and with this sole cytogenetic aberration. In addition, a variant breakpoint was described in a 52-year-old japanese woman with a therapy-related myelodysplastic syndrome (t-MDS) and also this sole translocation. Finally, another fusion variant was described in an AML-M4 female patient with the t(10;16) (q22;p13) and a t(11;17)(q23;q21). Variants There are no cytogenetic variants described, but there are molecular variants due to different breakpoints in the genes fused (see below). Genes involved and Proteins Gene MYST4 Name Location 10q22.2 Note This gene is also involved in rearrangements observed in uterine leiomyomata. 18 exons spanning 206.0 Kb. Transcription is from centromere to Dna / Rna telomere. Up to 7 alternative transcripts. Protein Histone acetyltransferase MYST4 is located probably in the nucleous. And it is probably involved in both positive (N-terminus) and negative (C-terminus) regulation of transcription, maybe involved in cerebral cortex development, required for RUNX2-dependent transcriptional activation and ubiquitously expressed in adult human tissues. Gene CREBBP Name Location 16p13.3 Note This gene is also involved in t(8;16)(p11;p13) with MYST3. CREBBP fusion observed in M4 ANLL and therapy related AML; t(11;16)(q23;p13) . with MLL CREBBP fusion observed also in therapy related. Mutations of CREBBP are associated with Rubinstein-Taybi syndrome. Up to 32 exons spanning 154,14 Kb. Transcription is from centromere to Dna / Rna telomere and up to 3 alternative transcripts between 8,0 and 8,7 Kb. Protein CREBBP is a wide expression histone acetyltransferase enzyme which locates in the nucleous. Function binds specifically to the DNA-binding protein CREB connecting it to the basal transcriptional machinery. Also acetylates non-histone proteins, like NCOA3 coactivator. It has an essential role in embryogenesis, cell differentiation, apoptosis, and proliferation and it is involved in the regulation of cell cycle during G1/S transition. Result of the chromosomal anomaly Hybrid gene Description Fusion in-frame between MYST4 exon 17 and CREBBP exon 3. Variants fusing MYST4 exon 16 and CREBBP exon 5; MYST4 exon 17 and CREBBP exon 7 have also been described.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 586 Transcript 5' MYST4-CREBBP 3' Detection CREBBP-MYST4 has been also detected.

Fusion Protein

Schematic representation of the fusion MYST4-CREBBP consequence of the t(10;16)(q22;p13). From up to down: MYST4 and CREBBP structures. H15 domain: domain in histone families 1 and 5; PHD zinc fingers: plant homeodomain (PHD) with a C4HC3-type motif, this domain is widely distributed in eukaryotes and it has been found in many chromatin regulatory factors; MOZ_SAS family region: this region has been suggested to be homologous to acetyltransferases but this similarity is not supported by sequence analysis; KIX domain: bind domain for CBP and P300, this domain also binds to transactivation domains of other nuclear factors including Myb and Jun.

Description In all cases published to date the breakpoints occur in the acidic domain of MYST4 but at different locations of the CREBBP protein: in the nuclear receptor-binding domain, in a C/H rich domain or between this domain and the KIX domain. The putative MYST4-CBP chimaeric protein retains the part of MYST4 that encodes the zinc fingers, two nuclear localization signals (NLS1 and NLS2), the HAT domain, and a portion of the acidic domain, and most of the CBP protein, including its HAT domain. Oncogenesis MYST4 has a 60% identity and 66% similarity to MYST3. All the fusions involving this genes result in several fusion proteins that target the acidic domain of MYST3 and MYST4. The partner fusion partners share also functional regions. All the fusion proteins are suspected to be leukaemogenic as a consequence of aberrant histone acetylation and transcription regulation, due probably but not exclusively, to the concomitant presence of two HAT domains coming from the different partners.

External links Other t(10;16)(q22;p13) Mitelman database (CGAP - NCBI) database Other t(10;16)(q22;p13) CancerChromosomes (NCBI) database

Atlas Genet Cytogenet Oncol Haematol 2006; 4 587 To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Panagopoulos I, Fioretos T, Isaksson M, Samuelsson U, Billstrom R, Strombeck B, Mitelman F, Johansson B. Hum Mol Genet 2001; 10: 395-404. Medline 11157802

A novel fusion variant of the MORF and CBP genes detected in therapy-related myelodysplastic syndrome with t(10;16)(q22;p13). Kojima K, Kaneda K, Yoshida C, Dansako H, Fujii N, Yano T, Shinagawa K, Yasukawa M, Fujita S, Tanimoto M. Br J Haematol 2003; 120: 271-273. Medline 12542485 t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukaemia. Vizmanos JL, Larrayoz MJ, Lahortiga I, Floristan F, Alvarez C, Odero MD, Novo FJ, Calasanz MJ. Genes Chromosomes Cancer 2003; 36: 402-405. Medline 12619164

Contributor(s) Written 05- José Luis Vizmanos 2006 Citation This paper should be referenced as such : Vizmanos JL . t(10;16)(q22;p13). Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t1016q22p13ID1332.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 588 Atlas of Genetics and Cytogenetics in Oncology and Haematology

I(9q) in ALL Identity Other Isochromosome 9q in precursor B-cell acute lymphoblastic leukemia names

iso (9q) G- banding - Courtesy of Andrew Carroll

Clinics and Pathology Disease Precursor B-cell lymphoblastic leukemia Phenotype / The cell of origin is thought to be a precursor B-lymphoblast. These cell stem cells are positive for terminal deoxynucleotidyl transferase, CD19, origin cytoplasmic CD79a, CD10, CD24. Variable expression for CD20 and CD22 may be seen. The myeloid lineage markers CD13 and CD33 may also be expressed Etiology Isochromosomes are relatively unusual and include i(6p), i(7q), i(9q), and i(17q). Epidemiology Precursor B-cell lymphoblastic leukemia is primarily a disease of children with most cases occurring before the age of six. Approximately 3000 new cases of lymphoblastic leukemia were reported in the United States in 2000. The presence of isochromosomes is a relatively unusual finding. In the few published studies available, isochromosomes occur in between 1- 4% of call cases of lymphoblastic leukemia, and were most commonly associated with a precursor B-cell immunophenotype. The most commonly seen isochromosome is i(9q), followed closely by i(17q), and i(7q). Clinics The presenting features of lymphoblastic leukemia include evidence of bone marrow failure including anemia, thrombocytopenia, and leukopenia. The leukocyte count may be elevated, normal, or even decreased. Other signs and symptoms may include hepatosplenomegaly, lymphadenopathy, bone pain, and arthralgias. A small number of patients may present with lymphoblastic lymphoma.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 589 Isochromosome 9q is generally associated with patient age greater than 10 years and a pre-B cell immunophenotype. In a series of 28 patients with i(9q), patients ranged in age from 1 to 17 years (median age 8 years). Cytology Precursor B-cell lymphoblastic leukemia is a neoplasm composed of small to medium-sized blast cells with high nuclear to cytoplasmic ratios, moderately condensed to open chromatin pattern, and inconspicuous nucleoli

Top: Peripheral blood smear stained with Wright's Giemsa stain obtained from a patient harboring an isochromosome 9q demonstrating a lymphocytosis. Numerous lymphoblasts characterized by high nuclear-cytoplasmic ratios, an open chromatin pattern, and nucleoli are present. This smear also demonstrates profound thrombocytopenia and neutropenia. Bottom Bone marrow biopsy section obtained from a patient with precursor B-cell lymphoblastic leukemia harboring an isochromosome

Atlas Genet Cytogenet Oncol Haematol 2006; 4 590 9q. Lymphoblasts have largely replaced the marrow space usually occupied with numerous myeloid and erythroid precursors.

Pathology The cells of lymphoblastic lymphoma may demonstrate a range of sizes. They may vary from small round cells with high nuclear- cytoplasmic ratios to larger cells with more cytoplasm (usually blue to grey-blue cytoplasm). Nuclear chromatin is usually uncondensed. Nucleoli are generally inconspicuous. Treatment Treatment is divided in induction, consolidation, and maintenance chemotherapy. Three drug induction chemotherapy including vincristine, a steroid (e.g. dexamethasone), and L-asparaginase in conjunction with intrathecal therapy induces a complete remission rate greater than 95%. Daunorubicin may be added for high risk patients. Consolidation therapy may involve high-dose methotrexate, the same drugs used in induction, or other drug combinations. Maintenance therapy in most protocols typically involves the use of oral methotrexate (weekly) and daily oral mercaptopurine. Evolution Precursor B-cell lymphoblastic leukemia progresses quickly if left untreated; however, this disease is one of the most curable cancers with survival rates now at its all-time peak. Older and very young patients tend to have lower survival rates Prognosis The prognosis of B-cell lymphoblastic leukemia is excellent. The overall complete remission rate is approximately 95% in pediatric patients and around 70-75% for adults. Cytogenetics Note Several isochromosome anomalies are readily identified in childhood ALL. These include: formation of chromosomes i(6p), i(7q), i(9q), and i(17q). The i(9q) can be found as a sole anomaly or in combination with a number of different chromosome anomalies. Cytogenetics The i(9q) can be fairly well recognized with two copies of the long arm Morphological of chromosome 9 accompanied with the loss of the short arm of chromosome 9p thus resulting in an unbalanced anomaly loss of 9p and gain of 9q. Additional isochromosome 9q was found associated with other non-random anomalies chromosomal abnormalities including t(1;19)(q23;p13) (involving the PBX and E2A genes), a finding in 4 of 28 cases, and t(9;22)(q34;q11) (involving fusion of the BCR and ABL genes) in one case. In a series of ten Down syndrome patients, i(9q) was identified in 3 of 10 cases. Bibliography Clinical and biological characteristics of acute lymphocytic leukemia in children with Down syndrome Kalwinsky DK, Raimondi SC, Bunin NJ, Fairclough D, Pui CH, Relling MV, Ribeiro R, Rivera GK Am J Med Genet Suppl 1990; 7: 267-271

Isochromosome 9q in acute lymphoblastic leukemia: a new non-random

Atlas Genet Cytogenet Oncol Haematol 2006; 4 591 finding Shippey CA, Lawlor E, Secker-Walker LM Leukemia 1989; 3: 195-199

Isochromosomes in childhood acute lymphoblastic leukemia: a collaborative study of 83 cases Pui CH, Carrroll AJ, Raimondi SC, Schell MJ, Head DR, Shuster JJ, Crist WM, Borowitz MJ, Link MP, Behm FG, Steuber CP, Land VJ. Blood 1992; 79: 2384-2391

Isochromosomes in acute lymphoblastic leukemia: i(21q) is a significant finding Martineau M, Clark R, Farrell DM, Hawkins JM, Moorman AV, Secker-Walker LM Genes Chromosomes Cancer 1996; 17: 21-30

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995 Gaynon PS, Trigg ME, Heerema NA, et al. Leukemia 2000; 14: 2223-2230.

Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Schrappe M, Reiter A, Zimmermann M, et al. Leukemia 2000; 14: 2205-2222

Contributor(s) Written 05- Noel A. Brownlee, Patrick Koty, David H. Buss, Mark J. 2006 Pettenati Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2006; 4 592 Atlas of Genetics and Cytogenetics in Oncology and Haematology

+10 or trisomy 10 (solely) - updated Clinics and Pathology Disease Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), Acute Biphenotypic Leukemia, and myelodysplastic syndromes (MDS). Note Classification : Approximately 33 cases with isolated Trisomy 10 have been described. Over two-thirds of cases associated with this cytogenetic abnormality are AML-M0, M1, or M2; M2 is the most common AML variant in the FAB classification (one-third of cases). Trisomy 10 has been, however, described in all of the FAB variants except . Over half of the AML cases have been associated with CD7 expression. Twenty-one cases of AML (including one of our own cases) have been described in the literature. One case each of biphenotypic acute leukemia and eosinophilic leukemia with trisomy 10 have been described. Two cases (including one of our own cases) of high grade MDS (i.e. refractory anemia with excess blasts-2 (RAEB-2)) have been associated with isolated trisomy 10. When specified, most cases of ALL were of the Pre-B type. There have been eight cases of ALL with +10 as the sole abnormality. Phenotype / ALL cases are mostly pre B ALL; AML cases are M0, M1 or M2 AML, cell stem with, in most cases, a CD7+, CD33+ phenotype. origin Epidemiology The incidence of isolated trisomy 10 is less than 1% in acute leukemia. About sixty percent of the AML cases have been in males while the ALL cases have had a near equal male to female ratio. About half of the AML cases have been in patients of Oriental descent. AML cases have ranged in age from two to eighty years of age with a median age of fifty-four years. ALL cases with this cytogenetic abnormality are not strictly seen in the pediatric age range. Three cases (including one of our own cases) have been seen in the adult population. Clinics in ANLL cases: WBC: 20 X 109/l; high blast percentage, low haemoglobin. Prognosis About half of the AML cases and two-thirds of the ALL cases have had at least a one year survival after diagnosis. The average survival for AML cases has been 26 months while the ALL cases had a 19 month average survival. Genetics genes involved are unknown Cytogenetics

Result of the chromosomal anomaly

Atlas Genet Cytogenet Oncol Haematol 2006; 4 593 External links Other +10 or trisomy 10 (solely) Mitelman database (CGAP - NCBI) database To be noted

Bibliography Agar Culture and Chromosome Analysis of Eosinophilic Leukemia. Goldman J, Najfeld V, and Th'ng K. J Clin Path 1975; 28: 956-961. Medline 1206119

The Relationship Between Growth in Agar, Karyotype, and Prognosis in Acute Leukemia. Gustavsson A, Mitelman F, Olofsson T, and Olsson I. Scand J Haematol 1984 (32): 351-363. Medline 6585926

A Subset of Acute Nonlymphocytic Leukemia with Expression of Surface Antigen CD7-Morphologic, Cytochemical, Immunocytochemical and T-cell Receptor Gene Analysis on 13 Patients. Tien H, Wang C, Su I, Liu F, Wu H, Chen Y, Lin K, Lee S, and Shen M. Leuk Res 1990; 14(6): 515-523. Medline 1695699

Chromosomenaberrationen bei akuten Leukamien im Kindesalter: Analyse von 1009 Patienten. Lampert F, Harbott J, and Ritterbach J. Kliniknahe Grundlagenforschung 1991; 203(4): 311-318.

Morphologic, Immunologic, and Cytogenetic Studies in Acute Myeloid Leukemia Following Occupational. Cuneo A, Fagioli F, Pazzi I, Tallarico A, Previati R, Piva N, Carli G, Balboni M, and Castoldi G. Leuk Res 1992; 16: 789-796. Medline 1528067

Distinct Cytogenetic and Clinicopathologic Features in Acute Myeloid Leukemia after Occupational Exposure to Pesticides and Organic Solvents. Fagioli F, Cuneo A, Piva N, Carli M, Previati R, Balboni M, Tomasi P, Cariani D, Scapoli G, and Castoldi G. Cancer 1992; 170(1): 77-85.

Hyperdiploid (47-50) Acute Lymphoblastic Leukemia in Children. Raimondi S, Roberson P, Pui C, Behm F, and Rivera G. Blood 1992; 79(12): 3245-3252.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 594 Medline 1596566

In Situ Hybridization to Interphase Nuclei in Acute Leukemia Romana S, Cherif D, Coniat M, Derre J, Flexor M, and Berger R. Genes Chr & Cancer 1993; 8: 98-103. Medline 7504523

Clonal Analysis of Progenitor Cells by Interphase Cytogenetics in Patients with Acute Myeloid Leukemia and Myelodysplasia. Van der Lely, Poddighe P, Wessels J, Hopman A, Geurts van Kessel A, and De Witte T. Leukemia 1995; 9: 1167-1172. Medline 7630192

Trisomy 10: age and leukemic lineage associations. Morgan R, Chen Z, Stone JF, Cohen J, Gustafson E, Jolly PC, Sandberg AA. Cancer Genet Cytogenet 1996; 89(2): 173-174. Medline 96319695

Trisomy 10 in acute myeloid leukemia. Ohyashiki K, Kodama A, Nakamura H, Wakasugi K, Uchida H, Shirota T, Ito H, Toyama K. Cancer Genet Cytogenet 1996; 89(2): 114-117. Medline 96319681

Trisomy 10 in leukemia. Estalilla O, Rintels P, Mark HF Cancer Genet Cytogenet 1998; 101(1): 68-71. Medline 98121836

Luno E, Payer AR, Luengo JR, Del Castillo TB, Garcia VP Cancer Genet Cytogenet 1998; 100(1):84-7. Medline 98069685

Trisomy 10 Survival: A Literature Review and Presentation of Seven New Cases. Pedersen B, Andersen C, Sogaard M, Norgaard J, Koch J, Krejci K, Brandsborg M, and Clausen N. Cancer Genet Cytogenet 1998; 103: 130-132. Medline 9614911

Are Cells with Trisomy 10 Always Malignant in Hematopoietic Disorders? Berger R, Busson-Le Coniat M. Ann Genet 1999; 42(1): 5-10. Medline 10214501

Atlas Genet Cytogenet Oncol Haematol 2006; 4 595 Trisomy 10 as a Sole Chromosomal Abnormality in AML-M2. Estalilla O, Rintels P, and Mark H. Cancer Genet Cytogenet 1999; 108: 175. Medline 9973950

Trisomy 10 in Acute Myeloid Leukemia: Three New Cases. Llewellyn I, Morris C, Stanworth S, Heaton D, and Spearing R. Cancer Genet Cytogenet 1999; 118: 148-150. Medline 10748296

Trisomy 10 in Acute Myeloid Leukemia: Revisited. Ma S, Wan T, Chan L, and Au W. Cancer Genet Cytogenet 1999; 109: 88-89. Medline 9973969

Trisomy 10 in Adult Pre-B-Cell Leukemia. Okamura A, Yamaguchi A, Shimizu S, Kadowaki S, Chihara K, Matsui T, Fujimoto T, Kanki K, and Fujio K. Am J of Hematol 1999; 60: 83. Medline 10331517

Trisomy 10 in a Child with Acute Nonlymphocytic Leukemia Followed by Relapse with a Different Clone. Sakai Y, Nakayama H, Matsuzaki A, Nagatoshi Y, Suminoe A, Honda K, Inamitsu T, Ohga S, Hara T. Cancer Genet Cytogenet 1999; 115: 47-51. Medline 10565299

Trisomy 10 as the Sole Abnormality in Biphenotypic Leukemia. Inoue T, Fujiyama Y, Kitamura S, Andoh A, Hodohara K, and Bamba T. Leuk and Lymph 2000; 39: 405-409. Medline 11342322

Trisomy 10 in Acute Myeloid Leukemia: Three Additional Cases form the Database of the Japan Adult Leukemia Study Group (JALSG) AML-92 and AML- 95. Suzuki A, Kimura Y, Ohyashiki K, Kitano K, Kageyama S, Kasai M, Miyawaki S, and Ohno R. Cancer Genet Cytogenet 2000; 120: 141-143. Medline 10942805

Trisomy 10 and Acute Myeloid Leukemia. Czepulkowski B, Powell A, Pagliuca A, and Mufti G. Cancer Genet Cytogenet 2002; 134: 81-83. Medline 11996802

Atlas Genet Cytogenet Oncol Haematol 2006; 4 596 Contributor(s) Written 08-

1998 Updated 05- Zachary T Lewis, Patrick P Koty, Mark J Pettenati 2006 Citation This paper should be referenced as such : Huret JL . +10 or trisomy 10 (solely). Atlas Genet Cytogenet Oncol Haematol. August 1998 . URL : http://AtlasGeneticsOncology.org/Anomalies/tri10ID1063.html Lewis ZT, Koty PP, Pettenati MJ . +10 or trisomy 10 (solely). Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/tri10ID1063.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 597 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(7;14)(p15;q11) Clinics and Pathology Disease T- Acute lymphoblastic leukemia (T-ALL) Phenotype / T lineage TCR gamma delta +, CD4/8 double positive (DP), CD1a- cell stem immunophenotype origin Epidemiology 1 case reported Clinics FABL1 or L2. The index case had hepatosplenomegaly without mediastinal involvement. Cytogenetics Cytogenetics Balanced t(7;14) Molecular Der(7):Intronic region of HOXA locus on 7p15 between HOXA6 and HOXA7 genes fused with Jd1 segment of TCRD on 14q11. Der(14): DREC segment on chromosome 14q11 rearranged with Dd2 and Dd3 segments and fused to the telomeric part of HOXA locus on 7p15

Fig1: FISH hybridization result using a TCRA/D distal (Green) and HOXA proximal (orange) FISH probes showing a fusion signal in 6 of 8 mitosis.

Additional This case also expressed (by RQ-PCR) a CALM-AF10 fusion transcript anomalies (t(10;11)(p13;q14-21)). Variants variant translocation cases are reported: 9 cases of T-ALLs having the HOXA locus translocated to TCRB in a t(7;7). The breakpoints on 7p15 in those HOXA-TCRB cases are more centromeric, close to HOXA9 Genes involved and Proteins

Atlas Genet Cytogenet Oncol Haematol 2006; 4 598 Gene HOXA (intronic region) Name Location 7p15 Note HOXA6 and HOXA7 lie at 6,9kb from each other on 7p15 Protein various HOXA genes act as transcription factors playing important roles in the differentiation and commitment processes of embryonic and hematopoietic cells. Gene TCRD Name Location 14q11 Note Breakpoint on der(7) lie 5' from Jd1. Breakpoint on der(14)lies 12 nucleotides 5' of the 3' end of the DREC segment. Protein Protein encoded by the TCRD locus are the T-cell receptor chains. Result of the chromosomal anomaly Hybrid gene

Fig2: Sequence of events leading to the final translocation. Exons are represented by boxes. Triangles represent RSS and show their orientation. E=enhancer.

Fusion Protein

Atlas Genet Cytogenet Oncol Haematol 2006; 4 599

Fig3: The nucleotide sequence of both derivatives implicated in the t(7 ;14) translocation. Underscored are RSS or RSS-like sequence in the vincinity of the breakpoints. In lower case letters: non templated nucleotides at the junction.

Description No fusion protein. Overexpression of HOXA genes as a result of the translocation with TCRD was expected, as it was demonstrated to be the case in HOXA-TCRB T-ALLs. However this case had a CALM- AF10 fusion in the same leukemic clone. CALM-AF10 is already known to be associated with HOXA cluster global overexpression. The HOXA pattern of expression in this case was similar to other CALM-AF10 T- ALL. Oncogenesis Probable, as several HOX/HOXA genes have been implicated in leukemic processes.

External links Other t(7;14)(p15;q11) Mitelman database (CGAP - NCBI) database Other t(7;14)(p15;q11) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Armstrong SA, Staunton E, Silverman LB, Pieters R, den Boer ML, Minden MD, Sallan SE, Lander ES, Golub TR, Korsmeyer SJ. Nat Genet 2002; 30: 41-47. Medline 11731795

Atlas Genet Cytogenet Oncol Haematol 2006; 4 600 V(D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. Marculescu R, Le T, Simon P, Jaeger U, Nadel B. J Exp Med 2002; 195: 85-98. Medline 11781368

MLL targets SET domain methyltransferase activity to Hox gene promoters. Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JH. Mol Cell 2002; 10(5): 1107-1117. Medline 12453418

CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCR{gamma}{delta} lineage. Asnafi V, Radford-Weiss I, Dastugue N, Bayle C, Leboeuf D, Charrin C, Garand R, Lafage-Pochitaloff M, Delabess E, Buzyn A Troussard X, Macintyre E. Blood 2003; 102(3): 1000-1006. Medline 12676784

Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy Asnafi V, Beldjord K, Libura M, Villarese P, Millien C, Ballerini P, Kuhlein E, Lafage- Pochitaloff M, Delabesse E, Bernard O, macintyre E. Blood 2004; 104(13): 4173-4180 Medline 15054041

CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes. Dik WA, Brahim W, Braun C, Asnafi V, Dastugue N, Bernard OA, van Doggen JJ, Langerak AW, Macintyre EA, Delabesse E. Leukemia 2005; 19: 1948-1957. Medline 16107895

A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias. Speleman F, Cauwelier B, Dastugue N, Cools J, Verhasselt B, Poppe B, Van Roy N, Vandesompele J, Graux C, Uyttebroeck A, Boogaerts M, De Moerloos B, Benoit Y, Selleslag D, billiet J, Robert A, Huguet F, Vandenberguhe P, De Paepe A, Marynen P, Hagemeijer A. Leukemia 2005; 19: 358-366. Medline 15674412

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HOXA cluster deregulation in T-ALL associated with both a TCRD-HOXA and a CALM-AF10 chromosomal translocation. Bergeron J, Clappier E, Cauwelier B, Dastugue N, Millien C, Delabesse E, Beldjord K, Speleman F, Soulier J, Macintyre E, Asnafi V. Leukemia 2006; 20, 1184-1187. Medline 16572206

Contributor(s) Written 06- Julie Bergeron, Elizabeth Macintyre, Vahid Asnafi. 2006 Citation This paper should be referenced as such : Bergeron J, Macintyre E, Asnafi V. . t(7;14)(p15;q11). Atlas Genet Cytogenet Oncol Haematol. June 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0714p15q11ID1435.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 602 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(1;1)(p36;q21) in Non Hodgkin Lymphoma Identity

.Unbalanced t(1;1)(p36;q21) in NHL with dup(q21q44) as observed by, G-band, M-FISH and M-BAND [ISCN2005: der(1)t(p36.3;q21.1- 2)dup(1)(q21.1-2q44)].

Clinics and Pathology Disease Non Hodgkin Lymphoma (NHL). Aberrations of chromosomal bands 1p36 and 1q11-q23 are among the most common chromosomal alterations in NHL. Phenotype / cell stem Lymphocytes (B-cell and T-cell). origin Etiology The exact etiology of NHL is still unknown, risk increases with exposed to ionizing radiation, chemicals such as pesticides or solvents, Epstein- Barr Virus infection, family history of NHL (although no hereditary pattern has been established, Human Immunodeficiency Virus (HIV) infection, immunosuppression or immunodeficiency, genetics. Epidemiology NHL is the 5th most frequently diagnosed cancer overall for both males and females, males are slightly more often affected than females, increasing over time. Clinics At diagnosis, painful swelling of lymph nodes located in the neck, underarm and groin, unexplained fever, night sweats, constant fatigue, unexplained weight loss, itchy skin. Cytology Anti-B-cell antibodies (e.g. CD19, CD20, CD10, CD23); anti-T-cell antibodies (e.g. CD3, CD4, CD2/HLADR); other antibodies (e.g. CD45 for total lymphocytes, CD10 for monocytes).

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Transformed follicular lymphoma (courtesy, Dr. R.D. Gascoyne, BC Cancer Agency, Vancouver, Canada).

Pathology t(1;1)(p36;q21) has been seen in following NHL types as characterized by pathology; follicular lymphoma (FL) grades 1-3; diffuse large B-cell lymphoma; T-cell lymphoma and peripheral T-cell lymphoma.

Univariate analyses using the Kaplan-Meier method for 1p36-, demonstrating the significance of this chromosomal change for overall survival. In multivariate analysis using the Cox regression model controlling for IPI, the significance remained intact.

Treatment Depend on the stage and type and genetics of NHL; "watch-and-wait" approach in case of indolent follicular lymphomas; radiotherapy to site of problem; systemic chemotherapy; oral agents; IV agents; antibody against CD20; stem cell or bone marrow transplant. Evolution Initial genomic aberration (such as t(14;18)(q32;q21) in follicular lymphoma) may or may not be sufficient for the initiation of the malignant phenotype. Additional genomic rearrangements are required

Atlas Genet Cytogenet Oncol Haematol 2006; 4 604 for disease progression. Prognosis Depend on the stage, type and genetics of NHL; in general, highly treatable and some times curable. However, a number of karyotype parameters have been reported to influence prognosis in NHL. It has been demonstrated that the cytogenetic abnormality 1p36-, as a result of t(1;1)(p36;q21) or another rearrangement involving chromosome 1, was found to be a significant predictors of adverse overall survival for FL (univariate and multivariate analysis). Genetics Initial cytogenetic changes often seen in e.g. FL and t(14;18)(q32;q21) (/BCL2); DLBL and t(3;14)(q27;q21)(BCL6/IGH). Additional acquired mutations are necessary to generate a fully malignant clonal proliferation. Many of these secondary genetic alterations (including chromosome 1) are visible in the clonal karyotype; it is now possible to identify the sequence by which they arise and their influence on clinical behavior by using computational methods to manipulate complex chromosomal data in large number of cases. Cytogenetics Note t(1;1)(p36;q21). G-band and M-BAND1 Detection of der(1)t(1;1). Cytogenetics Normal chromosome 1 with derivative chromosomes 1; Breakpoints are at Morphological chromosomal positions 1p36.3 and 1q21.1-2; duplication of the 1q21 to 1q44; adverse prognosis (?as a result of 1p36 suppressor genes deletions and/or duplication of 1q21q44 oncogenes); additional secondary abnormalities to t(1;1) of various complexity as usually seen in NHL.

A: The derivative chromosome 1 in all 16 NHL cases as seen by G-band analysis. Arrows indicate the additional unidentified dark band. B: The corresponding derivative chromosome 1 as seen by M-BAND1 analysis. Arrows indicate the dup(1)(q21.1q21.2) at the p/q-arm interface (broad orange/ pink bands). X indicates cases where no material was available for M-BAND1 analysis.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 605 C: Normal chromosome 1 as seen by G-band and M-BAND1 analysis, color classifier, and ISCN 550-band level ideogram.

Cytogenetics LS-FISH identification of 1p36.3 and 1q21.1-2 breakpoints on der(1)t(1;1); Two Molecular distinct types of 1p36.3 rearrangements were observed: One type involved deletions of SKI, MEL1, and TP73, and retained CASP9 the other type showed breakpoints telomeric to TP73; Four distinct types of 1q21.1-2 rearrangements were observed: The first type involved breakpoints at IRTA1 and IRTA2 with duplications of IRTA1, IRTA2, BCL9, AF1Q, JTB, and MUC1; the second type involved a breakpoint at BCL9 with duplications of BCL9, AF1Q, JTB, and MUC1; the third type involved a breakpoint at AF1Q with duplications of AF1Q, JTB, and MUC1; the fourth type involved an undefined breakpoint telomeric to MUC1.

Composite picture of all LS-FISH patterns observed in this study with representative examples. A: Normal color-coded chromosome 1 LS-FISH pattern, demonstrating the relative localization of all BAC probes. B: All der(1)t(1;1) combinations seen by LS-FISH. C: Two color-coded representative images corresponding to B and demonstrating the p/q-arm breakpoint interfaces.

Probes For genes MEL1, TP73, SKI, and CASP9 at 1p36; genes IRTA1, IRTA2, BCL9, AF1Q, JTB, and MUC1 at 1q21 and the =E1-satellite DNA probe for chromosome 1 (D1Z5, VYSIS). Genes involved and Proteins Note The remarkable frequency of centromeric/pericentromeric

Atlas Genet Cytogenet Oncol Haematol 2006; 4 606 rearrangements of chromosome 1 in B-cell malignancies has been clearly associated with tumor progression. A factor in the pathology associated with the centromeric/pericentromeric region 1q10-12 is a sequence-specific DNA-binding protein called Ikaros that is speculated to be essential for lymphocyte development. Methylation, interactions with proteins interfering with heterochromatin, and possible gene silencing attributed to heterochromatin may be responsible as well. The mechanisms, however, underlying the formation of recurring chromosome 1 aberrations in many hematological malignancies and the consequences of these various chromosomal rearrangements are largely undetermined. Conserved Homology for 1p36 and 1q21? It has been speculated that 1q21, 1p11-12, and 1p36 are evolutionarily conserved and that the homology between these regions is associated with chromosomal instability. A mechanism of homologous recombination may be in place that would explain the frequent chromosome 1 rearrangements involving 1p36, 1p11-12, and 1q21, but wouldn't explain the various breakpoints seen in these regions.

External links Other t(1;1)(p36;q21) in Non Hodgkin Mitelman database (CGAP - database Lymphoma NCBI) Other t(1;1)(p36;q21) in Non Hodgkin CancerChromosomes (NCBI) database Lymphoma Bibliography Uncovering novel inter- and intrachromosomal chromosome 1 aberrations in follicular lymphomas by using an innovative multicolor banding technique. Lestou VS, Gascoyne RD, Salski C, Connors JM, Horsman DE. Genes Chromosomes Cancer; 2002; 34: 201-210. Medline 11979554

Multicolour fluorescence in situ hybridization analysis of t(14;18)-positive follicular lymphoma and correlation with gene expression data and clinical outcome. Lestou VS, Gascoyne RD, Sehn L, Ludkovski O, Chhanabhai M, Klasa RJ, Husson H, Freedman AS, Connors JM, Horsman DE Br J Haematol 2003; 122: 745-759. Medline 12930384

Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes Horsman DE, Okamoto I, Ludkovski O, Le N, Harder L, Gesk S, Siebert R, Chhanabhai M, Sehn L, Connors JM, Gascoyne RD. Br J Haematol 2003; 120: 424-433. Medline 12580956

Atlas Genet Cytogenet Oncol Haematol 2006; 4 607 Characterization of the recurrent translocation t(1;1)(p36.3;q21.1-2) in non- Hodgkin lymphoma by multicolor banding and fluorescence in situ hybridization analysis. Lestou VS, Ludkovski O, Connors JM, Gascoyne RD, Lam WL, Horsman DE. Genes Chromosomes Cancer; 2003; 36: 375-381. Medline 12619161

Identification of cytogenetic subgroups and karyotypic pathways of clonal evolution in follicular lymphomas. Hoglund M, Sehn L, Connors JM, Gascoyne RD, Siebert R, Sall T, Mitelman F, Horsman DE. Genes Chromosomes Cancer; 2004; 39: 195-204. Medline 14732921

New insights into the evolution of chromosome 1. Weise A, Starke H, Mrasek K, Claussen U, Liehr T. Cytogenet Genome Res 2005; 108: 217-222. Medline 15545733

Contributor(s) Written 06- Valia S Lestou 2006 Citation This paper should be referenced as such : Lestou VS . t(1;1)(p36;q21) in Non Hodgkin Lymphoma. Atlas Genet Cytogenet Oncol Haematol. June 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0101p36q21ID1431.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 608 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(7;12)(q34;p13); t(12;14)(p13;q11) Identity Note The 2 translocations are variants of each other, and probably share the same biological significance

R-band analysis. Partial karyotypes showing t(7;12)(q34;p13) (left panel), and t(12;14)(p13;q11) (right panel)

Clinics and Pathology Disease T cell acute lymphoblastic leukemia (T-ALL) Phenotype / T cell precursor. These translocations are not restricted to a single cell stem maturation stage. origin Epidemiology less than 5% among T-ALL. Cytology Lymphoblasts Cytogenetics Cytogenetics t(7;12)(q34;p13) may be barely detectable by chromosome banding Morphological techniques alone.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 609

Example of FISH performed on bone marrow metaphase from a patient with t(7;12)(q34;p13). Dual color FISH using whole chromosome paint for chromosome 7 (green) and chromosome 12 (red) showed the reciprocal translocation.

Cytogenetics Rearrangement of the CCND2 locus at 12p13.3 may be detected by Molecular dual color FISH using CCND2 flanking probes.

Example of double colour FISH performed on bone marrow interphasic nuclei from a patient with t(7;12)(q34;p13) using CCND2 flanking probes at 12p13. The centromeric BAC clone RP11-388F6 (red) and the telomeric BAC clone RP11-320N7 (green) show one fusion signal at the normal chromosome 12, and dissociated signals at der(12) (red signal) and der(7) (green signal).

Atlas Genet Cytogenet Oncol Haematol 2006; 4 610

Genes involved and Proteins Note The t(7;12)(q34;p13) translocation has not to be confused with the t(7;12)(q36;p13) involving ETV6 at 12p13.1 and HLXB9 at 7q36, which is found in infant myeloid leukemias. Gene CCND2 Name Location 12p13.3 Dna / Rna 5 exons, 2.1 kb mRNA, 5'-3' telomere to centromere orientation. Protein Cyclin D2; 289 amino acids; 33 kDa. Cyclin D2 is a regulator of the progression through G1-phase and G1 to S-phase transition of the cell cycle. Gene TCRA Name Location 14q11 Protein T-cell receptor alpha Gene TCRD (TRD@) Name Location 14q11 Protein T-cell receptor delta Gene TCRB Name Location 7q34 Protein T-cell receptor beta Result of the chromosomal anomaly Hybrid gene Note No fusion protein Description t(7;12)(q34;p13) and t(12;14)(p13;q11) translocations result in juxtaposition of TRA/D or TRB regulatory sequences to the CCND2 gene, leading to deregulated expression of the CCND2 gene.

Fusion Protein Note T-ALL cases with t(7;12)(q34;p13) or t(12;14)(p13;q11) can be associated to other oncogenic abnormalities, such as overexpression of the oncogenes TAL1, TLX3/HOX11L2, or HOXA genes, activating NOTCH1 mutations, and/or CDKN2A/p16/ARF locus deletion. Oncogenesis CCND2 gene expression is tightly regulated throughout thymocyte differenciation. Its deregulated expression in T-ALL cases with t(7;12)(q34;p13) or t(12;14)(p13;q34) is likely to play a role in T-cell oncogenesis.

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External links Other t(7;12)(q34;p13) Mitelman database (CGAP - NCBI) database Other t(7;12)(q34;p13) CancerChromosomes (NCBI) database Other t(12;14)(p13;q11) Mitelman database (CGAP - NCBI) database Other t(12;14)(p13;q11) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography A new breakpoint, telomeric to TEL/ETV6, on the short arm of chromosome 12 in T cell acute lymphoblastic leukemia. Le Coniat M, Della Valle V, Marynen P, Berger R. Leukemia 1997;11(8): 1360-1363. Medline 9264392

Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias. Clappier E, Cuccuini W, Cayuela JM, Vecchione D, Baruchel A, Dombret H, Sigaux F, Soulier J. Leukemia 2006; 20(1): 82-86 Medline 16270038

Deregulation of cyclin D2 by juxtaposition with T-cell receptor alpha/delta locus in t(12;14)(p13;q11)-positive childhood T-cell acute lymphoblastic leukemia. Karrman K, Andersson A, Bjorgvinsdottir H, Strombeck B, Lassen C, Olofsson T, Nguyen-Khac F, Berger R, Bernard O, Fioretos T, Johansson B. Eur J Haematol. 2006; [Epub ahead of print] Medline 16548914

Contributor(s) Written 06- Emmanuelle Clappier, Jean Soulier 2006 Citation This paper should be referenced as such : Clappier E, Soulier J . t(7;12)(q34;p13),t(12;14)(p13;q11). Atlas Genet Cytogenet Oncol Haematol. June 2006 .

Atlas Genet Cytogenet Oncol Haematol 2006; 4 612 URL : http://AtlasGeneticsOncology.org/Anomalies/t0712q34p13ID1434.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 613 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Polycythemia Vera (PV) - updated Clinics and Pathology Disease Polycythemia Vera (PV) Phenotype / The disease is a chronic myeloproliferative disorder originating from a cell stem mutated pluripotent stem cell capable of producing red blood cells, origin granulocytes and megakaryocytes. In some cases, B-lymphocyte involvement by the clonal proliferation was documented; T- lymphocytes are rarely involved by the malignant process. Epidemiology PV is the most common chronic myeloproliferative disorder with a 2-3 /100,000 incidence. The prevalence of the disease was 300 cases per one million. The male-to-female ratio is 1.2 and the average age at diagnosis is 60 years. Clinics PV must be distinguished from secondary erythrocytosis, and from spurious polycythemia. The diagnosis of PV can reasonably be made in the presence of a raised red cell mass (above 25% above predicted, or hematocrit 0.60 in males or above 0.56 in females), in the absence of causes of secondary erythrocytosis (normal arterial oxygen saturation and no elevation of serum erythropoietin. Some patients may show at diagnosis palpable splenomegaly, thrombocytosis (platelets above 400 x 109/L), neutrophilia (neutrophils above 10 x 109/L). Endogenous erythroid colonies usually grow in vitro and serum erythropoietin levels are low. The Presence of JAK2 V617F mutation has an emerging role in the diagnosis of the disease. Cytology The bone marrow is hypercellular with normal morphology. Clusterd mature megakaryocytes may be seen. The iron stores are absent. Significant increase of reticulin fibers may be present. Treatment Phlebotomy is the mainstay of treatment, aiming at a reduction of hematocrit level to the normal. Low dose aspirin is necessary to reduce the risk of thrombotic complications. interferon (young patients) or hydroxyurea can be used if cytoreduction is necessary (thrombocytosis, splenomegaly). Evolution The disease symptoms are usually related to arterial thrombosis and deep venous thrombosis, which are much more frequent in the untreated patient. 30-40% of the deaths are accounted for by major thrombotic events. Post polycythemic myeloid metaplasia (spent polycythemia) may occur in 5-50% of the patients and these patients are at risk (20-50%) of developing acute leukemia. Prognosis A significant prolongation of survival was achieved by modern treatment strategies and a cumulative median survival in excess of 15 years was documented. Cytogenetics Cytogenetics Overall, 25-35% of the patients show a clonal chromosome defect.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 614 Morphological Only 10-15% of the untreated patients have a clonal aberration, whereas up to 60% of previously treated cases may show a defect. The vast majority of patients studied at disease transformation harbours cytogenetically abnormal clones. Non-random chromosome aberrations found before treatment include +8, +9, del(13q), del(20q) and gain of 1q. The latter anomaly is frequently seen in the spent phase of PV; a common trisomic region at 1q21-1q32 was identified. These aberrations have little prognostic significance as they are frequently associated with indolent disease. The appearance of sub- clones and/or 5q- may herald disease transformation. Cytogenetics a) Fluorescence in situ hybridization (FISH) and molecular studies. Molecular Interphase FISH may increase the sensitivity of conventional cytogenetics. Using this technique, additional 9p was shown to represent the most frequent chromosome aberration in PV. Genome- wide screening for loss-of-heterozigosity (LOH) showed the existence of LOH at 9p, 10q and 11q. LOH at 9p is the most frequent defect in PV, where it occur in approximately 30% of the cases and it affects both myeloid and lymphoid cells. LOH at 9p is due to mitotic recombination with uniparental disomy and, hence, it is not detectable by karyotyping and by molecular cytogenetic analysis. The JAK2 gene is located at 9p (vide infra). b) Janus Kinase JAK2 mutation. A valine to phenylalanine substitution at position 617 (JAK2 V617F mutation) is present in 65-97% of the patients, leading to constitutive kinase activity. The mutation is acquired and occurs at the level of a pluripotent stem cell originating myeloid and lymphoid cells. Mitotic recombination at 9p may lead to the emergence of a clone with JAK2 V617F mutated homozygous cells. The mutated JAK2 protein binds to the cytoplasmic domain of Epo-R and promotes signalling independent of Epo stimulation. The JAK2 protein is coded for by a gene mapping at 9p and it is activated upon erythropoietin binding to the receptor. JAK2 signalling involves the phosphorylation of several Y residues at the Epo receptor with activation of STAT, MAP kinase PI-3-kinase and AKT. These events lead to survival and proliferation of erythroid progenitors. JAK2 is involved in intracellular signalling following stimulation by IL3, TPO and GM-CSF, and erythroid progenitors in PV are hypersensitive to stimulation by these cytokines. Bibliography A chromosomal profile of polycythemia vera. Rege-Cambrin G, Mecucci C, Tricot G, Michaux JL, Louwagie A, Van Hove W, Francart H, Van den Berghe H. Cancer Genet Cytogenet 1987; 25: 233-45. Medline 3828970

A prospective long-term cytogenetic study in polycythemia vera in relation to treatment and clinical course. Swolin B, Weinfeld A, Westin J.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 615 Blood 1988; 72(2): 386-395. Medline 3401588

Gain of 9p in the pathogenesis of polycythemia vera. Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Genes Chromosomes Cancer 1998; 22: 321-324. Medline 9669670

Myeloproliferative disorders. Bench AJ, Cross NC, Huntly BJ, Nacheva EP, Green AR. Best Pract Res Clin Haematol 2001; 14: 531-551. Review. Medline 11640868

Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Kralovics R, Guan Y, Prchal JT. Exp Hematol 2002; 30: 229-236. Medline 11882360

Exploring polycythaemia vera with fluorescence in situ hybridization: additional cryptic 9p is the most frequent abnormality detected. Najfeld V, Montella L, Scalise A, Fruchtman S. Br J Haematol 2002; 119: 558-566. Medline 12406101

Karyotypic abnormalities in myelofibrosis following polycythemia vera. Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Lai JL. Cancer Genet Cytogenet 2003; 140: 118-123. Medline 12645649

The rate of progression to polycythemia vera or essential thrombocythemia in patients with erythrocytosis or thrombocytosis. Ruggeri M, Tosetto A, Frezzato M, Rodeghiero F. Ann Intern Med. 2003; 139: 470-475. Medline 13679323

Conventional cytogenetics of myeloproliferative diseases other than CML contribute valid information. Bacher U, Haferlach T, Kern W, Hiddemann W, Schnittger S, Schoch C. Ann Hematol 2005; 84: 250-257. Medline 15692838

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS,

Atlas Genet Cytogenet Oncol Haematol 2006; 4 616 Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR. Lancet 2005; 365: 1054-1061. Medline 15781101

A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. Nature 2005; 434 (7037): 1144-1148. Medline 15793561

A gain-of-function mutation of JAK2 in myeloproliferative disorders. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. N Engl J Med 2005; 352: 1779-1790. Medline 15858187

Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. Cancer Cell 2005; 7: 387-397. Medline 15837627

Identification of an acquired JAK2 mutation in polycythemia vera. Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, Zhao ZJ. J Biol Chem 2005; 280: 22788-22792. Medline 15863514

Management of Polycythemia Vera and Essential Thrombocythemia. Campbell PJ, Green AR. ASH Educational Book; 2005:201-208.

The polycthemias. Hoffman R, Baker K, Prchal J. Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silbertsein LE, McGlave P (Eds). Hematology. Basic Principles and practice. Elsevier, Philadelphia, Pennsylvania; 2005; 1209-1245

A Unique Activating Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera and Allows a New Classification of Myeloproliferative Diseases Vainchenker W. Constantinescu SN. ASH Educational Book; 2005:195-200.

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Involvement of various hematopoietic cell lineages by the JAK2V617F mutation in polycythemia vera. Ishii T, Bruno E, Hoffman R, Xu M. Blood. 2006 Jun 6; [Epub ahead of print] Medline 16757685

The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Jamieson CH, Gotlib J, Durocher JA, Chao MP, Mariappan MR, Lay M, Jones C, Zehnder JL, Lilleberg SL, Weissman IL. Proc Natl Acad Sci U S A. 2006; 103: 6224-6229. Medline 16603627

The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Lippert E, Boissinot M, Kralovics R, Girodon F, Dobo I, Praloran V, Boiret-Dupre N, Skoda RC, Hermouet S. Blood. 2006 May 25; [Epub ahead of print] Medline 16728702

Progenitors homozygous for the V617F JAK2 mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Scott LM, Scott MA, Campbell PJ, Green AR. Blood. 2006 Jun 13; [Epub ahead of print] Medline 16772604

Contributor(s) Written 07- Jean-Loup Huret, Nicole Smadja 1997 Updated 07- Antonio Cuneo, Francesco Cavazzini. 2006 Citation This paper should be referenced as such : Huret JL, Smadja N . Polycythemia Vera (PV). Atlas Genet Cytogenet Oncol Haematol. July 1997 . URL : http://AtlasGeneticsOncology.org/Anomalies/PV.html Cuneo A, Cavazzini F . Polycythemia Vera (PV). Atlas Genet Cytogenet Oncol Haematol. July 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/PV.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 618 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clear Cell Hidradenoma of the Skin (CCH) Identity Other Nodular Hidradenomas names Eccrine Acrospiromas

Morphology of a CCH with typical clear cells, squamous differentiation, and ductal structures (inset). Reprinted partially from Publication ³Genes Chromosomes Cancer;43(2), Behboudi A., Winnes M., Gorunova L., van den Oord J.J., Mertens F., Enlund F., Stenman G. Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)--associated TORC1-MAML2 gene fusion, 202-205, Copyright (2005), with permission from John Wiley and Sons Inc.² Clinics and Pathology Disease Clear Cell Hidradenomas of the skin (CCH) are benign sweat gland tumors of eccrine duct origin often presenting as solitary, intradermal nodules. They are usually circumscribed, nonencapsulated tumors composed of polyhedral or fusiform cells with clear or eosinophilic cytoplasm. In some tumors, epidermoid differentiation may also be encountered. CCHs rarely undergo malignant transformation. Cytogenetics Cytogenetics t(11;19)(q21;p13) translocation

Atlas Genet Cytogenet Oncol Haematol 2006; 4 619 Molecular Genes involved and Proteins Gene CREB regulated transcription coactivator 1 (CRTC1) Name Location 19p13.11 Note Alias: MECT1, WAMTP1, TORC1 Dna / Rna DNA: spans about 94 kb and includes 14 to 16 exons. RNA: two variants of 2342 bp and 2505 bp in size. Protein 634 amino acids; 67300 Da

Gene Mastermind-like 2 (MAML2) Name Location 11q21 Dna / Rna DNA: spans about 365 kb and includes 5 exons. RNA: a major transcript of 7.5 kb. Protein 1153 aa, 125000 Da; conserved N-terminal basic domain (aa 29-92) which binds to the ankyrin repeat domain of Notch receptors; two acidic domains (aa 263-360 and 1124-1153) and a C-terminal transcriptional activation domain.

Result of the chromosomal anomaly Hybrid Gene

Nucleotide and deduced amino acid sequences of the CRTC1-MAML2 breakpoint junction. The MAML2 exon 2 sequence is shown in bold. Reprinted partially from Publication ³Exp Cell Res 292, Enlund F., Behboudi A., Andren Y., Oberg C., Lendahl U., Mark J., Stenman G., Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors, 21-28, Copyright (2004), with permission from Elsevier.

Detection 1- RT-PCR using total RNA from frozen tumor tissue or paraffin-embedded tumor tissue: amplification of the CRTC1-MAML2 fusion transcript by nested RT-PCR using the first-round primers CRTC1, 5'- AGGAGGTGGAGGAGGAGGAG-3', and MAML2, 5'-

Atlas Genet Cytogenet Oncol Haematol 2006; 4 620 TGTTGGCAGGAGATAGGTTAACTACCTG-3' (product size 221 bp), and the second-round primers CRTC1, 5'-GAGAAGATCGCGCTGCAC-3', and MAML2, 5'-GTTAACTACCTGTTTTCTTTTCAAGG-3' (product size 127 bp). 2- Dual-color FISH on metaphase chromosomes: The CRTC1MAML2 fusion gene may be detected by dual-color FISH, using BAC RP11-697H10 (MAML2) and cosmid LLNLR-255A4 (MECT1) as probes. Fusion

Protein

Description Schematic representation of the MAML2 protein and the CRTC1-MAML2 fusion protein. Reprinted partially from Publication ³Exp Cell Res 292, see above.

Expression Nucleus Localisation

Bibliography Skin pathology. Weedon D. 2002 2nd ed. New York, Churchill Livingstone: 895.

Histological typing of skin tumors. Heenan PJ, Elder DE, Sobin LH. World Health Organization International Histological Classification of Tumours 1996 2nd ed. Berlin, Springer-Verlag:54.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2006; 4 621 Written 05- Afrouz Behboudi, Göran Stenman 2006 Citation This paper should be referenced as such : Behboudi A, Stenman G . Clear Cell Hidradenoma of the Skin (CCH). Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Tumors/ClearCelHidradID5419.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 622 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Schinzel-Giedion midface retraction syndrome

Identity Note The use of the long form of the name, Schinzel-Giedion midface retraction syndrome, is preferred to prevent confusion with Schinzel ulnar-mammary syndrome, a completely unrelated and clinically non-overlapping condition also described by Dr Schinzel. Other Schinzel-Giedion syndrome names Inheritance Schinzel-Giedion midface retraction syndrome is presumed to be inherited as autosomal recessive on the basis of several pairs of affected sibs with normal parents. No specific gene or chromosome region has been identified. Among 44 reported families there are only 2 well-documented affected sib pairs and 2 more pairs in which a previous deceased sib was reported to have had similar anomalies. Therefore alternative hypotheses such as an autosomal dominant mutation, microdeletion, or microduplication with the few recurrence being explained by parental gonadal mosaicism must also be considered.

Frontal view of an infant with Schinzel-Giedion midface retraction Syndrome. Lateral views of an infant with Schinzel-Giedion midface retraction Syndrome.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 623 Clinics Phenotype The craniofacial appearance is essential to the diagnosis. Hydronephrosis is and clinics present in over 90% of cases. Other features, particularly skeletal findings, are helpful, but less specific. No generally accepted diagnostic guidelines exist. Craniofacies: In addition to the pathognomonic "midface retraction" consisting of shallow orbits and midface hypoplasia with resulting prominence of the forehead, all reported patients have high forehead, large fontanelles and widely patent cranial sutures, particularly the metopic suture. The facial appearance is often described as coarse. Hypertelorism, flat nasal bridge, anteverted nares and lowset ears with protruding lobules are frequent. Nearly half the patients have choanal stenosis. Central nervous system: Mental deficiency is usually profound. Both hypotonia and spasticity are common and may occur at different times in the same patient. Seizures of varying types, often including infantile spasms, are reported in most patients. Central nervous system malformations, particularly agenesis of the corpus callosum are reported occasionally, but the major anomaly on cranial MRI is cerebral atrophy which has been documented to progress over time in many of the longer surviving patients. Skeletal: The skull base is steep, short, and often sclerotic with wide occipital synchondrosis, and multiple wormian bones. The ribs are broad and the clavicles are long. There is frequent hypoplasia of the first ribs, pubis, and distal phalanges. There is mild mesomelic shortening with widening of distal femur and increased density and broad cortex of the long bones. Additional limb anomalies such as polydactyly and talipes are found in a significant minority of patients. Urogenital: Hydronephrosis on prenatal ultrasound is often the first abnormality noted. A few patients have died neonatally from lung hypoplasia related to either oligohydramnios sequence or compression from massive dilated kidneys. Virtually all patients have renal anomalies, primarily hydronephrosis, but only a few require treatment for obstructive lesions. Most patients have varying degrees of genital hypoplasia with hypospadias, micropenis and occasional ambiguous genitalia in males and labial hypoplasia, hymenal atresia and occasional bicornuate uterus in females. Cardiac: About 1/3 of the patients have congenital heart disease, most commonly atrial septal defect. Ventricular septal defect, pulmonic stenosis, AV canal, and carctation have also been reported. Dermatologic: Most patients have hypertrichosis, redundant nuchal skin, hypoplastic nipples, hyperconvex nails and hypoplastic dermal ridges. Facial hemangiomas are common. Other: Alacrima, visual impairment, hearing loss, macroglossia. Gingival hyperplasia occurs in long-term survivors.

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Gluteal area of same patient supine. Sacral asymmetry is due to a mass, which proved to be a primitive neurectodermal tumor.

Neoplastic Among 46 reported patients, 7 (15%) have had childhood tumors including 3 risk sacrococcygeal teratomas, 2 primitive neurectodermal tumors arising in the sacral area, 1 hepatoblastoma, and 1 Wilms tumor arising in a multicystic dysplastic kidney. Both of the latter tumors arose in older children (above age 2), raising concern that long term survivors need to be followed for possible tumor development. Because of early deaths and lack of follow-up reports for many patients, the reported incidence of tumors must be considered a minimal estimate. Among 15 patients known to have survived beyond age 2, three (20%) have had tumors. Treatment Treatment is entirely symptomatic and directed at complications. The profound central nervous system involvement is the major cause of morbidity and mortality. Seizures are frequent and difficult to control with many patients failing to respond to anticonvulsants or ketogenic diet. Several patients with hearing loss have had some benefit from hearing aids. Hydronephrosis is usually stable, and only a few patients have required surgery for obstruction. Patients with tumors have responded to standard care including surgery and/or chemotherapy. Evolution Facial features may become less characteristic in long-term survivors. Hydronephrosis rarely progresses to renal failure. Progressive gingival hyperplasia in older patients raises concern about a storage disease, but patients coming to autopsy do not have evidence of a lysosomal disorder. Unfortunately the neurologic status tends to deteriorate over time. Developmental delay is usually profound with most patients remaining non- ambulatory and non-verbal throughout their lives. Seizures can develop at any age and tend to become increasingly difficult to control. Patients who were hypotonic as neonates may develop severe spasticity. Follow-up MRI studies

Atlas Genet Cytogenet Oncol Haematol 2006; 4 625 often show worsening cerebral atrophy and increasing ventriculomegaly without obstructive hydrocephalus. Prognosis Half of all reported patients were deceased at the time of the initial report. 20% died in the first year, another 17% in the second year and 13% between 2 and 10 years of age. Only 4 patients (<10%) are known to have lived beyond age 4 and all of these were severely cognitively impaired.. The most common cause of death is progressive neurologic deterioration resulting in pneumonia and other infections. Several patients died neonatally from respiratory distress related to massive nephromegaly. Two patients had local recurrences of cancer, but only one patient, a 9 year old with Wilms tumor, died from metastatic cancer. Cytogenetics Note Chromosome studies are normal in Schinzel-Giedion midface retraction syndrome. A single patient coincidentally had Klinefelter syndrome, which was not thought to contribute to the observed phenotype. Cytogenetics Tumor cytogenetic data are available in only one case, an infant with of cancer Schinzel-Giedion midface retraction and a neuroepithelial tumor in the sacral area. The infant had a normal 46, XY constitutional karyotype but the tumor contained a clone with duplication of the 17q22 region and a marker consisting of extra material from 17q {47,XY,dup?(17)(q22),+mar[5]- ishdup?(17)(q22)(wcp17+),der(17)(wcp17+)/46,XY[35]}. Other findings Note None known. The Schinzel-Giedion midface retraction phenotype is suggestive of biochemical or storage disease but metabolic studies and organ histology at autopsy are not indicative of any unusual material being stored. External links Association Schinzel-Giedion Support Group

Patricks Promise 14398 East Carroll Boulevard, Cleveland, Ohio USA Association 44118

Bibliography A syndrome of severe midface retraction, multiple skull anomalies, clubfeet and cardiac and renal malformations in sibs. Schinzel A, Giedion A Am J Med Genet, 1978; 1: 361-375. Medline 665725

Congenital Hydronephrosis, skeletal dysplasia, and severe developmental retardation: the Kelley RI, Zackai EH, Charney EB J Pediatr 1982; 100; 943-946.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 626 Medline 7086596

Mittelgesichtshypoplasie, Skelettanomalien, Apnoen, Retardierung-eine weitere Beobachtung. Burck U In Tolksdorf M, Spranger J (eds) 1982: "Klinische Genetik in der Pediatrie"3 symposium in Kiel, Jahrgang 8, Heft 5.

The Schinzel-Giedion syndrome. A case report and review of the literature. Pul M, Yilmaz N, Komsuoglu B Clin Pediatr (Phila) 1990; 29: 235-239 REVIEW Medline 2184969

New finding of Schinzel-Giedion syndrome: a case with malignant sacrococcygeal teratoma. Robin NH, Grace K, DeSouza TG, McDonald-McGinn D, Zackai EH Am J Med Genet 1993; 47: 852-856. Medline 7506484

Schinzel-Giedion syndrome. Alavi S, Kher A, Bharucha BA. Indian Pediatr 1994; 31: 1111-1114. Medline 7883373

Schinzel-Giedion syndrome: autopsy report and additional clinical manifestations. Rodriguez JI, Jimenez-Hefferman JA, Leal J Am J Med Genet. 1994; 53: 374-377. Medline 7864048

Schinzel-Giedion syndrome: report of two sibs. Antich J, Manzanares R, Camarasa F, Kraauel X, Vila J, Cusi V Am J Med Genet 1995; 59: 96-99 Medline 8849020

Schinzel-Giedion syndrome: further delineation of the phenotype Elliott AM, Meagher-Villemure K, Oudjhane K, der Kaloustian VM Clin Dysmorphol 1996; 5: 135-142. REVIEW Medline 8723563

Agenesis of the corpus callosum in Schinzel-Giedion syndrome associated with 47,XXY karyotype. Ozkinay FF, Akisu M, Kultursay N, Oral R, Tansug N, Sapmaz G Clin Genet 1996; 50: 145-148. Medline 8946113

Atlas Genet Cytogenet Oncol Haematol 2006; 4 627 Sacral tumors in Schinzel-Giedion syndrome. McPherson E, Clemens M, Hoffner L, Surti U. Am J Med Genet 1998; 79: 62-63. Medline 9738870

Schinzel-Giedion syndrome: evidence for a neurodegenerative process Shah AM, Smith MF, Griffiths PD, Quarrell OW Am J Med Genet 1999; 82: 344-347. Medline 10051170

A case of Schinzel-Giedion syndrome complicated by progressive severe gingival hyperplasia and progressive brain atrophy. Kondoh T, Kamimura N, Tsuru A, Matsumoto T, Matsuzaka T, Moriuchi H. Pediatr Int 2001; 43: 181-184. Medline 11328425

Schinzel-Giedion syndrome with scarococcygeal teratoma Sandri A, Manazza AD, Bertin D, Silengo M, Basso ME, Forni M, Madon E. J Pediatr Hematol Oncol 2003; 25: 558-561. Medline 12847324

Malignant retroperitoneal tumor arising in a multicystic dysplastic kidney of a girl with Schinzel-Giedion syndrome. Matsumoto F, Tohda A, Shimada K, Okamoto N Int J Urol 2005; 12: 1061-1062. Medline 16409612.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 4-2006 Elizabeth McPherson Citation This paper should be referenced as such : McPherson E . Schinzel-Giedion midface retraction syndrome. Atlas Genet Cytogenet Oncol Haematol. . URL : http://AtlasGeneticsOncology.org/Kprones/SchinzelGiedionID10129.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 628 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Melanoma-Astrocytoma syndrome

Identity Other Melanoma and neural system tumour syndrome names Inheritance Autosomal dominant inheritance with high penetrance and variable expression Clinics Note Listed as a rare disease by the Office of Rare Disease (ORD) of the NIH. The disease affects less than 200,000 people in the USA. Phenotype Characterised by families with cutaneous malignant melanoma (CMM) and clinics and nervous system tumours. Initially described in a family with malignant melanoma and/or cerebral astrocytoma in eight members over three generations. Astroctytomas and cutaneous malignant melanoma have been identified in a number of well defined syndromes such as neurofibromatosis, Turcot¹s, Lynch type II cancer, Li-Fraumeni and tuberous sclerosis. However, astrocytomas and CMM have been reported in families where the disease pattern does not fit the defined syndromes due to the absence of additional cancer types normally associated with these syndromes and mutations in genes known to predispose to these conditions (NF1, TP53, APC, MSH2 MLH1, TSC1, TSC2). In addition to astrocytoma, melanoma-astrocytoma syndrome families show other tumours such as medullablastomas, glioblastoma multiforme, ependymoma, glioma, meningioma, neuroblastomas, schwannoma and acoustic neurilemmoma. All these tumours are of neural crest, mesenchymal and/or neuroepithelium origin. These families may/may not show evidence of the dysplastic naevus syndrome (DNS) common in familial melanoma. Neoplastic The neoplastic risk of melanoma-astocytoma syndrome has not been risk determined due to the small number of families identified. However penetrance appears consistent with that of melanoma in CDKN2A carriers. This was investigated in 2002 by the International Melanoma Genetics Consortium (GenoMEL) and is estimated to be 67% by 80 years of age. Treatment Treatment consistent with that of familial melanoma patients Yearly surveillance of patients and first and second degree relatives. Prognosis Melanoma has a good clinical outcome if identified at an early stage. Increasing thickness of tumour is associated with a rapid decline in life expectancy, highlighting the need for careful surveillance for precursor lesions. Prognosis of nervous system tumours is dependent on type, location and stage, however it is generally poor. Cancer Research UK

Atlas Genet Cytogenet Oncol Haematol 2006; 4 629 reports a 5yr survival of between 10 and 15% for brain and central nervous system tumours since the mid-eighties. Genes involved and Proteins Note To date all published families documented with melanoma-astrocytoma syndrome are linked to the CDKN2 locus on 9p21.

Gene CDKN2A Name Location 9p21 Note First identified gene associated with susceptibility to cutaneous malignant melanoma (CMM) DNA/RNA Note CDKN2A has a gene structure unique in the human genome. Two common exons, 2 and 3, are spliced to one of two alternative first exons, 1a or 1b, in two different reading frames. This results in two functionally unrelated protein products, p16 and p14ARF.

The CDKN2A gene showing the alternate exon usage and distinct splice products p16 and p14ARF. The asterisks indicate the stop codons for the two splice products.

Description Four exons. 1a, 1b, 2 and 3. Protein Note CDKN2A encodes two functionally distinct cell cycle proteins, p16 and p14ARF, through use of an alternative first exon coupled with alternate reading frames

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Functional significance of p16 and p14ARF in the cell cycle. P16 inhibits the G1 to S transition by inhibiting binding of Cyclin D to CDK4 and CDK6, in turn preventing phosphorylation of RB, release of E2F and transcription of S-phase genes. P14ARF inhibits both the G1 to S and G2 to M transitions by sequestering HDM2 preventing it from targeting p53 for ubiquitination. This stabilisation of p53 leads to upregulation of p21 and 14.3.3sigma. p21 inhibits binding of CDK2 and Cyclin E thus inhibiting the RB pathway while 14.3.3sigma binds to the CDC2/Cyclin B complex leading to export from the nucleus which prevents G1 to M transition

Description p16. Exons 1a, 2 and 3. Encodes 156 amino acids. ~15.8kD protein Expression Both p16 and p14ARF expression levels are low in normal tissue. Both proteins are upregulated in cells during in vitro senescence consistent with a role in ageing. Expression of p16 is often lost during progression of a tumour. Localisation Following controversy concerning the cellular localisation of p16 it has recently been shown that p16 can be expressed in both the nuclear and cytoplasmic compartments and that both nuclear and cytoplasmic p16 forms complexes with CDK4 and CDK6. Cytoplasmic p16 occurs in two forms whilst nuclear p16 appears predominantly in just one. The p14ARF protein is predominantly localised to the nucleolus but can also be detected in the nucleoplasm. Function Cell cycle regulation. P16 inhibits the binding of CDK4 and 6 to Cyclin D preventing phosphorylation of Rb and leading to G1 arrest. P14ARF sequesters HDM2 in the nucleolus preventing the targeting of p53 for ubiquitination and thus p53 stabilisation and G2 arrest

Atlas Genet Cytogenet Oncol Haematol 2006; 4 631 Homology The p16 protein has functional homology with p15 the product of the CDKN2B gene (exon 2 of both genes share 90% sequence homology), also located at 9p21. In contrast p14ARF appears to be unique with no obvious homology with any known proteins. Mutation s Note The majority of mutations identified in CDKN2A are located in exons 1a and 2. These mutations affect either p16 alone or both p16 and p14ARF and appear to be associated solely with susceptibility to melanoma. A small number of mutations have been identified in exon 1b which appear to affect p14ARF alone.

Mutation spectrum for Melanoma-Astrocytoma Syndrome families. The extent of some deletions (pale blue) were predicted according to the map of 9p21 region at the time of publishing which has since been revised. The known regions of deletion given the current knowledge of the map of 9p21 are shown in dark blue.

Germinal Germline mutations affecting the CDKN2A locus have been described for a number of melanoma-astrocytoma syndrome families. To date no missense or nonsense mutations of the coding region have been identified. To date three families have been identified with deletions of part or all of the CDKN2 locus and a further two families have been identified with a splice acceptor mutation intron 1 of the CDKN2A gene leading to abnormal p16 and p14ARF mRNA transcripts. Concurrent loss of both p14ARF and p16 may therefore be responsible for the development of NSTs in this syndrome. In one family a deletion affecting the p14ARF-specific exon 1b was observed which was not predicted to affect p16 function suggesting abnormal p14ARF function alone may be the key factor in this family. Somatic According to COSMIC somatic mutations of CDKN2A are found in approximately 24% of sporadic melanoma and around 22% of tumours of the central nervous system dependent on tumour type.

External links Other http://www.sanger.ac.uk/genetics/CGP/cosmic/ database

Atlas Genet Cytogenet Oncol Haematol 2006; 4 632 Other http://www.wmi.usyd.edu.au:8080/melanoma.html database

Other http://www.genomel.org/ database

Bibliography A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma. Kaufman DK, Kimmel DW, Parisi JE, Michels VV. Neurology 1993; 43: 1728-1731 Medline 8414022

Familial cutaneous malignant melanoma and tumors of the nervous system. Azizi E, Friedman J, Pavlovsky F, Iscovich J, Bornstein A, Shafir R, Trau H, Brenner H, Nass D. Cancer 1995; 76: 1571-1578 Medline 8635060

Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumours. Bahuau M, Vidaud D, Jenkins RB, Bieche I, Kimmel DW, Assouline B, Smith JS, Alderete B, Cayuela J-M, Harpey J-P, Caille B, Vidaud M. Cancer Res. 1998; 58: 2298-2303 Medline 9622062

CDKN2A germline splicing mutation affecting both p16INK4A and p14ARF RNA processing in a melanoma/neurofibroma kindred. Petronzelli F, Sollima D, Coppola G, Martini-Neri ME, Neri G, Genuardi M. Genes Chrom. Cancer 2001; 31: 398-401. Medline 11433531

A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Randerson-Moor JA, Harland M, Williams S, Cuthbert-Heavens D, Sheridan E, Aveyard J, Sibley K, Whitaker L, Knowles M, Newton Bishop J, Bishop DT. Hum. Molec. Genet. 2001; 10: 55-62. Medline 11136714

Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma kindred. Prowse AH, Schultz DC, Guo S, Venderveer L, Dangel J, Bove B, Cairns P, Daly M, Godwin AK. J Med Genet 2003; 40: 102-108. Medline 12920094

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Trends and socioeconomic inequalities in cancer survival in England and Wales up to 2001. Coleman MP, Rachet B, Woods LM, Mitry E, Riga M, Cooper N, Quinn MJ, Brenner H, Esteve J. Br J Cancer 2004 ;90:1367-1373. Medline 15054456

Subcellular localization, modification and protein complex formation of the cdk-inhibitor p16 in Rb-functional and Rb-inactivated tumor cells. Nilsson K, Landberg G. Int J Cancer 2006;118:1120-1125. Medline 16161044

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 04- Juliette Randerson-Moor, Kairen Kukalizch, D Timothy Bishop 2006 Citation This paper should be referenced as such : Randerson-Moor J, Kukalizch K, Bishop TD . Melanoma-Astrocytoma syndrome. Atlas Genet Cytogenet Oncol Haematol. April 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/MelanomAstrocytomID10115.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 634 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MUTYH associated polyposis

Identity Other MAP (MUTYH-Associated Polyposis). names Inheritance MUTYH associated polyposis (MAP) is an autosomal recessive disorder, the frequency of heterozygotes carriers is 1-2% and the frequency of bi-allelic mutation carriers (according to Hardy-Weinberg equilibrium) lies between 1 per 10.000 and 40.000 newborns. Clinics Phenotype The penetrance for colon polyps is close to 100% and bi-allelic and clinics MUTYH mutation carriers generally develop 10-100¹s adenomatous polyps/adenomas of the colon and the rectum. Approximately one third of patients also develop polyps/adenomas in the upper gastrointestinal tract. Other manifestations frequently seen in Familial Adenomatous Polyposis (FAP) are also present in minority of MAP patients: osteomas, pigmented retinal lesions (congenital hypertrophy of the retinal pigment epithelium; CHRPE) and tooth disorders. Recently also sebaceous gland tumors (Muir-Torre syndrome) and pilomatricomas have been reported in MAP-kindreds. Neoplastic Because of the development of multiple polyps, the risk for colorectal risk carcinoma is high. About 60-70% of MAP patients were diagnosed with colorectal carcinoma at a mean age of 47 years, most at first presentation. The actual penetrance is probably higher, because the development of colorectal carcinoma can be prevented through intensive colorectal screening. Duodenum carcinoma reported in a minority (2 out of 50 MAP patients in the Netherlands). Treatment Colorectal screening, colonoscopy, starting from the age 20-25 years, every 2years. Upper gastrointestinal tract screening from the age of 25-30 years, depending of the stage of identified tumours (Spigelman stadia), follow- up every 1-5 years. In case the number of polyps is too large to be endoscopically removed, subtotal colectomy is indicated. Prognosis When frequent colorectal and upper gastrointestinal tract screening is performed in a MAP-patient who has not developed (colorectal) carcinoma, the change of developing (colorectal) carcinoma is small and prognosis will be comparable to that of a healthy population. In MAP patients who have developed colorectal carcinoma, survival will depend on the age of diagnosis and (Dukes) stage of the colorectal

Atlas Genet Cytogenet Oncol Haematol 2006; 4 635 carcinoma. Other findings Note In heterozygous MUTYH mutation carriers a (slight) increased risk for developing colorectal carcinoma has been found. A large case control research showed a relative risk of 1,5 for CRC in MUTYH heterozygous carriers aged > 55 years. Recently a ~3 fold increased risk in heterozygous carriers was found in a study based on relatives of MAP patients, which was significant in persons aged > 55 years and non- significant in persons aged < 55 years. So far, there is no conclusive evidence justifying colonoscopic screening in heterozygous MUTYH carriers. A possible relation between MUTYH and breast cancer has been reported because of a high prevalence of breast cancer cases in a group of Dutch female MAP patients (standardised morbidity ratio=3,75). Moreover, MUTYH knockout mouse that also carry heterozygous APC mutations are more prone to develop mammary tumours than APC-heterozygotes only. Case control studies will be necessary to confirm this relation in humans. In 148 gastric cancer cases one bi-allelic splice site mutation encoding a truncated MUTYH protein, c.IVS10-2A>G, was found. However, there was no significant higher number of MUTYH heterozygotes as compared to controls. Furthermore, no overrepresentation of MUTYH mutations (mono or bi-allelic) was found in patients with lung cancer, hepatocellular carcinoma, cholangiocarcinoma and (childhood) leukemia, compared to healthy controls. A suggested explanation for the relative absence of tumor growth at other places in MAP-patients is that oxidation is a more common effect in the digestive system and that the APC-gene has more sequences (AGAA or TGAA motifs, see heading somatic mutations) which are relatively dependent of MUTYH oxidative damage repair.

Genes involved and Proteins

Gene MUTYH (MUTYH (mutY homolog (E. coli))) Name Location 1p32.1-p34.3 DNA/RNA Description The MUTYH gene is composed of 16 exons and 15 introns. Protein

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Three component system of 8-oxoG repair The MUTYH-protein recognizes the 8-oxoG:A base-pair and excises the improperly incorporated adenine during replication, after which other reparation proteins can place a cytosine opposite the 8-oxoG. OGG1 then can excise the 8-oxoG from the 8-oxoG:C base-pair (a) MTH1 works separately, and cleanses the cellular nucleotide pool

from oxidized precursors of guanine (d°GTP) en prevents incorporation of 8-oxo G in the DNA (b) The three components 'base excision repair' mechanism thus prevents the incorporation of d°GTP in the DNA and subsequently G:C naar T:A and A:T to C:G transversions. Based on figure from Michaels 1992.

Description The full-length MUTYH protein contains 546 amino acids (60-65kDa). For mutation description the coding sequence is described and used, which differs because of the absence of 11 codons in exon 3. DESCRIPTION Alternative splicing generates a gene product of 521 amino Acids, referred as type 2. Type 1 is transported to the mitochondria, while type 2 lacks the first exon containing a mitochondrial targeting signal (MTS) and is transported to nucleus. Expression Expression of MUTYH has been found among others in the digestive system, germ cells, thymus,(rat-) brain, (mouse-) liver and (canine-) myocardium. Probably, the MUTYH protein is expressed widely, because the production of reactive oxygen species (ROS) leading to oxidative damage is generated during normal cellular oxygen metabolism and by oxygen stress conditions in all cells. Localisation MUTYH is located in the nucleus and mitochondria. Function The MUTYH protein is a base excision repair glycosylase which is involved in the repair of one of the most frequent and stable forms of oxidative damage, oxidation of a guanine leading to 8-oxo-7,8-dihydro-

Atlas Genet Cytogenet Oncol Haematol 2006; 4 637 2'-deoxyguanosine (8-oxoG). Other base excision repair glycosylases involved in oxidised guanine repair are the OGG1 and MTH1 protein (figure1) MUTYH recognizes an oxoG:A mismatch and subsequently excises the undamaged adenine base using a baseflipping mechanism. To a lesser extent also G:A, C:A, 8-oxoG:G and 8-oxoA:G mispairs are recognised and catalysed by MUTYH. The MUTYH protein consists of different functional domains. The N-terminal domain on the 5' side contains the catalytic region and includes a helixhairpinhelix (HhH), pseudo HhH and an ironsulfur cluster loop motif, which are also common motifs in other BER glycosylases. The C-terminal domain on the 3' side is shares homology with MTH1 and plays a role in 8-oxoG recognition. Furthermore, MUTYH has binding sites for PCNA (proliferating cell nuclear antigen), RPA (replication protein A) and AP (apurinic/apyrimidinic) endonuclease. The interaction with these replication enzymes and a reported increase of expression during the S phase suggests a role for MUTYH especially in the replication-coupled repair. In E.coli it was demonstrated that the MUTYH homologue, mutY, recognizes the nascent strand in association with various cellular proteins such as PCNA or a mismatch repair genes complex. Remarkably, it was demonstrated that amino acid residues 232-254 of MUTYH interacts with the MSH2/MSH6 heterodimer via MSH6 and this interaction stimulates the glycosylase activities of MUTYH. Homology The percentage of similarity between the human muty gene (MUTYH) and that of various organisms is: 99% in chimpanzee, 80% in dog, 79% in mouse, 77% in rat, 66% in chicken and 41% in E.coli. Mutations Germinal About thirty pathogenic mutations in the MUTYH gene have been described; predominantly missense mutations, but to a lesser extent also small deletions, small insertions, (putative) splice site mutations and one gross deletion. Most common mutations found (in Western population) are the Tyr165Cys (Y165C) and Gly382Asp (G382D), which compromise about 70-75% of mutations in Western MAP patients. Other common mutations are: A371fs (c.1105delC, sometimes referred to as 1103delC); c.891+3A>C; P391L in Dutch patients (14%); Glu466del (c.1395delGGA) in Italian and the E466X in Indian people. The Y165C mutation is located in the pseudo HhH region that is involved in mismatch specificity and flipping of the adenine into the base specificity pocket. The G382D is located in the C-terminal domain involved in 8-oxoG recognition. In functional tests especially the Y165C, but also the G382D variants, have shown to be devoid of glycosylase activity directed towards 8-oxoG:A. The corresponding variant of G382D in mice, G365D, does not suppress the elevated spontaneous mutations in MUTHY-null ES cells and failed to prevent OGG1 from excising 8-oxo G opposite the generated AP site-which would then result in double strand DNA breaks. Recently, the 1105 delC variant showed significantly lowered binding and cleavage activities with heteroduplex oligonucleotides containing

Atlas Genet Cytogenet Oncol Haematol 2006; 4 638 A:8-oxoG and 8-oxoA:G mispairs. Several SNP's (single nucleotide polymorphism) with amino acid substitutions have been registered in the NCBI database. Most frequently found in cases and controls: His 324Gln (Q324H) in 40-45% and IVS6+ 35 (462 +35) G>A in 20-25%. Pathogenic significance of the V22M SNP is disputed; it¹s prevalence in controls and in cases is comparable (10-15%). Somatic In the tumours of MAP patients specific G:C>T:A somatic transversions are found in APC and KRAS2 genes in up to 40% and 64% of cases, respectively. In APC G>T transversions have a predilection for G bases in AGAA or TGAA motifs, whereas in KRAS2 a preferential GGT>TGT transition of codon 12 (p.Gly12Cys) is found. All MAP tumours examined so far are MSI stable. One study found 18q LOH and P53 over-expression in the same frequency as in sporadic carcinomas. Few P53 mutations were found however and predominantly not G>T changes. No BRAF, SMAD4 or TGFBIIR mutations were detected in the same group of MAP-carcinomas. Twelve out of 13 MAP cancers tested were near-diploid. This last finding is in contrast with a more recent study that found aneuploidy in 80% of MAP- adenomas and also frequent losses at chromosome 1p, 17, 19, and 22 and gains affecting chromosomes 7 and 13. Authors explained the difference in outcomes because of the use of more sensitive and specific techniques in the last.

Bibliography The GO system protects organisms from the mutagenic effect of the spontaneous lesion 8-hydroxyguanine (7,8-dihydro-8-oxoguanine). Michaels ML, Miller JH. J Bacteriol 1992; 174(20): 6321-6325. (REVIEW). Medline 1328155

Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. Slupska MM, Baikalov C, Luther WM, Chiang JH, Wei YF, Miller JH. J Bacteriol 1996; 178(13): 3885-3892 Medline 8682794

Cloning, overexpression, and biochemical characterization of the catalytic domain of MutY. Manuel RC, Lloyd RS. Biochemistry 1997; 36(37): 11140-1152. Medline 9287157

MutY catalytic core, mutant and bound adenine structures define specificity for DNA repair enzyme superfamily. Guan Y, Manuel RC, Arvai AS, Parikh SS, Mol CD, Miller JH, Lloyd S, Tainer JA.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 639 Nat Struct Biol 1998; 5: 1058-1064. Medline 9846876

Differential subcellular localization of human MutY homolog (hMYH) and the functional activity of adenine:8-oxoguanine DNA glycosylas. Takao M, Zhang QM, Yonei S, Yasui A. Nucleic Acids Res 1999; 27(18): 3638-3644. Medline 10471731

Purification and characterization of a mammalian homolog of Escherichia coli MutY mismatch repair protein from calf liver mitochondria. Parker A, Gu Y, Lu AL. Nucleic Acids Res 2000; 28(17): 3206-3015. Medline 10954587

Efficient recognition of substrates and substrate analogs by the adenine glycosylase MutY requires the C-terminal domain. Chmiel NH, Golinelli M-P, Francis AW, David SS. Nucl Acids Res 2001; 29: 553-564 Medline 11139626

Repair of oxidative DNA damage: mechanisms and functions. Lu AL, Li X, Gu Y, Wright PM, Chang DY. Cell Biochem Biophys 2001; 35(2): 141-170. (REVIEW). Medline 11892789

Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair. Parker A, Gu Y, Mahoney W, Lee SH, Singh KK, Lu AL. J Biol Chem 2001; 276(8): 5547-5555. Epub 2000 Nov 22. Medline 11092888

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Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, Hodges AK, Davies DR, David SS, Sampson JR, Cheadle JP. Nat Genet 2002; 30(2): 227-232. Epub 2002 Jan 30. Medline 11818965

Hypoxia induces mitochondrial DNA damage and stimulates expression of a DNA repair enzyme, the Escherichia coli MutY DNA glycosylase homolog (MYH), in vivo, in the rat brain. Lee HM, Wang C, Hu Z, Greeley GH, Makalowski W, Hellmich HL, Englander EW. J Neurochem 2002; 80(5): 928-937. Medline 11948257

Analysis of MYH Tyr165Cys and Gly382Asp variants in childhood leukemias. Akyerli CB, Ozbek U, Aydin-Sayitoglu M, Sirma S, Ozcelik T. J Cancer Res Clin Oncol 2003; 129(10): 604-605. Medline 12920580

Exposing the MYtH about base excision repair and human inherited disease. Cheadle JP, Sampson JR. Hum Mol Genet 2003; 12 Spec No 2: R159-65. (REVIEW). Medline 12915454

Mutator phenotype of MUTYH-null mouse embryonic stem cells. Hirano Y, Tominaga A, Ichinoe Y, Ushijima D, Tsuchimoto Y, Honda-Ohnishi T, Ohtsubo K, Sakumi Y, Nakabeppu. J Biol Chem 2003; 278: 38121-38124. Medline 12917422

Atlas Genet Cytogenet Oncol Haematol 2006; 4 641 Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, Bisgaard ML, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJ, Tomlinson IP. N Engl J Med 2003; 348(9): 791-799. Medline 12606733

Inherited variants in MYH are unlikely to contribute to the risk of lung carcinoma. Al-Tassan N, Eisen T, Maynard J, Bridle H, Shah B, Fleischmann C, Sampson JR, Cheadle JP, Houlston RS. Hum Genet 2004; 114(2): 207-210. Medline 14579148

Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Gismondi V, Meta M, Bonelli L, Radice P, Sala P, Bertario L, Viel A, Fornasarig M, Arrigoni A, Gentile M, Ponz de Leon M, Anselmi L, Mareni C, Bruzzi P, Varesco L. Int J Cancer 2004; 109(5): 680-684. Medline 14999774

Role of inherited defects of MYH in the development of sporadic colorectal cancer. Kambara T, Whitehall VL, Spring KJ, Barker MA, Arnold S, Wynter CV, Matsubara N, Tanaka N, Young JP, Leggett BA, Jass JR. Genes Chromosomes Cancer 2004; 40(1): 1-9. Medline 15034862

Genetic alterations of the MYH gene in gastric cancer. Kim CJ, Cho YG, Park CH, Kim SY, Nam SW, Lee SH, Yoo NJ, Lee JY, Park WS. Oncogene 2004; 23(40): 6820-6822. Medline 15273732

Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease. Gao D, Wei C, Chen L, Huang J, Yang S, Diehl AM. Am J Physiol Gastrointest Liver Physiol 2004; 287(5): G1070-G1077. Medline 15231485

Atlas Genet Cytogenet Oncol Haematol 2006; 4 642 Expression of DNA repair protein: MYH, NTH1, and MTH1 in colorectal cancer. Koketsu S, Watanabe T, Nagawa H. Hepatogastroenterology 2004; 51(57): 638-642. Medline 15143881

Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/+) mice. Sieber OM, Howarth KM, Thirlwell C, Rowan A, Mandir N, Goodlad RA, Gilkar A, Spencer-Dene B, Stamp G, Johnson V, Silver A, Yang H, Miller JH, Ilyas M, Tomlinson IP. Cancer Res 2004; 64(24): 8876-8881. Medline 15604247

A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus. Tao H, Shinmura K, Hanaoka T, Natsukawa S, Shaura K, Koizumi Y, Kasuga Y, Ozawa T, Tsujinaka T, Li Z, Yamaguchi S, Yokota J, Sugimura H, Tsugane S. Carcinogenesis 2004; 25 (10): 1859-1866. Medline 15180946

MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain. Tominaga Y, Ushijima Y, Tsuchimoto D, Mishima M, Shirakawa M, Hirano S, Sakumi K, Nakabeppu Y. Nucleic Acids Res 2004; 32: 3198-3211. Medline 15199168

Identification of critical residues required for the mutation avoidance function of human MutY (hMYH) and implications in colorectal cancer. Wooden SH, Bassett HM, Wood TG, McCullough AK. Cancer Lett 2004; 205: 89-95. Medline 15036665

A kindred with MYH-associated polyposis and pilomatricomas. Baglioni S, Melean G, Gensini F, Santucci M, Scatizzi M, Papi L, Genuardi M. Am J Med Genet A. 2005; 134(2): 212-214. Medline 15690400

Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Farrington SM, Tenesa A, Barnetson R, Wiltshire A, Prendergast J, Porteous M, Campbell H, Dunlop MG. Am J Hum Genet 2005; 77(1): 112-119. Medline 15931596

Atlas Genet Cytogenet Oncol Haematol 2006; 4 643 Attenuation of DNA damage in canine hearts preserved by continuous hypothermic perfusion. Fitton TP, Barreiro CJ, Bonde PN, Wei C, Gage F, Rodriguez R, Conte JV. Ann Thorac Surg 2005; 80(5): 1812-1820. Medline 16242460

Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). Nielsen M, Franken PF, Reinards TH, Weiss MM, Wagner A, van der Klift H, Kloosterman S, Houwing-Duistermaat JJ, Aalfs CM, Ausems MG, Brocker-Vriends AH, Gomez Garcia EB, Hoogerbrugge N, Menko FH, Sijmons RH, Verhoef S, Kuipers EJ, Morreau H, Breuning MH, Tops CM, Wijnen JT, Vasen HF, Fodde R, Hes FJ. J Med Genet 2005; 42(9): e54. Medline 16140997

Cells with pathogenic bi-allelic mutations in the human MUTYH gene are defective in DNA damage binding and repair. Parker AR, Sieber OM, Shi C, Hua L, Takao M, Tomlinson IP, Eshleman JR. Carcinogenesis 2005; 26(11): 2010-2018. Medline 15987719

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations. Ponti G, Ponz de Leon M, Maffei S, Pedroni M, Losi L, Di Gregorio C, Gismondi V, Scarselli A, Benatti P, Roncari B, Seidenari S, Pellacani G, Varotti C, Prete E, Varesco L, Roncucci L. Clin Genet 2005; 68(5): 442-447. Medline 16207212

MYH Y165C and G382D mutations in hepatocellular carcinoma and cholangiocarcinoma patients. Baudhuin LM, Roberts LR, Enders FT, Swanson RL, Mettler TA, Aderca I, Stadheim LM, Highsmith WE. J Cancer Res Clin Oncol 2006; 132(3): 159-162. Medline 16292541

Chromosomal instability in MYH- and APC-mutant adenomatous polyps. Cardoso J, Molenaar L, de Menezes RX, van Leerdam M, Rosenberg C, Moslein G, Sampson J, Morreau H, Boer JM, Fodde R. Cancer Res 2006; 66(5): 2514-2519. Medline 16510566

Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Jenkins MA, Croitoru ME, Monga N, Cleary SP, Cotterchio M, Hopper JL, Gallinger S.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 644 Cancer Epidemiol Biomarkers Prev 2006; 15(2): 312-314. Medline 16492921

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 05- Maartje Nielsen, Frederik J. Hes 2006 Citation This paper should be referenced as such : Nielsen M, Hes F . MUTYH associated polyposis. Atlas Genet Cytogenet Oncol Haematol. May 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/MYHpolypID10121.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 645 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MAP (MUTYH-Associated Polyposis )

Identity Note MAP is a recently described condition predisposing to colorectal cancer, caused by germline mutations in the base excision repair (BER) gene MUTYH (MYH). The first description of an affected family was provided in 2002. Other MYH associated polyposis names Inheritance Autosomal recessive. Heterozygote frequency in the general population is currently estimated as 0.01-0.02. Clinics Phenotype The phenotype is often undistinguishable from that of autosomal and clinics dominant familial adenomatous polyposis (FAP) caused by mutations in APC gene. The number of adenomas is often lower in MAP (from 5 to more than 100), and affected patients are often sporadic cases. Biallelic MUTYH mutations have also been detected in patients affected with early-onset colorectal cancer (CRC) without polyps and in one with more than 1000 polyps. Cancers are more frequently located in the proximal side of the colon compared to APC-related FAP. Generally, mean age at diagnosis of MAP is 48-56 years, later than in APC-related FAP. A number of extracolonic manifestations have been observed, although their incidence is not yet well established. These include manifestations that are also associated with APC-related FAP, such as duodenal polyposis, duodenal cancer, osteomas, dental cysts and congenital hypertrophy of the retinal pigment epithelium. Breast cancer and thyroid cancer, and cutaneous tumors (pilomatricomas and sebaceous gland tumors) have also been reported. Neoplastic Penetrance of CRC is approximately 100% by age 65 years. risk Approximately 50% of patients present with CRC at the time of diagnosis. CRC risk in heterozygotes is not defined: some authors believe that monoallelic mutations may act as low penetrance alleles, increasing CRC risk, but larger studies with sufficient statistical power are necessary to accurately estimate the magnitude of such risk, if any. Treatment No specific screening guidelines have yet been established. Periodic colonoscopy of the entire colon should be offered to biallelic mutations carriers. Prophylactic colectomy should be considered when number, size and/or dysplasia of the polyps make continued surveillance unmanageable. Upper gastrointestinal surveillance is also indicated. Parents and children of individuals with biallelic mutations are obligate carriers of at least one MUTYH mutation. A baseline colonscopy has been suggested for these carriers, and, if findings are negative,

Atlas Genet Cytogenet Oncol Haematol 2006; 4 646 screening should be repeated every 3-5 years. Genes involved and Proteins

Gene MUTYH (human MutY homologue) Name Location 1p34.3-p32.1 Protein Note MUTYH glycosylase Description MUTYH is a DNA glycosylase that plays a key role in BER-mediated removal of 8-oxoG:A mismatches. Mutations Note Most reported mutations in this gene cause production of a nonfunctional or low-functioning glycosylase enzyme. The two most common mutations in Caucasians, accounting for about 75%-80% of mutant alleles, are Y165C (or Tyr165Cys) and G382D (or Gly382Asp).

Bibliography Inherited variants of MYH associated with somatic G:C --> T:A mutations in colorectal tumors. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, Hodges AK, Davies DR, David SS, Sampson JR, Cheadle JP. Nat Genet 2002; 30: 227232. Medline 11818965

Proportion and phenotype of MYH associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients. Enholm S, Hienonen T, Suomalainen A, Lipton L, Tomlinson I, Karja V, Eskelinen M, Mecklin JP, Karhu A, Jarvinen HJ, Aaltonen LA. Am J Pathol 2003; 163: 827832. Medline 12937124

Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers Halford SE, Rowan AJ, Lipton L, Sieber OM, Pack K, Thomas HJ, Hodgson SV, Bodmer WF, Tomlinson IP. Am J Pathol 2003; 162: 1545-1548. Medline 12707038

Atlas Genet Cytogenet Oncol Haematol 2006; 4 647 IP. Cancer Res 2003; 63:7595-7599. Medline 14633673

Comprehensive analysis of the contribution of germline MYH variation to early- onset colorectal cancer. Fleischmann C, Peto J, Cheadle J, Shah B, Sampson J, Houlston RS. Int J Cancer 2004; 109: 554558. Medline 14991577

MYH mutations in patients with attenuated and classic polyposis and with

Atlas Genet Cytogenet Oncol Haematol 2006; 4 648 young-onset colorectal cancer without polyps. Wang L, Baudhuin LM, Boardman LA, Steenblock KJ, Petersen GM, Halling KC, French AJ, Johnson RA, Burgart LJ, Rabe K, Lindor NM, Thibodeau SN. Gastroenterology 2004; 127: 9-16. Medline 15236166

A kindred with MYH-associated polyposis and pilomatricomas. Baglioni S, Melean G, Gensini F, Santucci M, Scatizzi M, Papi L, Genuardi M Am J Med Genet 2005; 134: 212-214. Medline 15690400

Germline Susceptibility to Colorectal Cancer Due to Base-Excision Repair Gene Defects. Farrington SM, Tenesa A, Barnetson R, Wiltshire A, Prendergast J, Porteous M, Campbell H, Dunlop MG. Am J Hum Genet 2005; 77:112-119. Medline 15931596

Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations. Kairupan CF, Meldrum CJ, Crooks R, Milward EA, Spigelman AD, Burgess B, Groombridge C, Kirk J, Tucker K, Ward R, Williams R, Scott RJ. Int J Cancer 2005; 113: 73-77. Medline 15761860

Is prophylactic colectomy indicated in patients with MYH-associated polyposis? Leite JS, Isidro G, Martins M, Regateiro F, Albuquerque O, Amaro P, Romaozinho JM, Boavida G, Castro-Sousa F. Colorectal Dis 2005; 327-331. Medline 15932553

Atlas Genet Cytogenet Oncol Haematol 2006; 4 649 Clin Genet 2005; 68: 442-447. Medline 16207212

MutYH (MYH) and colorectal cancer. Sampson JR, Jones S, Dolwani S, Cheadle JP Biochem Soc Trans 2005; 33: 679-683. Medline 16042573

A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history. Truta B, Allen BA, Conrad PG, Weinberg V, Miller GA, Pomponio R, Lipton LR, Guerra G, Tomlinson IP, Sleisenger MH, Kim YS, Terdiman JP. Fam Cancer 2005; 4:127-133. Medline 15951963

Germline mutations in the MYH gene in Swedish familial and sporadic colorectal cancer. Zhou XL, Djureinovic T, Werelius B, Lindmark G, Sun XF, Lindblom A; Swedish Low- Risk Colorectal Cancer Group. Genet Test 2005; 9:147-151. Medline 15943555

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W. Int J Cancer 2006; [Epub ahead of print] Medline 16557584

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 06- Benedetta Toschi, Maurizio Genuardi 2006 Citation This paper should be referenced as such : Toschi B, Genuardi M . MAP (MUTYH-Associated Polyposis ). Atlas Genet Cytogenet Oncol Haematol. June 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/MAPID10092.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 650 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Dianzani Autoimmune Lymphoproliferative Disease (DALD)

Identity Note Variant of the Autoimmune Lymphoproliferative Syndrome (ALPS) Inheritance Possibly, an oligogenic disease. Clinics Phenotype Paediatric onset with: and clinics 1) Autoimmunity, that is predominantly haematological, but any other autoimmunity can be displayed; 2) Enlargement of the spleen and/or lymph nodes due to accumulation of polyclonal lymphocytes; 3) Decreased function of the Fas death receptor. These patients lack the peripheral blood expansion of T cells expressing the TCR alpha/TCR beta but not CD4and CD8 (double-negative T cells), that are present in the typical form of ALPS. Neoplastic 2.5 fold increased risk of cancer (both haematological and not risk haematological). Treatment Immune suppression. Evolution Autoimmunity may remit in adulthood but lymphoproliferation generally persists. Increased risk of lymphomas and other cancers in adulthood. Prognosis Good on survival, but the autoimmune haemolitic anemia may be occasionally lethal. Genes involved and Proteins Note The disease is due to inherited defects decreasing function of the Fas (CD95) death receptor, involved in switching off the immune response by triggering apoptosis of activated lymphocytes. The mutation possibly hits unknown genes involved in Fas signalling. The Fas, Fas ligand, caspase-10, caspase-8 genes, that can be involved in ALPS are not mutated. The genetic background may influence the disease onset. Variants of the gene of osteopontin or perforin (see above) can act as predisposition factors.

Gene OPN Name Location 4q21-q25

Atlas Genet Cytogenet Oncol Haematol 2006; 4 651 DNA/RNA Description Encoded in 7 exons spanning 5.4-8.2 Kb. Protein Description Protein of 287-314 aa. Several OPN forms originate from alternative splicing, phosphorylation, glycosylation, and proteolitic cleavage and mediate partly distinct functions. Expression Constitutively expressed by bone and several epithelial tissues, whereas in endothelial cells, macrophages and smooth muscle cells, it is mainly expressed upon activation in inflammatory contexts. Moreover, it is expressed by activated T-cells. Localisation Secreted cytokine. Function Functions as a free cytokine in body fluids or an immobilized extracellular matrix molecule in mineralized tissues. Plays a role in cell-to-cell and cell-to-extracellular matrix interaction by binding to several integrins and the CD44v6-7 isoforms, triggering signals involved in cell activation and migration. Involved in bone remodeling, tissue repair, and cell migration. It potentiates T-cell proliferation, IFN-gamma production, and CD40L expression, which in turn favor B-cell proliferation and antibody production. Mutations Germinal Polymorphic variants of the gene have been associated with increased susceptibility to develop DALD. Four polymorphisms, corresponding to position +282T/C (exon VI), +750C/T (exon VII, coding region), +1083A/G and +1239A/C (3¹ UTR) (ATG = +1), form 3 haplotypic combinations: Haplotype-A (282T-750C-1083A-1239A), Haplotype-B (282C-750T-1083A-1239C), Haplotype-C (282C-750T-1083G-1239C). Subjects carrying haplotype-B and/or -C have a 8-fold higher risk of developing DALD than haplotype-A homozygotes. Haplotype-B and -C causes production of increased levels of osteopontin, possibly because of higher stability of its mRNA.

Gene PRF1 Name Location 10q22 Note Biallelic mutations of PRF1 cause the familial hemophagocytic lymphohistiocytosis (HLH), an immune deficiency ascribed to decreased capacity of cytotoxic lymphocytes (CD8+ T cells and NK cells) to kill virus-infected cells. DNA/RNA Description Encoded in 3 exons spanning 5.4 Kb.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 652 Protein Description Protein of 436 aa. Expression Expressed by cytotoxic effector lymphocytes (activated cytototoxic T cells and NK cells). Localisation It is stored in the lytic granules and secreted against the target cell. Function It polymerizes on the membrane of target cells and forms pores. Homology High sequenze homology to the C9 complement component. Mutations Germinal Several PRF1 mutations have been associated with HLH and lymphomas. These mutations can inhibit either expression or function of perforin. The A91V amino acid substitution decreases perforin function by altering its conformation, decreasing its cleavage to the active form, and increasing its degradation. Carriers of this variation show decreased NK activity. A91V is relatively frequent in control population (4.6%), but it has been associated with HLH, when combined with a second PRF1 variation. By contrast, it may favor DALD development when inherited defects hitting Fas function are also present. Its presence, in fact, increases the risk of DALD by 3 fold.

Bibliography Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. Dianzani U, Bragardo M, DiFranco D, Alliaudi C, Scagni P, Buonfiglio D, Redoglia V, Bonissoni S, Correra A, Dianzani I, Ramenghi U. Blood 1997; 89: 2871-2879. Medline 9108407

Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint Basile G, Kumar V. Science 1999; 286: 1957-1959. Medline 10583959

Deficiency of the Fas apoptosis pathway without Fas gene mutations is a familial trait predisposing to development of autoimmune diseases and cancer. Ramenghi U, Bonissoni S, Migliaretti G, DeFranco S, Bottarel F, Gambaruto C, DiFranco D, Priori R, Conti F, Dianzani I, Valesini G, Merletti F, Dianzani U. Blood 2000; 95: 3176-3182. Medline 10807785

High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation. Chiocchetti A, Indelicato M, Bensi T, Mesturini R, Giordano M, Sametti S, Castelli L, Bottarel F, Mazzarino MC, Garbarini L, Giacopelli F, Valesini G, Santoro C, Dianzani

Atlas Genet Cytogenet Oncol Haematol 2006; 4 653 I, Ramenghi U, Dianzani U. Blood 2004; 103:1376-1382. Medline 14592838

The broad spectrum of autoimmune lymphoproliferative disease: molecular bases, clinical features and long-term follow-up in 31 patients. Campagnoli MF, Garbarini L, Quarello P, Garelli E, Carando A, Baravalle V, Doria A, Biava A, Chiocchetti A, Rosolen A, Dufour C, Dianzani U, Ramenghi U. Haematologica 2006; 91:538-541. Medline 16537120

Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective fas function. Clementi R, Chiocchetti A, Cappellano G, Cerutti E, Ferretti M, Orilieri E, Dianzani I, Ferrarini M, Bregni M, Danesino C, Bozzi V, Putti MC, Cerutti F, Cometa A, Locatelli F, Maccario R, Ramenghi U, Dianzani U. Blood. 2006, [Epub ahead of print] Medline 16720836

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 07- Umberto Dianzani, Ugo Ramenghi, Annalisa Chiocchetti 2006 Citation This paper should be referenced as such : Dianzani U, Ramenghi U, Chiocchetti A . Dianzani Autoimmune Lymphoproliferative Disease (DALD). Atlas Genet Cytogenet Oncol Haematol. July 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/DianzaniALDID10111.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 654 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Autoimmune Lymphoproliferative Syndrome

Identity Other ALPS names Inheritance autosomal dominant or recessive Clinics Phenotype Paediatric onset with : and clinics 1) autoimmunity, that is predominantly haematological, but any other autoimmunity can be displayed. 2) enlargement of the spleen and/or lymph nodes due to accumulation of polyclonal lymphocytes. 3) peripheral blood expansion of T cells expressing the TCRalpha/beta but not CD4 and CD8 (double-negative T cells). 4) decreased function of the Fas death receptor. Neoplastic increased risk of lymphomas risk Treatment vigorous immune suppression Evolution autoimmunity may remit in adulthood but lymphoproliferation generally persists. Increased risk of lymphomas in adulthood. Prognosis good on survival, but autoimmune haemolytic anaemia may be occasionally lethal. Genes involved and Proteins Note The disease is due to inherited defects decreasing function of the Fas (CD95) death receptor, involved in switching off the immune response by triggering apoptosis of activated lymphocytes. The mutation mostly hits the Fas gene (ALPS type-Ia), but rare mutations of the Fas ligand gene (ALPS type-Ib) or the caspase-10 gene (ALPS-type-IIa) gene have also been described. Two siblings carrying a homozygous mutation of the caspase-8 gene displayed ALPS plus hypogammaglobulinemia and increased susceptibility to infections; this disease has been named caspase-8 deficiency, but some authors included it in ALPS as ALPS type-IIb. Caspase-8 and caspase-10 are involved in Fas signalling. Some authors used the term ALPS type-III to name the disease caused by unknown mutations hitting the Fas signalling pathway, others used it to name ALPS displayed by patients with normal Fas function. Rieux-Laucat described a subgroup of patients carrying somatic mutations of the Fas gene in a subset of peripheral lymphocytes (mosaic ALPS type-Ia or ALPS type-Iam).

Atlas Genet Cytogenet Oncol Haematol 2006; 4 655 Since most patients with ALPS-Ia are heterozygous, the term ALPS type-0 has been used to name the rare and aggressive disease caused by homozygous mutations of the Fas gene. The genetic background may influence the disease onset. Variants of the gene of perforin can act as predisposition factors.

Gene TNFRSF6 Name Location 10q24.1 DNA/RNA Description encoded in 9 exons spanning 25 Kb Protein Description protein of 320 aa. Several isoforms originating from alternative splicing have been described. It contains three Cysteine-rich Domains and one Death Domain. Expression expressed by activated lymphocytes, but also in multiple tissues and cell types. Localisation type-1 transmembrane protein Function death receptor. It triggers apoptosis upon ligation by its ligand (Fas ligand, FasL). It is involved in switching off the immune response and cell-mediated cytotoxicity. Homology Belongs to the tumor necrosis factor receptor family, subgroup pf death receptor Mutations Germinal multiple loss-of-function mutations have been reported in ALPS. They may decrease Fas expression or cause expression of receptors with dominant negative activity on Fas function. Mutations in the death domain have the highest penetrance. Somatic somatic mutations of the Fas gene have been reported in ALPS type- Iam

Gene FasL Name Location 1q23 DNA/RNA Description encoded in 4 exons spanning 7.8 Kb Protein Description protein of 281 aa Expression activated cytotoxic cells (CTL and NK) and TH1 cells, but also

Atlas Genet Cytogenet Oncol Haematol 2006; 4 656 expressed in other tissues Localisation type II transmembrane protein Function triggers apoptosis of Fas-expressing cells Mutations Germinal two patients with ALPS type-Ib have been described to date. One carried a 84-bp deletion in exon 4 causing a 28-aa in-frame deletion. The other carried a A247E substitution in exon 4. Both mutations decreased FasL function.

Gene CASP10 Name Location 2q33-q34 DNA/RNA Description encoded in 9 exons spanning 37 Kb Protein Description protein of 479 amino acids Expression ubiquitous Localisation cytosolic Function cystein-aspartate protease (caspase) triggering apoptosis. It is involved in the extrinsic pathway of apoptosis. Mutations Germinal heterozygous L285F and I406L substitutions have been detected in 2 patients with ALPS type-IIa

Gene CASP8 Name Location 2q33-q34 DNA/RNA Description encoded in 10 exons spanning 54 Kb Protein Description protein of 496 amino acids. Several isoforms deriving from alternative splicing have been described. Expression ubiquitous Localisation cytosolic Function cystein-aspartate protease (caspase) triggering apoptosis. It binds to the adapter molecule FADD that associates with the intracytoplasmic tail of death receptors such as Fas and triggers the extrinsic pathway of

Atlas Genet Cytogenet Oncol Haematol 2006; 4 657 apoptosis. Mutations Germinal homozygous R248W substitutions has been described in two siblings with ALPS plus immunodeficiency. The mutated protein lost the enzyme activity.

Gene PRF1 Name Location 10q22 Note biallelic mutations of PRF1 cause the familial hemophagocytic lymphohistiocytosis (HLH), an immune deficiency ascribed to decreased capacity of cytotoxic lymphocytes (CD8+ T cells and NK cells) to kill virus-infected cells. DNA/RNA Description encoded in 3 exons spanning 5.4 Kb Protein Description protein of 436 aa Expression expressed by cytotoxic effector lymphocytes (activated cytototoxic T cells and NK cells) Localisation it is stored in the lytic granules and secreted against the target cell Function it polymerizes on the membrane of target cells and forms pores Homology high sequenze homology to the C9 complement component Mutations Germinal several PRF1 mutations have been associated with HLH and lymphomas. These mutations can inhibit either expression or function of perforin. A heterozygous N252S amino acid substitution has been described in one patient with ALPS type-Ia (i.e. carrying also a heterozygous mutation of the Fas gene) and one patient with ALPS type-III (i.e. with defective Fas function caused by an unknown gene alteration). It has been suggested that the PRF1 mutation may cooperate with the mutation hitting the Fas system in inducing ALPS development.

Bibliography Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM. Cell 1995; 81:935-946. Medline 7540117

Atlas Genet Cytogenet Oncol Haematol 2006; 4 658 Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, de Villartay JP. Science 1995; 268:1347-1349. Medline 7539157

Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. Wu J, Wilson J, He J, Xiang L, Schur PH, Mountz JD. J Clin Invest 1996; 98:1107-1113. Medline 8787672

Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. Dianzani U, Bragardo M, DiFranco D, Alliaudi C, Scagni P, Buonfiglio D, Redoglia V, Bonissoni S, Correra A, Dianzani I, Ramenghi U. Blood 1997; 89: 2871-2879. Medline 9108407

Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M, Yao X, Puck JM, Straus SE, Lenardo MJ. Cell. 1999 Jul 9;98(1):47-58. Medline 10412980

Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Jackson CE, Fischer RE, Hsu AP, Anderson SM, Choi Y, Wang J, Dale JK, Fleisher TA, Middelton LA, Sneller MC, Lenardo MJ, Straus SE, Puck JM. Am J Hum Genet 1999; 64:1002-14. Medline 10090885

Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ. Nature 2002; 419:395-9. Medline 12353035

A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome. Del-Rey M, Ruiz-Contreras J, Bosque A, Calleja S, Gomez-Rial J, Roldan E, Morales P, Serrano A, Anel A, Paz-Artal E, Allende LM. Blood 2006 [Epub ahead of print]. Medline 16627752

Atlas Genet Cytogenet Oncol Haematol 2006; 4 659

Autoimmune lymphoproliferative syndrome with somatic Fas mutations. Holzelova E, Vonarbourg C, Stolzenberg MC, Arkwright PD, Selz F, Prieur AM, Blanche S, Bartunkova J, Vilmer E, Fischer A, Le Deist F, Rieux-Laucat F. N Engl J Med 2004; 351:1409-18. Medline 15459302

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 07- Umberto Dianzani, Ugo Ramenghi 2006 Citation This paper should be referenced as such : Dianzani U, Ramenghi U . Autoimmune Lymphoproliferative Syndrome. Atlas Genet Cytogenet Oncol Haematol. July 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/AutoimmLymphoID10116.html

Atlas Genet Cytogenet Oncol Haematol 2006; 4 660 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Architecture de la chromatine dans le noyau interphasique (The English version will soon replace this version)

* Introduction I. Organisation 3D de la chromatine dans le noyau interphasique 1. Relations de la chromatine avec les structures nucléaires 2. Notion de territoires chromosomiques 3. Topographie des territoires 4. Interface entre territoires voisins 5. Modèle d’organisation de la chromatine dans le noyau interphasique II. Evolution relative des territoires les uns par rapport aux autres au cours des cycles cellulaires successifs III. Le noyau, une structure dynamique à 4 dimensions Conclusion *

Introduction Depuis la fin du XIXe siècle et les travaux de Rabl, de nombreuses hypothèses ont été émises quant à l'existence ou non d'une architecture organisée et contrôlée de la chromatine pendant l'interphase, hypothèses qui ont évolué en fonction des techniques disponibles pour les vérifier. Ainsi, pour Rabl, il devait exister une compartimentalisation du noyau, chaque chromosome occupant un territoire défini. Cette hypothèse reposait essentiellement sur des concepts théoriques puisque les techniques de microscopie optique, si elles ont permis de décrire certaines structures comme les nucléoles, n'avaient pas la résolution nécessaire pour distinguer les fibres de chromatine les unes des autres. Cette idée de l'organisation du noyau interphasique a été remise en cause par les travaux de microscopie électronique effectués dans les années 60 et 70. Les résultats en ont été décevants puisque malgré l'excellente résolution obtenue, aucune architecture particulière des molécules d'ADN n'a pu être décrite. L'idée prévalente alors était que le noyau était une « simple » enveloppe contenant les molécules d'ADN décondensées et mélangées de façon aléatoire. Depuis une vingtaine d'années, l'apparition et le développement rapide des techniques d'hybridation in situ fluorescente (FISH pour Fluorescent In Situ Hybridization) a conduit à réexaminer le sujet grâce à des outils d'imagerie qui permettent enfin de visualiser spécifiquement chaque molécule d'ADN au sein du noyau.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 661 I. Organisation 3D de la chromatine dans le noyau interphasique 1. Relations de la chromatine avec les structures nucléaires Principal composant du noyau, la chromatine est en relation avec les deux principales structures nucléaires identifiées en microscopie, la membrane nucléaire et les nucléoles. a. Les nucléoles ont été identifiés depuis longtemps comme étant le lieu de synthèse des (ARNr). Ces structures intra-nucléaires ne sont pas limitées par une enveloppe et s'assemblent en nombre variable (en général 2 par noyau) lors de la reprise des transcriptions en G1, après la mitose. Ils sont constitués de plusieurs domaines visibles en microscopie électronique :

• Un ou plusieurs centres fibrillaires, correspondant à la zone de transcription à partir des molécules d'ADN;

• Un composé fibrillaire dense qui entoure le(s) centre(s) fibrillaire(s), contenant les transcrits primaires ;

• Un composé granulaire moins dense en périphérie, correspondant à la zone d'assemblage des pré-ribosomes. Il s'agit donc de structures fonctionnelles liées à la synthèse des ARNr et non pas de structures pré-établies indispensables à cette synthèse. Cette synthèse s'effectue à partir de répétés quelques centaines de fois dans le génome et tous situés au niveau des bras courts des chromosomes acrocentriques (chromosomes 13, 14, 15, 21 et 22). Ces régions sont appelées régions organisatrices des nucléoles (NOR pour Nucleolar Organising Regions) car leur rapprochement entraîne la mise en place du nucléole par concentration en un endroit donné des composants nécessaires à la transcription et à la maturation des ARNr. Cette proximité physique des bras courts des chromosomes acrocentriques peut se retrouver parfois jusque pendant la mitose où l'on peut observer une juxtaposition des NORs de plusieurs chromosomes acrocentriques.

b. Le noyau est délimité par une enveloppe constituée d'une double membrane (membranes nucléaires interne et externe, séparées par l'espace péri-nucléaire). A la face interne de la membrane nucléaire interne, on trouve un feutrage de filaments intermédiaires, la lamina, composée de trois protéines essentielles : les lamines A, B et C. La lamina possède de très nombreuses interactions avec des protéines de la membrane nucléaire interne et avec la chromatine, en relation avec ses fonctions dans l'organisation de l'enveloppe nucléaire et probablement dans la régulation de l'expression des gènes. En effet, un certain nombre de régulateurs transcriptionnels interagissent avec les lamines, de même que la protéine HP1 qui se fixe spécifiquement sur l'hétérochromatine. Par le biais de la lamina, l'enveloppe nucléaire pourrait donc participer à l'organisation de

Atlas Genet Cytogenet Oncol Haematol 2006; 4 662 l'hétérochromatine dans le noyau et plus largement au contrôle régional de la par relocalisation de gènes au contact de l'hétérochromatine pour les inactiver.

2. Notion de territoires chromosomiques Au début des années 80, grâce à des expériences d'irradiation laser de cellules de hamster, ont été apportés les premiers éléments d'observation en faveur de l'existence de territoires chromosomiques. Mais c'est l'hybridation in situ avec des sondes de peinture chromosomique qui, en permettant de visualiser directement le matériel génétique spécifique à chaque chromosome, a montré que chacun occupe un territoire bien délimité, sans mélange ni recouvrement avec les territoires voisins, confirmant ainsi la théorie de Rabl. Ces résultats ont été retrouvés pour toutes les paires chromosomiques et constituent la première preuve d'une organisation de la chromatine pendant l'interphase. Au sein de ces territoires, la fibre de chromatine conserve une organisation permettant d'identifier des sous-domaines correspondant aux bras ou aux bandes chromosomiques. La surface occupée par ces territoires est proportionnelle grossièrement à la taille du chromosome, mais d'autres paramètres peuvent la moduler comme, par exemple, le niveau global d'expression du chromosome. Ces territoires chromatiniens ne constituent pas des compartiments nucléaires au même titre que les nucléoles car ils sont perméables comme le démontre la diffusion passive de dont la taille peut aller jusqu'à 500 kDa dans tout le noyau.

3. Topographie des territoires Existe-t-il un arrangement précis et régulé des chromosomes les uns par rapport aux autres pendant l'interphase? Cette question difficile n'est toujours pas résolue de manière définitive car des résultats divergents et parfois contradictoires ont été rapportés, soit en faveur, soit contre cette hypothèse, mais il faut souligner que les premières études ont été menées sur des types cellulaires différents voire dans des espèces différentes, ce qui suggère l'existence d'une variabilité fonctionnelle et/ou tissulaire. Cependant, les résultats les plus récents semblent confirmer l'existence d'un arrangement non aléatoire des territoires chromosomiques les uns par rapport aux autres pendant l'interphase, en fonction de leur taille et/ou de leur contenu en gènes. Ainsi, il existe une localisation préférentielle des petits chromosomes vers l'intérieur du noyau alors que les plus grands sont plus fréquemment observés vers la périphérie. Cependant, le contenu en gènes intervient également comme le prouve le cas des chromosomes 18 et 19. Bien que de tailles comparables, le chromosome 19 riche en gènes est situé plus vers le centre du noyau que le 18, pauvre en gènes et observé en périphérie. Cette corrélation entre densité en gène accrue et position plus centrale dans le noyau interphasique a depuis été retrouvée pour d'autres paires. Si l'on admet donc l'existence d'une organisation non aléatoire des territoires au sein du noyau, une autre question à résoudre est de savoir si elle est associée à un arrangement particulier des homologues ou de certaines paires entre elles. Là encore les résultats obtenus jusqu'ici sont discordants et ne permettent pas encore de répondre de manière définitive. Cependant, quelques observations récentes concernant les positions respectives de chromosomes impliqués dans certaines translocations réciproques militent en faveur d'un positionnement non aléatoire des chromosomes les uns par rapport aux autres.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 663 4. Interface entre territoires voisins (Figure 1) Deux modèles sont proposés pour décrire les relations qui existent entre territoires chromosomiques voisins. a) Dans le premier modèle (modèle ICD : Interchromatin Domain), il existerait des espaces dépourvus de chromatine appelés espaces interchromatiniens. Ces espaces forment un réseau en trois dimensions de canaux qui débutent au niveau des pores de la membrane nucléaire et s'étendent entre les territoires chromosomiques dans lesquels ils s'invaginent. Leur taille est variable, avec des lacunes de quelques micromètres de diamètre alors que les régions les plus fines pourraient n'avoir que quelques nanomètres de large. Ces espaces interchromatiniens seraient l'endroit où serait concentré tout le matériel non chromatinien (corps nucléaires, pré-ARNm, facteurs de transcription) et constitueraient à ce titre soit un simple lieu de stockage des macromolécules, soit directement le lieu des réactions enzymatiques. En tout état de cause, il est en revanche déjà acquis que ces espaces servent également de voies de circulation au sein du noyau par simple diffusion passive permettant de distribuer les protéines nécessaires à la transcription et d'exporter en retour les produits. b) Le deuxième modèle (modèle ICN : Interchromosomal network) suppose au contraire qu'il existe des zones de recouvrement entre territoires voisins au niveau desquelles les fibres de chromatine des deux chromosomes sont étroitement associées. Ce modèle repose sur des observations faites sur des coupes ultrafines qui permettent de mieux conserver l'architecture de la chromatine que les préparations standard de FISH 3D. Environ 40% de chaque territoire serait ainsi mélangé en périphérie avec les territoires voisins. L'importance de la zone frontalière serait fonction notamment de la compaction du territoire chromosomique (plus la chromatine est compacte moins il y a de possibilités d'interpénétration), elle-même étant proportionnelle à la richesse en gènes du chromosome et à son activité transcriptionnelle. Dans ce modèle, les protéines nécessaires à la transcription, la réplication, la réparation de l'ADN ainsi que les ARN diffuseraient librement entre les boucles de chromatine au sein de chaque territoire sans être confinées au sein d'espaces spécialisés. Le principal intérêt de ce modèle est de pouvoir concilier la notion de territoire chromosomique avec la fréquence observée des translocations réciproques. En effet, pour chaque chromosome, il existe une très bonne corrélation entre la proportion de territoire mélangé avec les territoires voisins et la fréquence des translocations réciproques impliquant la paire considérée.

Atlas Genet Cytogenet Oncol Haematol 2006; 4 664

5. Modèle d'organisation de la chromatine dans le noyau interphasique Des différentes observations réalisées jusqu'à maintenant, se dégage un modèle d'organisation fonctionnelle du noyau interphasique constitué de territoires chromosomiques contenant l'information génétique sous la forme de chromatine. Au sein du noyau, les protéines et les ARN produits peuvent diffuser librement pour atteindre leur site de fixation ou pour être exportés vers le cytoplasme, soit via un réseau d'espaces canaliculaires connectés aux pores nucléaires et séparant les territoires (modèle ICD), soit directement entre les boucles de chromatine des différents territoires (modèle ICN). Dans les deux modèles, les activités de transcription qui se font au contact de la chromatine peuvent être régulées en modifiant l'accessibilité aux gènes. Les gènes actifs sont accessibles aux complexes de transcription soit parce qu'ils sont proches d'un espace interchromatinien dans le modèle ICD, soit parce qu'ils sont situés sur une grande boucle d'ADN dans le modèle ICN. L'observation que l'activation d'un gène peut être associée à sa relocalisation dans un territoire voisin permet de plus d'envisager de nouveaux modes de co-régulation de gènes participants à des voies métaboliques communes et éventuellement situés sur des chromosomes distincts. Quelque soit le modèle qui s'avèrera le plus proche de la réalité, cette organisation de la chromatine permet d'inactiver facilement des groupes de gènes en modifiant leur position au sein des territoires et en les rendant ainsi inaccessibles à la machinerie transcriptionnelle. Parmi les nombreux points qui restent à élucider, il y a la question de savoir si l'organisation en territoires chromosomiques est un préalable permettant d'organiser

Atlas Genet Cytogenet Oncol Haematol 2006; 4 665 et de réguler la transcription ou si au contraire cette organisation ne serait pas la conséquence de l'activité transcriptionnelle de la cellule, générant des régions de chromatine compacte puisque inactive et d'autres plus « aérées », au contact de zones riches en protéines et ARNm résultant de la transcription.

II. Evolution relative des territoires les uns par rapport aux autres au cours des cycles cellulaires successifs. Les chromosomes sont-ils positionnés de façon aléatoire au sein du noyau ou au contraire présentent-ils un arrangement spécifique les uns par rapport aux autres? La question n'est pas résolue mais elle ouvre d'intéressantes perspectives dans la mesure ou un tel arrangement pourrait constituer une information épigénétique importante dans le cadre de la différenciation cellulaire et pourrait expliquer (ou être expliqué par) une expression différentielle de certains gènes dans différentes lignées cellulaires. Si cette hypothèse est vérifiée, la transmission à l'identique de cette information positionnelle prend une importance capitale pour conserver les caractéristiques propres à chaque type cellulaire. Deux arguments sont actuellement en faveur d'une organisation coordonnée des territoires les uns par rapport aux autre. • La probabilité qu'un remaniement entre deux chromosomes survienne à l'occasion d'une irradiation dépend notamment de la distance existant entre eux pendant l'interphase. D'un type cellulaire à l'autre, on observe des fréquences variables des différentes associations possibles, suggérant donc que la position relative des chromosomes les uns par rapport aux autres varie en fonction de la lignée cellulaire considérée.

• La position relative des territoires chromosomiques les uns par rapport aux autres est transmise à l'identique à chaque division cellulaire aux cellules filles. Les observations réalisées par fluorescence sur cellules vivantes montrent que tous les territoires situés dans une même moitié du noyau de la cellule mère se retrouvent associés dans une moitié du noyau de chaque cellules filles. Le mécanisme actuellement retenu pour expliquer cette conservation de la position après la métaphase où tous les chromosomes sont réunis sur un même plan, consiste en un asynchronisme de séparation des chromatides lors de l'anaphase, les chromosomes qui vont se positionner dans les cellules filles dans la moitié de noyau la plus périphérique par rapport au plan de division métaphasique se séparant avant ceux destinés à occuper une position plus centrale (toujours par rapport au plan de division) (cf figure 2). Un des éléments clé pour le contrôle de cet asynchronisme de séparation des chromosomes pourrait être la quantité d'hétérochromatine centromérique dont on sait qu'elle est indispensable à la cohésion des chromatides au niveau des . En effet, si on altère cette hétérochromatine (par exemple en incorporant du Hoescht qui empêche une condensation correcte), on observe une répartition cette fois aléatoire des chromosomes dans les cellules filles. Si la position relative des différents territoires chromosomiques constitue bien une information épigénétique (ce qui reste à démontrer de façon définitive), il est d'ores et

Atlas Genet Cytogenet Oncol Haematol 2006; 4 666 déjà probable que la transmission de cette information n'est pas absolue, et que des variations surviennent après un nombre plus ou moins important de permettant une adaptation fonctionnelle des cellules.

III. Le noyau, une structure dynamique à 4 dimensions Les territoires chromosomiques ont une position stable dans le noyau au cours du cycle cellulaire, traduisant l'immobilité globale de la chromatine dans le noyau. Les techniques d'analyse en fluorescence sur cellules vivantes montrent en effet une grande stabilité des traceurs utilisés pendant les phases G1, S et G2. Cette immobilité est probablement en rapport avec le peu d'espace disponible à l'intérieur du noyau, mais elle résulte également en partie de l'ancrage de la chromatine à certains compartiments nucléaires, nucléoles et enveloppe principalement. Cependant, si l'on change l'échelle d'analyse, on s'aperçoit que la chromatine n'est pas figée dans le noyau mais que deux types de mouvements peuvent être observés. a. D'une part, le marquage en fluorescence de toutes petites régions chromosomiques (˜ 10 kb) a permis de mettre en évidence l'existence de mouvements de faible ampleur, sur une distance inférieure à 0,5 µm. Ces mouvements sont de type Browniens, orientés dans toutes les directions de l'espace, mais en raison de leur faible amplitude, le locus considéré reste circonscrit dans une région réduite du noyau (environ 1/1000e du volume total). Ces mouvements sont donc compatibles avec la notion de territoire chromosomique clairement individualisé et relativement immobile. Tous les loci étudiés ne montrent pas les mêmes possibilités de mouvement, certains semblent moins mobiles comme les télomères, les centromères ou certains domaines le long des chromosomes, correspondant peut être à des sites d'ancrage de la chromatine aux structures nucléaires. b. D'autre part, des mouvements de plus grande ampleur sont susceptibles d'être observés en relation avec une modification de l'activité transcriptionnelle de la cellule, comme par exemple lors de la ré entrée dans le cycle d'une cellule en phase de quiescence, ou au cours de la différenciation cellulaire comme cela a été observé dans des Lymphocytes B. Ces mouvements pourraient avoir un rôle fonctionnel important au cours des processus de différenciation cellulaire en modulant l'expression de certains gènes par un repositionnement dans des régions favorisant ou au contraire inhibant la transcription. Par ailleurs, l'existence de ces mouvements de la chromatine permettent d'expliquer la colocalisation au sein de complexes de transcription de gènes situés sur des chromosomes distincts, d'autant qu'il existe une corrélation entre l'activité

Atlas Genet Cytogenet Oncol Haematol 2006; 4 667 transcriptionelle d'une cellule et l'importance du recouvrement des territoires chromosomiques entre eux.

Conclusion Dès le XIXe siècle, Rabl avait eu la bonne intuition : le noyau n'est pas un organite servant uniquement à séparer le génome du cytoplasme, mais il joue un rôle probablement essentiel dans l'organisation de la chromatine et le contrôle de l'expression des gènes. Au sein de cet organite, le génome est arrangé de façon non aléatoire, chaque chromosome occupant un territoire bien défini, et il est maintenu globalement en place par des contacts avec diverses sous structures nucléaires ; cet arrangement, éventuellement propre à certaines cellules ou tissus, est transmis aux cellules filles au cours des divisions cellulaires. Enfin, des mouvements sont possibles malgré tout au niveau de certains loci qui peuvent être relocalisés dans d'autres régions du noyau notamment au cours des phénomènes de différenciation cellulaire ou de reprise de la transcription. Ces modifications de position, ainsi que l'existence d'un arrangement non aléatoire des territoires chromosomiques suggèrent qu'il existe peut-être dans le noyau des zones plus ou moins favorables à la transcription et donc à l'expression des gènes. En fonction de son emplacement, tel ou tel ensemble de gènes pourra ainsi être activé ou inactivé dans sa globalité, sans avoir à assurer un contrôle individuel de chacun d'eux. De plus, l'existence de zones d'exclusion faciliterait l'action des protéines chargées de la transcription (enhancers, polymerases, etc…) en réduisant le nombre de cibles potentielles et en augmentant la concentration apparente des facteurs de transcription vis à vis des gènes actifs. Il existerait ainsi une plasticité génétique corrélée avec la mobilité de la chromatine, qui participerait à l'adaptation des cellules à un environnement changeant. L'importance de cette organisation et des structures qui la maintiennent (notamment l'enveloppe nucléaire) dans la régulation fonctionnelle du génome est attestée par les troubles associés aux laminopathies. L'étude de la physiopathologie exacte de ces maladies apportera probablement de nouveaux éclaircissements sur les mécanismes de méta régulation de l'expression des gènes au niveau régional. Parmi ceux-ci, les modifications épigénétiques de l'ADN (méthylation des Cytosines, méthylation / acétylation des histones) constituent un axe de recherche privilégié en raison des nombreux arguments existant en faveur d'une relation entre épigenèse, structure de la chromatine, organisation du génome et expression génique.

Contributor(s) Written 06- Jean Michel Dupont 2006 Citation This paper should be referenced as such : Dupont JM . Architecture de la chromatine dans le noyau interphasique. Atlas Genet Cytogenet Oncol Haematol. June 2006 . URL : http://AtlasGeneticsOncology.org/Educ/ArchitectChromatinID30016FS.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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