Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home Leukemias Solid Tumours Cancer-Prone Deep Insight Portal Teaching X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

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 12, Number 6, Nov-Dec 2008 Previous Issue / Next Issue Genes BCL8 (B-cell CLL/lymphoma 8) (15q11). Silvia Rasi, Gianluca Gaidano. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 781-784. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/BCL8ID781ch15q11.html CDC25A (Cell division cycle 25A) (3p21). Dipankar Ray, Hiroaki Kiyokawa. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 785-791. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CDC25AID40004ch3p21.html CDC73 (cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)) (1q31.2). Leslie Farber, Bin Tean Teh. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 792-797. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CDC73D181ch1q31.html EIF3C (eukaryotic initiation factor 3, subunit C) (16p11.2). Daniel R Scoles. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 798-802. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/EIF3CID44187ch16p11.html ELAC2 (elaC homolog 2 (E. coli)) (17p11.2). Yang Chen, Sean Tavtigian, Donna Shattuck. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 803-806. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/ELAC2ID40437ch17p11.html FOXM1 (forkhead box M1) (12p13). Jamila Laoukili, Monica Alvarez Fernandez, René H Medema. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 807-813. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/FOXM1ID40631ch12p13.html PTCH2 ( homolog 2 (Drosophila)) (1p34.1). Peter Zaphiropoulos. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 814-820. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PTCH2ID41892ch1p34.html PTPN21 ( tyrosine phosphatase, non-receptor type 21) (14q31.3). Antonio Feliciello. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 821-824. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PTPN21ID41916ch14q21.html S100A13 (S100 calcium binding protein A13) (1q21.3).

Atlas Genet Cytogenet Oncol Haematol 2008; 6 I Carlo Barone, Cinzia Bagalà, Matteo Landriscina. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 825-830. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/S100A13ID44197ch1q21.html TACSTD1 (tumor-associated calcium signal transducer 1) (2p21). Olivier Gires. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 831-836. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TACSTD1ID42459ch2p21.html TNC (tenascin C (hexabrachion)) (9q33.1). Martin Degen, Ruth Chiquet-Ehrismann. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 837-842. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TNCID42597ch9q33.html TNN (tenascin N) (1q25.1). Martin Degen, Ruth Chiquet-Ehrismann. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 843-847. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TNNID44209ch1q25.html VTCN1 (V-set domain containing T cell activation inhibitor 1) (1p13.1). Panduka Samarawardana, Kenneth R Shroyer. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 848-853. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/VTCN1ID44144ch1p13.html Leukaemias t(8;12)(q24;q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 854-855. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0812q24q22ID2057.html t(7;21)(p22;q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 856-857. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0721p22q22ID1449.html t(6;11)(q13;q23). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 858-859. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0611q13q23ID1408.html inv(11)(p15q22). Cristina Morerio, Claudio Panarello. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 860-862. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/inv11p15q22ID1116.html t(4;11)(q35;q23). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 863-864. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0411q35q23ID1423.html t(3;8)(q26;q24). Pei Lin. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 865-867. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0308q26q24ID1463.html t(1;9)(q24;q34). Etienne De Braekeleer, Marc De Braekeleer. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 868-871. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0109q24q34ID2109.html t(12;13)(p13;q14). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 872-874. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t1213p13q14ID1323.html Solid Tumours

Atlas Genet Cytogenet Oncol Haematol 2008; 6 II Thyroid: Anaplastic (undifferentiated) carcinoma - updated. Sai-Ching Jim Yeung. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 875-880. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Tumors/AnaCarciThyroidID5069.html Cancer Prone Diseases Cartilage-hair hypoplasia (CHH). Pia Hermanns, Brendan Lee. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 881-887. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Kprones/CartilageHairHypoID10105.html Deep Insights Case Reports A case of trisomy 8 and loss of the Y- as secondary aberrations in a ten year old boy with de novo AML FAB M2 and t(16;21)(q24;q22). Jutta Bradtke, Peter Vorwerk, Jochen Harbott. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 888-891. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Reports/1621BradtkeID100031.html Educational Items Evolution. Robert Kalmes. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (6): 892-895. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Educ/EvolutionID30026ES.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Portal Teaching

For comments and suggestions or contributions, please contact us [email protected].

Atlas Genet Cytogenet Oncol Haematol 2008; 6 III Atlas of Genetics and Cytogenetics in Oncology and Haematology

BCL8 (B-cell CLL/lymphoma 8)

Identity Other names BCL8A HGNC BCL8 Location 15q11 Location_base_pair Starts at 19130067 and ends at 19159209 bp from pter ( according to hg18- Mar_2006). DNA/RNA

Description of 86686 bp with 3 exons(1bp-222bp/84886bp-85041bp/86517bp-86686bp). The 5' part of exon 1 and the 3' part of exon 3 are non coding. Transcription Two alternative transcripts: a major transcript of 2.6Kb and a less expressed transcript of 4.5Kb, due to differential polyadenylation. Coding sequence: CDS 208-510. The direction of transcription is from telomere to centromere. Pseudogene Identified a family of evolutionarily conserved human genes with extensive homology to BCL8; these genes are BCL8B (chr.13), BCL8C (chr.22), BCL8D (chr.2), and BCL8E (chr.10). BCL8B is the most complete gene, whereas the other genes are truncated, can yield only sterile transcripts, and thus are probably pseudogenes. Protein Description 100 amino acids, predicted molecular weight of 19 kDa; predicted: similar to protein neurobeachin (Lysosomal trafficking regulator 2). Expression mRNA predominantly expressed in testis and prostate, with no transcripts normally found in hematopoietic tissues. Its expression in lymphoid tissues can be activated by chromosomal translocation or by other mechanisms in diffuse large B-cell lymphoma (DLBCL) patients. BCL8 expression was detected in all patients with 15q11-13 abnormalities and in a significant proportion of DLBCL patients. Function Probably produced truncated polypeptides with uncertain function. Homology Interspecies: homolog to N-terminal of Caenorhabditis elegans F10.f2.1 (59% homology) and to N-terminal of Drosophila melanogaster protein kinase A (PKA) anchoring protein RG (67% homology). Implicated in Entity t(14;15)(q32;q11) --> IghV - BCL8 Note Possibly other translocations of BCL8 involve other sites such as 22q11, 9p13, 1p32, 7p13, 12q24, and 15q22. Disease Translocations affecting BCL8 gene and various partners occur in about 4% of diffuse large B-cell lymphoma (DLBCL). Translocations involving the chromosomal region 15q11-13 have also been identified in non lymphoid tumors. Prognosis The effect of BCL8 expression on the prognosis of patients has yet to be investigated. Hybrid/Mutated The chromosomal translocation does not led to the formation of a hybrid gene. Gene Oncogenesis Chromosomal translocation in DLBCL causes activation of the BCL8 proto-oncogene by deregulated expression of BCL8. Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2008; 6 781

External links Nomenclature HGNC BCL8 1007 Entrez_Gene BCL8 606 B-cell CLL/lymphoma 8 Cards Atlas BCL8ID781ch15q11 GeneCards BCL8 Ensembl ENSG00000110987 [Gene_View] BCL8 [Vega] Genatlas BCL8 Genomic and cartography BCL8 - 15q11 chr15:19130067-19159209 - 15q11-q13 [Description] (hg18- GoldenPath Mar_2006) Ensembl BCL8 - 15q11-q13 [CytoView] NCBI Mapview OMIM 601889 Disease map [OMIM] HomoloGene BCL8 Gene and transcription Genbank AL832227 [ ] Genbank DA278599 [ ENTREZ ] RefSeq NC_000015 [ SRS ] NC_000015 [ ENTREZ ] RefSeq NT_037852 [ SRS ] NT_037852 [ ENTREZ ] CCDS BCL8 CCDS - NCBI AceView BCL8 AceView - NCBI Unigene Hs.657985 [ SRS ] Hs.657985 [ NCBI ] Protein : pattern, domain, 3D structure P0C6P0 [ SRS] P0C6P0 [ EXPASY ] P0C6P0 [ INTERPRO ] P0C6P0 SwissProt [ UNIPROT ] P0C6P0 [ VarSplice FASTA ] CluSTr P0C6P0 Blocks P0C6P0 Protein Interaction databases DIP P0C6P0 IntAct P0C6P0 Polymorphism : SNP, mutations, diseases OMIM 601889 [ map ] GENETests 601889 SNP BCL8 [dbSNP-NCBI] SNP BCL8 [GeneSNPs - Utah] BCL8] [HGBASE - SRS] HAPMAP BCL8 [HAPMAP] HGMD BCL8 Genetic BCL8 Association

Atlas Genet Cytogenet Oncol Haematol 2008; 6 782 CDC HuGE BCL8 General knowledge Family BCL8 [UCSC Family Browser] Browser SMD Hs.657985 SAGE Hs.657985 PubGene BCL8 TreeFam BCL8 CTD 606 [Comparative ToxicoGenomics Database] Other databases Probes Probe BCL8 Related clones (RZPD - Berlin) PubMed PubMed 5 Pubmed reference(s) in Entrez Bibliography BCL8, a novel gene involved in translocations affecting band 15q11-13 in diffuse large-cell lymphoma. Dyomin VG, Rao PH, Dalla-Favera R, Chaganti RS Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (11) : 5728-5732. PMID 9159141

Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma. Macintyre E, Willerford D, Morris SW Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2000 : 180-204. PMID 11701542

BCL8 is a novel, evolutionarily conserved human gene family encoding with presumptive protein kinase A anchoring function. Dyomin VG, Chaganti SR, Dyomina K, Palanisamy N, Murty VV, Dalla-Favera R, Chaganti RS Genomics. 2002 ; 80 (2) : 158-165. PMID 12160729

Organisation of the pericentromeric region of : at least four partial gene copies are amplified in patients with a proximal duplication of 15q. Fantes JA, Mewborn SK, Lese CM, Hedrick J, Brown RL, Dyomin V, Chaganti RS, Christian SL, Ledbetter DH Journal of medical genetics. 2002 ; 39 (3) : 170-177. PMID 11897815

Molecular heterogeneity of diffuse large B-cell lymphoma: implications for disease management and prognosis. Rossi D, Gaidano G Hematology (Amsterdam, Netherlands). 2002 ; 7 (4) : 239-252. PMID 14972786

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Silvia Rasi, Gianluca Gaidano Division of Hematology, Department of Clinical and Experimental Medicine and Center of Biotechnologies for Applied Medical Research, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy

Atlas Genet Cytogenet Oncol Haematol 2008; 6 783 Citation This paper should be referenced as such : Rasi S, Gaidano G . BCL8 (B-cell CLL/lymphoma 8). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/BCL8ID781ch15q11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 784 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CDC25A (Cell division cycle 25A)

Identity Other names CDC25A2 HGNC CDC25A Location 3p21 Location_base_pair Starts at 48173672 and ends at 48204805 bp from pter ( according to hg18- Mar_2006). The gene is located telomeric to CAMP (cathelicidin antimicrobial peptide) and centromeric to LOC729349 (a pseudogene similar to 60S ribosomal protein L17 Local_order (L23)). The gene starts at 48,173,672 bp from pter and ends at 48,204,805 bp from pter with a total size of 31,133 bases. DNA/RNA

Genomic organization of human CDC25A gene on chromosome 3 p-ter. Description CDC25A is about 31.13 Kb located on the short (p) arm of chromosome 3, in the centromere-to-telomere orientation. The gene has 15 exons and the start codon is located at the end of exon 1 and stop codon in the beginning of exon 15. Transcription The CDC25A transcript is 3704 bp in length. So far there are two major transcript variant have been reported, CDC25A1 and A2. The transcript variant CDC25A2, has a deletion of 120 (exon 6) resulted in a protein having truncation of 40 amino acid (between amino acid 143-182). However, both the N-terminal and C-terminal end of the protein is the same in both splice variant. Protein

Domains of different isoforms of CDC25A (A1 and A2). The splice variant A2 lacks an in-frame exon (exon 6) encoding 40 amino acids (amino acid 143-182), however, have the same N- and C-termini compared to isoform A1. The approx. molecular weight of each isoform is mentioned in parenthesis. Description The full length CDC25A protein consists of 524 amino acids with an estimated molecular weight of 59 kDa. The other reported isoform CDC25A2, consists of 484 amino acids with a molecular weight of 54.4 kDa. Both the isoforms have the same N- and C-terminal end, thus expected to have similar catalytic activity. The N-terminal regulatory domain contains several phosphorylation sites and show low between CDC25 family members, whereas C-terminal end has conserved Rhodanese homology domain containing the active site cysteine. The catalytic site contain the CX5R motif (C= cysteine; X= any amino acid; R= arginine) common to all protein tyrosine phosphatases. Expression CDC25A is expressed early during embryonic stages and in adults it is expressed in a variety of normal cells and tissues. CDC25A is a highly expressed gene in a variety of human cancers including breast, esophageal, gastric, lung, thyroid, head and neck cancers and also in high grade lymphomas.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 785 Localisation CDC25A initially believed to be a nuclear protein. But using fluorescence loss in photobleaching (FLIP) the more dynamic nuclear-cytosolic shuttling of CDC25A localization have been reported. At the very N-terminus end between amino acid 38-59, the nuclear export sequence (NES) is located, whereas between amino acid 272-294, a bipartite nuclear localization signal (NLS) proved to be important for its nuclear localization. Function - It is a member of the M-phase inducer (MPI) phosphatase family protein, which not only regulates mitotic progression by activating mitotic CDKs in a dosage-dependent manner, it is also equally important for G1 to S-phase transition. - During G1 to S transition, it activates CDK2 by removing two inhibitory phosphates on residues threonine 14 and tyrosine 15. During G2/M transition CDC25A similarly regulates the activity of CDK1 (CDC2). - It is an important checkpoint protein in response to damage by ionizing radiation (IR), ultraviolet light (UV), replication inhibitor and by various DNA damaging agents. In response to DNA damage, CDC25A undergoes CHK1/CHK2-mediated phosphorylation followed by ubiquitination-dependent degradation leading to growth arrest in a - independent manner. - CDC25A is essential for early embryonic development as Cdc25A-null mice die in utero by embryonic day 7. - CDC25A is overexpressed in a variety of human cancers including breast, esophageal, gastric, lung, thyroid, head and neck cancers and lymphomas. CDC25A overexpression at least in breast cancer is mainly due to post-translation stabilization as oppose to gene amplification or transcriptional upregulation. - CDC25A protein level is important for oncogene-induced transformation and mouse mammary tumor virus (MMTV)-neu/ras induced mammary tumorigenesis. - During early cell cycle progression glycogen synthase kinase 3-beta (GSK-3β) can phosphorylate and degrade CDC25A, thus maintain the lower cellular levels of CDC25A. Interestingly, the same report showed that overproduction of CDC25A in human cancers is correlated to the inactivation of GSK-3β. - It is an inhibitor of apoptosis by inhibiting apoptosis signal-regulating kinase 1 (ASK1). - CDC25A plays an important role in spermatogenesis as decreased transcript level of Cdc25A is correlated with spermatogenic failure and failed sperm retrieval in infertile men. Homology CDC25A gene is highly conserved among mammals (99% homology with Chimpanzee; 90% with dog; about 86% with rat and about 85% with mouse). In mammals, CDC25A has two orthologs, CDC25B and CDC25C. Among them, the N-terminal regulatory region show low sequence homology (20-25% identity), however, the C-terminal catalytic region is quite conserved with about 64% homology with CDC25B and about 58% homology to CDC25C. Mutations Note Gene mutation or amplification is not commonly reported for CDC25A. A naturally occurring point mutation (C to A) of mouse Cdc25A gene has been reported where Histidine 128 (CAC) has been converted to Glutamine (CAA). This change caused an increase in CDC25A phosphatase activity and thereby affected erythropoiesis in mice only under certain genetic background. Implicated in Note CDC25A is overexpressed in a variety of human cancers including breast, hepatocellular, ovarian, colorectal, esophageal, head and neck cancer and also in non- Hodgkin lymphoma. Entity Breast cancer Note - In about 47% of early (T1) stage breast cancer patients CDC25A is reported to be overexpressed. - Although the mechanism of CDC25A upregulation in human patients is not yet clear, however, in some breast cancer cell lines it was reported that CDC25A overexpression is mainly due to increased protein stability as oppose to gene amplification or transcriptional upregulation. - In mice, overexpression of CDC25A alone in mammary gland using mouse mammary tumor virus (MMTV) promoter, is not sufficient to induce mammary tumorigenesis. However, such mammary specific overexpression of CDC25A does cooperate with

Atlas Genet Cytogenet Oncol Haematol 2008; 6 786 HER2/neu-ras signaling to form more aggressive tumors with enhanced genomic instability. - In contrast, hemizygous loss of Cdc25A in mice protected them significantly from MMTV-neu/ras-induced mammary tumorigenesis, possibly by restricting precancerous cell proliferation and also by enhancing G2-checkpoint response. Thus the protein level of CDC25A is crucial for the initiation and/or progression of breast tumorigenesis in mice. Prognosis Overexpression of CDC25A is correlated with more aggressive breast cancer with poor prognosis. Cytogenetics CDC25A overexpression in MMTV-CDC25A; MMTV-neu double transgenic mice caused faster tumor growth as compared to MMTV-neu single transgenic mice. Importantly, such CDC25A overexpressing tumor cells displayed miscoordination of S phase and mitosis, and had severe genomic instability as evidenced by aneuploidy and deletion of fragile chromosomal regions (e.g., telomeric region of , which is homologous to human chromosome 1p31-36, a hotspot for several human cancers including breast cancer). Entity Hepatocellular carcinoma Note Different CDC25 inhibitor (such as vitamin K analog Cpd 5; phenyl maleimide compound PM-20; 2-Methoxyestadiol, a physiological metabolite of estrogen) are capable of inhibiting the hepatocellular carcinoma growth both in vitro and in vivo. Prognosis CDC25A overexpression is associated with poor prognosis of hepatocellular carcinoma. External links Nomenclature HGNC CDC25A 1725 Entrez_Gene CDC25A 993 cell division cycle 25 homolog A (S. pombe) Cards Atlas CDC25AID40004ch3p21 GeneCards CDC25A Ensembl ENSG00000164045 [Gene_View] CDC25A [Vega] Genatlas CDC25A Genomic and cartography GoldenPath CDC25A - 3p21 chr3:48173672-48204805 - 3p21 [Description] (hg18-Mar_2006) Ensembl CDC25A - 3p21 [CytoView] NCBI Mapview OMIM 116947 Disease map [OMIM] HomoloGene CDC25A Gene and transcription Genbank AF277722 [ ENTREZ ] Genbank AI917350 [ ENTREZ ] Genbank AK290554 [ ENTREZ ] Genbank AY137580 [ ENTREZ ] Genbank BC007401 [ ENTREZ ] RefSeq NM_001789 [ SRS ] NM_001789 [ ENTREZ ] RefSeq NM_201567 [ SRS ] NM_201567 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq AC_000135 [ SRS ] AC_000135 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022517 [ SRS ] NT_022517 [ ENTREZ ] RefSeq NW_001838877 [ SRS ] NW_001838877 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ] CCDS CDC25A CCDS - NCBI AceView CDC25A AceView - NCBI Unigene Hs.437705 [ SRS ] Hs.437705 [ NCBI ] Fast-db 5783 (alternative variants) Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2008; 6 787 P30304 [ SRS] P30304 [ EXPASY ] P30304 [ INTERPRO ] P30304 SwissProt [ UNIPROT ] P30304 [ VarSplice FASTA ] Prosite PS50206 RHODANESE_3 [ SRS ] PS50206 RHODANESE_3 [ Expasy ] Interpro IPR000751 MPI_Phosphatase [ SRS ] IPR000751 MPI_Phosphatase [ EBI ] Interpro IPR001763 Rhodanese-like [ SRS ] IPR001763 Rhodanese-like [ EBI ] CluSTr P30304 PF06617 M-inducer_phosp [ SRS ] PF06617 M-inducer_phosp Pfam [ Sanger ] pfam06617 [ NCBI-CDD ] PF00581 Rhodanese [ SRS ] PF00581 Rhodanese [ Sanger ] pfam00581 [ NCBI- Pfam CDD ] Smart SM00450 RHOD [EMBL] Blocks P30304 PDB 1C25 [ SRS ] 1C25 [ PdbSum ], 1C25 [ IMB ] 1C25 [ RSDB ] HPRD 00305 Protein Interaction databases DIP P30304 IntAct P30304 Polymorphism : SNP, mutations, diseases OMIM 116947 [ map ] GENETests 116947 SNP CDC25A [dbSNP-NCBI] SNP NM_001789 [SNP-NCI] SNP NM_201567 [SNP-NCI] SNP CDC25A [GeneSNPs - Utah] CDC25A] [HGBASE - SRS] HAPMAP CDC25A [HAPMAP] COSMIC CDC25A [Somatic mutation (COSMIC-CGP-Sanger)] HGMD CDC25A Genetic CDC25A Association CDC HuGE CDC25A General knowledge Family CDC25A [UCSC Family Browser] Browser SOURCE NM_001789 SOURCE NM_201567 SMD Hs.437705 SAGE Hs.437705 3.1.3.48 [ -Expasy ] 3.1.3.48 [ Enzyme-SRS ] 3.1.3.48 [ IntEnz- Enzyme EBI ] 3.1.3.48 [ BRENDA ] 3.1.3.48 [ KEGG ] regulation of cyclin-dependent protein kinase activity [Amigo] regulation of cyclin- GO dependent protein kinase activity GO protein tyrosine phosphatase activity [Amigo] protein tyrosine phosphatase activity GO protein binding [Amigo] protein binding GO cellular_component [Amigo] cellular_component GO intracellular [Amigo] intracellular GO nucleoplasm [Amigo] nucleoplasm GO DNA replication [Amigo] DNA replication GO protein amino acid dephosphorylation [Amigo] protein amino acid dephosphorylation GO cell cycle [Amigo] cell cycle GO mitosis [Amigo] mitosis GO cell proliferation [Amigo] cell proliferation GO hydrolase activity [Amigo] hydrolase activity GO cell division [Amigo] cell division BIOCARTA Cyclins and Cell Cycle Regulation [Genes]

Atlas Genet Cytogenet Oncol Haematol 2008; 6 788 BIOCARTA Cell Cycle: G1/S Check Point [Genes] KEGG Cell cycle PubGene CDC25A TreeFam CDC25A CTD 993 [Comparative ToxicoGenomics Database] Other databases Probes Probe CDC25A Related clones (RZPD - Berlin) PubMed PubMed 73 Pubmed reference(s) in Entrez Bibliography Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins. Galaktionov K, Beach D Cell. 1991 ; 67 (6) : 1181-1194. PMID 1836978

Chromosome mapping of human CDC25A and CDC25B phosphatases. Demetrick DJ, Beach DH Genomics. 1993 ; 18 (1) : 144-147. PMID 8276402

Rapid destruction of human Cdc25A in response to DNA damage. Mailand N, Falck J, Lukas C, Syljuasen RG, Welcker M, Bartek J, Lukas J Science (New York, N.Y.). 2000 ; 288 (5470) : 1425-1429. PMID 10827953

Alternative splicing in the regulatory region of the human phosphatases CDC25A and CDC25C. Wegener S, Hampe W, Herrmann D, Schaller HC European journal of cell biology. 2000 ; 79 (11) : 810-815. PMID 11139144

Mammalian G1- and S-phase checkpoints in response to DNA damage. Bartek J, Lukas J Current opinion in cell biology. 2001 ; 13 (6) : 738-747. PMID 11698191

Involvement of Cdc25A phosphatase in Hep3B hepatoma cell growth inhibition induced by novel K vitamin analogs. Wang Z, Southwick EC, Wang M, Kar S, Rosi KS, Wilcox CS, Lazo JS, Carr BI Cancer research. 2001 ; 61 (19) : 7211-7216. PMID 11585757

The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1. Zou X, Tsutsui T, Ray D, Blomquist JF, Ichijo H, Ucker DS, Kiyokawa H Molecular and cellular biology. 2001 ; 21 (14) : 4818-4828. PMID 11416155

Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability. Mailand N, Podtelejnikov AV, Groth A, Mann M, Bartek J, Lukas J The EMBO journal. 2002 ; 21 (21) : 5911-5920. PMID 12411508

A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is associated with altered cell-cycle status of early erythroid progenitor cells. Melkun E, Pilione M, Paulson RF Blood. 2002 ; 100 (10) : 3804-3811. PMID 12411323

Atlas Genet Cytogenet Oncol Haematol 2008; 6 789

Distinct modes of deregulation of the proto-oncogenic Cdc25A phosphatase in human breast cancer cell lines. Loffler H, Syljuasen RG, Bartkova J, Worm J, Lukas J, Bartek J Oncogene. 2003 ; 22 (50) : 8063-8071. PMID 14603247

Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S, Zhang H The Journal of biological chemistry. 2003 ; 278 (24) : 21767-21773. PMID 12676925

Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas. Xu X, Yamamoto H, Sakon M, Yasui M, Ngan CY, Fukunaga H, Morita T, Ogawa M, Nagano H, Nakamori S, Sekimoto M, Matsuura N, Monden M Clinical cancer research : an official journal of the American Association for Cancer Research. 2003 ; 9 (5) : 1764-1772. PMID 12738732

Cdc25A localisation and shuttling: characterisation of sequences mediating nuclear export and import. Kallstrom H, Lindqvist A, Pospisil V, Lundgren A, Rosenthal CK Experimental cell research. 2005 ; 303 (1) : 89-100. PMID 15572030

PM-20, a novel inhibitor of Cdc25A, induces extracellular signal-regulated kinase 1/2 phosphorylation and inhibits hepatocellular carcinoma growth in vitro and in vivo. Kar S, Wang M, Yao W, Michejda CJ, Carr BI Molecular cancer therapeutics. 2006 ; 5 (6) : 1511-1519. PMID 16818510

CDC25 phosphatases in cancer cells: key players? Good targets? Boutros R, Lobjois V, Ducommun B Nature reviews. Cancer. 2007 ; 7 (7) : 495-507. PMID 17568790

CDC25A levels determine the balance of proliferation and checkpoint response. Ray D, Kiyokawa H Cell cycle (Georgetown, Tex.). 2007 ; 6 (24) : 3039-3042. PMID 18073536

Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability. Ray D, Terao Y, Fuhrken PG, Ma ZQ, DeMayo FJ, Christov K, Heerema NA, Franks R, Tsai SY, Papoutsakis ET, Kiyokawa H Cancer research. 2007 ; 67 (3) : 984-991. PMID 17283130

Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice. Ray D, Terao Y, Nimbalkar D, Hirai H, Osmundson EC, Zou X, Franks R, Christov K, Kiyokawa H Cancer research. 2007 ; 67 (14) : 6605-6611. PMID 17638870

GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. Kang T, Wei Y, Honaker Y, Yamaguchi H, Appella E, Hung MC, Piwnica-Worms H Cancer cell. 2008 ; 13 (1) : 36-47. PMID 18167338

Atlas Genet Cytogenet Oncol Haematol 2008; 6 790

2-Methoxyestradiol inhibits hepatocellular carcinoma cell growth by inhibiting Cdc25 and inducing cell cycle arrest and apoptosis. Kar S, Wang M, Carr BI Cancer chemotherapy and pharmacology. 2008. PMID 18246350

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Dipankar Ray, Hiroaki Kiyokawa Dept. of Mol. Pharmacol & Biol. Chem, Northwestern University, Chicago, IL 60611, USA (DR, HK); Robert H. Lurie Compre. Cancer Center, Northwestern University, Chicago, IL 60611, USA (HK) Citation This paper should be referenced as such : Ray D, Kiyokawa H . CDC25A (Cell division cycle 25A). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/CDC25AID40004ch3p21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 791 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CDC73 (cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae))

Identity Other names C1orf28 FLJ23316 HPT-JT HRPT2 HGNC CDC73 Location 1q31.2 Location_base_pair Starts at 191357784 and ends at 191487679 bp from pter ( according to hg18- Mar_2006). Note Defects in CDC73 are the cause of hyperparathyroidism-jaw tumor syndrome. Mutations in CDC73 are also a cause of parathyroid carcinoma (see below). DNA/RNA Description 17 exons (all coding) Transcription CDC73 encodes a 2.7 kb mRNA with a 1596 bp ORF. The transcript has been detected in all tissues tested to date. Protein Description 531-amino acid protein (64 kD); termed parafibromin. Expression Ubiquitously expressed Localisation Nuclear, bipartite nuclear localization signal Function CDC73 is a encoding a protein called parafibromin. Parafibromin is a member of the human RNA polymerase II-associated complex, Paf1. The human Paf1 complex is composed of parafibromin, LEO1, PAF1, and CTR9. Parafibromin's interaction with this complex is dependent on its C-terminal domain, which is deleted in ca. 80% of clinically relevant mutations. Homology Parafibromin shares 54% identity and 67% similarity with the D. melanogaster ortholog and 25% identity and 45% similarity with the C. elegans ortholog. There were no homologies to known protein domains, but moderate identity (32%) and similarity (54%) to the S. cerevisiae ortholog, Cdc73. Mutations Germinal Various types of mutations often leading to inactivation of protein Somatic Various somatic inactivating mutations found in sporadic parathyroid carcinoma Implicated in Entity Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT) Disease HPT-JT is an autosomal dominant, multiple neoplasia syndrome. Oncogenesis HPT-JT syndrome is primarily characterized by hyperparathyroidism due to parathyroid tumors. Thirty percent of individuals with HPT-JT also develop ossifying fibromas, primarily of the mandible and maxilla, which are distinct from the brown tumors associated with severe hyperparathyroidism. Kidney lesions also occur in HPT-JT as bilateral cysts, renal hamartomas or Wilms tumors. Entity Familial isolated hyperthyroidism Disease Familial isolated primary hyperparathyroidism is an autosomal dominant disorder that can represent an early stage of either the multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndromes; or alternatively caused by a distinct entity involving another locus. Entity Sporadic parathyroid carcinoma Disease These cancers characteristically result in more profound clinical manifestations of hyperparathyroidism than do parathyroid adenomas. Parathyroid carcinomas cause hyperparathyroidism. The hyperparathyroidism is usually severe, with high serum

Atlas Genet Cytogenet Oncol Haematol 2008; 6 792 calcium level, severe bone disease, and renal stones. Prognosis 5-years survival rate is between 50% and 70%. Oncogenesis Loss of parafibromin expression strongly predicts parathyroid malignancy Entity Sporadic Renal Tumors Cytogenetics Loss of heterozygosity (LOH) of HRPT2 was found in clear cell , papillary, chromophobe renal cell carcinomas, oncocytomas, and Wilms tumors. In addition, two novel HRPT2 point mutations were detected in clear cell carcinoma and Wilms tumor. External links Nomenclature HGNC CDC73 16783 CDC73 79577 cell division cycle 73, Paf1/RNA polymerase II complex component, Entrez_Gene homolog (S. cerevisiae) Cards Atlas CDC73D181ch1q31 GeneCards CDC73 Ensembl ENSG00000134371 [Gene_View] CDC73 [Vega] Genatlas CDC73 Genomic and cartography CDC73 - 1q31.2 chr1:191357784-191487679 + 1q25 [Description] (hg18- GoldenPath Mar_2006) Ensembl CDC73 - 1q25 [CytoView] NCBI Mapview OMIM 145000 Disease map [OMIM] OMIM 145001 Disease map [OMIM] OMIM 607393 Disease map [OMIM] OMIM 608266 Disease map [OMIM] HomoloGene CDC73 Gene and transcription Genbank AF312865 [ ENTREZ ] Genbank AK026969 [ ENTREZ ] Genbank AK226038 [ ENTREZ ] Genbank AK314772 [ ENTREZ ] Genbank BC007325 [ ENTREZ ] RefSeq NM_024529 [ SRS ] NM_024529 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004487 [ SRS ] NT_004487 [ ENTREZ ] RefSeq NW_001838533 [ SRS ] NW_001838533 [ ENTREZ ] RefSeq NW_926128 [ SRS ] NW_926128 [ ENTREZ ] CCDS CDC73 CCDS - NCBI AceView CDC73 AceView - NCBI Unigene Hs.576497 [ SRS ] Hs.576497 [ NCBI ] Fast-db 17668 (alternative variants) Protein : pattern, domain, 3D structure Q6P1J9 [ SRS] Q6P1J9 [ EXPASY ] Q6P1J9 [ INTERPRO ] Q6P1J9 SwissProt [ UNIPROT ] Q6P1J9 [ VarSplice FASTA ] IPR007852 RNA_pol_access_fac_Cdc73 [ SRS ] IPR007852 Interpro RNA_pol_access_fac_Cdc73 [ EBI ] CluSTr Q6P1J9 Pfam PF05179 CDC73 [ SRS ] PF05179 CDC73 [ Sanger ] pfam05179 [ NCBI-CDD ] Blocks Q6P1J9 HPRD 09581 Protein Interaction databases

Atlas Genet Cytogenet Oncol Haematol 2008; 6 793 DIP Q6P1J9 IntAct Q6P1J9 Polymorphism : SNP, mutations, diseases OMIM 145000 [ map ] OMIM 145001 [ map ] OMIM 607393 [ map ] OMIM 608266 [ map ] GENETests 145000 GENETests 145001 GENETests 607393 GENETests 608266 SNP CDC73 [dbSNP-NCBI] SNP NM_024529 [SNP-NCI] SNP CDC73 [GeneSNPs - Utah] CDC73] [HGBASE - SRS] HAPMAP CDC73 [HAPMAP] COSMIC CDC73 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD CDC73 Genetic CDC73 Association CDC HuGE CDC73 General knowledge Family CDC73 [UCSC Family Browser] Browser SOURCE NM_024529 SMD Hs.576497 SAGE Hs.576497 GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription GO negative regulation of cell cycle [Amigo] negative regulation of cell cycle PubGene CDC73 TreeFam CDC73 CTD 79577 [Comparative ToxicoGenomics Database] Other databases Probes Probe CDC73 Related clones (RZPD - Berlin) PubMed PubMed 47 Pubmed reference(s) in Entrez Bibliography Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. Liontos M, Koutsami M, Sideridou M, Evangelou K, Kletsas D, Levy B, Kotsinas A, Nahum O, Zoumpourlis V, Kouloukoussa M, Lygerou Z, Taraviras S, Kittas C, Bartkova J, Papavassiliou AG, Bartek J, Halazonetis TD, Gorgoulis VG Cancer research. 2007 ; 67 (22) : 10899-10909. PMID 18006835

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Hoog A, Heath H 3rd, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, Besser GM, Jackson CE, Morreau H, Trent JM, Thakker RV, Marx SJ, Teh BT, Larsson C, Hobbs MR Nature genetics. 2002 ; 32 (4) : 676-680. PMID 12434154

Atlas Genet Cytogenet Oncol Haematol 2008; 6 794 HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh DJ, Morreau H, Teh BT Journal of medical genetics. 2003 ; 40 (9) : 657-663. PMID 12960210

Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, Farnebo LO, Larsson C, Arnold A The New England journal of medicine. 2003 ; 349 (18) : 1722-1729. PMID 14585940

Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene. Cavaco BM, Guerra L, Bradley KJ, Carvalho D, Harding B, Oliveira A, Santos MA, Sobrinho LG, Thakker RV, Leite V The Journal of clinical endocrinology and metabolism. 2004 ; 89 (4) : 1747-1752. PMID 15070940

Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. Cetani F, Pardi E, Borsari S, Viacava P, Dipollina G, Cianferotti L, Ambrogini E, Gazzerro E, Colussi G, Berti P, Miccoli P, Pinchera A, Marcocci C The Journal of clinical endocrinology and metabolism. 2004 ; 89 (11) : 5583-5591. PMID 15531515

Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype. Haven CJ, Howell VM, Eilers PH, Dunne R, Takahashi M, van Puijenbroek M, Furge K, Kievit J, Tan MH, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Dralle H, Hoang-Vu C, Gimm O, Morreau H, Marsh DJ, Teh BT Cancer research. 2004 ; 64 (20) : 7405-7411. PMID 15492263

Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD, Marx SJ The Journal of clinical endocrinology and metabolism. 2004 ; 89 (1) : 96-102. PMID 14715834

The parafibromin tumor suppressor protein is part of a human Paf1 complex. Rozenblatt-Rosen O, Hughes CM, Nannepaga SJ, Shanmugam KS, Copeland TD, Guszczynski T, Resau JH, Meyerson M Molecular and cellular biology. 2005 ; 25 (2) : 612-620. PMID 15632063

HRPT2, a tumor suppressor gene for hyperparathyroidism-jaw tumor syndrome. Wang PF, Tan MH, Zhang C, Morreau H, Teh BT Hormone and metabolic research. Hormon- und Stoffwechselforschung. Hormones et metabolisme. 2005 ; 37 (6) : 380-383. PMID 16001331

Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Woodard GE, Lin L, Zhang JH, Agarwal SK, Marx SJ, Simonds WF Oncogene. 2005 ; 24 (7) : 1272-1276. PMID 15580289

The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and

Atlas Genet Cytogenet Oncol Haematol 2008; 6 795 RNA polymerase II. Yart A, Gstaiger M, Wirbelauer C, Pecnik M, Anastasiou D, Hess D, Krek W Molecular and cellular biology. 2005 ; 25 (12) : 5052-5060. PMID 15923622

Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome. Mizusawa N, Uchino S, Iwata T, Tsuyuguchi M, Suzuki Y, Mizukoshi T, Yamashita Y, Sakurai A, Suzuki S, Beniko M, Tahara H, Fujisawa M, Kamata N, Fujisawa K, Yashiro T, Nagao D, Golam HM, Sano T, Noguchi S, Yoshimoto K Clinical endocrinology. 2006 ; 65 (1) : 9-16. PMID 16817812

Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta- catenin/Armadillo. Mosimann C, Hausmann G, Basler K Cell. 2006 ; 125 (2) : 327-341. PMID 16630820

Parafibromin inhibits cancer cell growth and causes G1 phase arrest. Zhang C, Kong D, Tan MH, Pappas DL Jr, Wang PF, Chen J, Farber L, Zhang N, Koo HM, Weinreich M, Williams BO, Teh BT Biochemical and biophysical research communications. 2006 ; 350 (1) : 17-24. PMID 16989776

Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation. Cetani F, Pardi E, Ambrogini E, Viacava P, Borsari S, Lemmi M, Cianferotti L, Miccoli P, Pinchera A, Arnold A, Marcocci C Endocrine-related cancer. 2007 ; 14 (2) : 493-499. PMID 17639062

Nucleolar localization of parafibromin is mediated by three nucleolar localization signals. Hahn MA, Marsh DJ FEBS letters. 2007 ; 581 (26) : 5070-5074. PMID 17923126

Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification. Juhlin CC, Villablanca A, Sandelin K, Haglund F, Nordenstrom J, Forsberg L, Branstrom R, Obara T, Arnold A, Larsson C, Hoog A Endocrine-related cancer. 2007 ; 14 (2) : 501-512. PMID 17639063

Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism-jaw tumor syndrome enhances its proapoptotic function. Lin L, Czapiga M, Nini L, Zhang JH, Simonds WF Molecular cancer research : MCR. 2007 ; 5 (2) : 183-193. PMID 17314275

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene. Zhao J, Yart A, Frigerio S, Perren A, Schraml P, Weisstanner C, Stallmach T, Krek W, Moch H Oncogene. 2007 ; 26 (23) : 3440-3449. PMID 17130827

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

Search in all EBI NCBI

Atlas Genet Cytogenet Oncol Haematol 2008; 6 796 Contributor(s) Written 02-2008 Leslie Farber, Bin Tean Teh Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA Citation This paper should be referenced as such : Farber L, Teh BT . CDC73 (cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/CDC73D181ch1q31.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 797 Atlas of Genetics and Cytogenetics in Oncology and Haematology

EIF3C (eukaryotic translation initiation factor 3, subunit C)

Identity Other names EIF3S8 eIF3-p110 eIF3 subunit p110 p110 HGNC EIF3C Location 16p11.2 Location_base_pair Starts at 28630283 and ends at 28654551 bp from pter ( according to hg18- Mar_2006). Note eIF3c is one of 12 subunit proteins comprising the eukaryotic initiation factor 3 (eIF3) complex. DNA/RNA Description The EIF3C gene is composed of 21 exons. No alternative splicing has been reported for eIF3c. The EIF3C gene is located on chromosome 16p11.2 within an unstable region prone to duplication, and intact duplication of the entire EIF3C gene has been demonstrated in multiple tissue types. One mechanism of eIF3c overexpression, observed in various tumor types, may be gene duplication. Protein

Schematic of the 913 amino acid eIF3c protein with amino acid positions shown and locations of the PCI domain. Also indicated are the known minimal regions in eIF3c required for binding by interacting proteins. These include eIF complexes eIF1 and eIF5, the NF2 tumor suppressor merlin, and murine viral stress mediated inhibitors of protein translation MuP56 and MuP54. For merlin, the broken line indicates a region promoting stronger merlin binding when included. Note that eIF3c also binds the COP9 signalosome protein CSN7 in Arabidopsis, which may mediate inhibition of protein translation. Description The eIF3c protein is 913 amino acids in length. The eIF3c protein possesses the PCI (proteasome component region) domain within its C-terminal half (also referred to as PINT domain). Domain searching reveals that EIF3c also possesses a winged helix repressor DNA-binding domain overlapping with the PCI domain. Expression Ubiquitous. Localisation eIF3c is cytoplasmic. There is some evidence of eIF3c occurring in the nucleus consistent with reports of intranuclear protein translation as well as regulation of protein translation by interaction with the COP9 signalosome. Function The initiation of protein translation is a complex sequence of events mediated by the interaction of eIF3 with phosphorylated mTOR . Multiple interactions by eIF3 subsequently take place during the progression of protein translation initiation including the proper positioning of the preinitiation complex on the 40S ribosome mediated by eIF3. EIF3c has a significant role in binding to two AUG recognition factors, eIF1 and eIF5, and these interactions are required for proper AUG scanning by the preinitiation complex.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 798 EIF3c is overexpressed in some tumors including seminomas and meningiomas. EIF3c can also interact with the neurofibromatosis 2 (NF2) tumor suppressor merlin (schwannomin) and merlin can inhibit eIF3c mediated cell proliferation. In meningiomas eIF3c expression was inversely related to merlin expression and was overexpressed in meningiomas that had lost merlin expression. EIF3c overexpression can also transform NIH/3T3 fibroblasts, indicated by decreased doubling times, increased clonogenicity, increased viability, facilitated S-phase entry, attenuated apoptosis, formation of transformed foci, and anchorage-independent growth. Murine EIF3c is also a target of inhibitory proteins induced by viral stress. Viral induced MuP56 and MuP54 bind eIF3c in different locations resulting in protein translation inhibition. In Arabidopsis, eIF3c also interacts with the COP9 signalosome subunit CSN7 in the nucleus. COP9 binding is thought to be associated with downregulated protein translation. eIF3c possesses the PCI domain common among proteasome member proteins and also found in other eIF subunit proteins. Homology eIF3c is the homolog to yeast NIP1 (37% identity). Mutations Note No eIF3c mutations have been reported. Implicated in Entity Various Cancer Oncogenesis eIF3c has been noted overexpressed in a subset of testicular tumors (seminomas). EIF3c has also been shown overexpressed in meningiomas that have lost expression of the neurofibromatosis 2 tumor suppressor merlin (approximately 50% of sporadic meningiomas). To be noted eIF3c is an oncoprotein overexpressed in tumors. As such eIF3c is a potential therapeutic target. eIF3c may be a particularly good therapeutic target for NF2 since all tumors that had lost merlin function had overexpressed eIF3c. External links Nomenclature HGNC EIF3C 3279 Entrez_Gene EIF3C 8663 eukaryotic translation initiation factor 3, subunit C Cards Atlas S100A13ID44197ch1q21 GeneCards EIF3C Ensembl ENSG00000184110 [Gene_View] EIF3C [Vega] Genatlas EIF3C Genomic and cartography EIF3C - 16p11.2 chr16:28630283-28654551 + 16p11.2 [Description] (hg18- GoldenPath Mar_2006) Ensembl EIF3C - 16p11.2 [CytoView] NCBI Mapview OMIM 603916 Disease map [OMIM] HomoloGene EIF3C Gene and transcription Genbank AK000739 [ ENTREZ ] Genbank AK055366 [ ENTREZ ] Genbank AK130531 [ ENTREZ ] Genbank AK292155 [ ENTREZ ] Genbank AK293264 [ ENTREZ ] RefSeq NM_001037808 [ SRS ] NM_001037808 [ ENTREZ ] RefSeq NM_003752 [ SRS ] NM_003752 [ ENTREZ ] RefSeq AC_000059 [ SRS ] AC_000059 [ ENTREZ ] RefSeq NC_000016 [ SRS ] NC_000016 [ ENTREZ ] RefSeq NT_010393 [ SRS ] NT_010393 [ ENTREZ ] RefSeq NW_926284 [ SRS ] NW_926284 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2008; 6 799 CCDS EIF3C CCDS - NCBI AceView EIF3C AceView - NCBI Unigene Hs.567374 [ SRS ] Hs.567374 [ NCBI ] Protein : pattern, domain, 3D structure Q3B7B9 [ SRS] Q3B7B9 [ EXPASY ] Q3B7B9 [ INTERPRO ] Q3B7B9 SwissProt [ UNIPROT ] Q3B7B9 [ VarSplice FASTA ] Interpro IPR008905 eIF3c_N [ SRS ] IPR008905 eIF3c_N [ EBI ] CluSTr Q3B7B9 Pfam PF05470 eIF-3c_N [ SRS ] PF05470 eIF-3c_N [ Sanger ] pfam05470 [ NCBI-CDD ] Blocks Q3B7B9 HPRD 04889 Protein Interaction databases DIP Q3B7B9 IntAct Q3B7B9 Polymorphism : SNP, mutations, diseases OMIM 603916 [ map ] GENETests 603916 SNP EIF3C [dbSNP-NCBI] SNP NM_001037808 [SNP-NCI] SNP NM_003752 [SNP-NCI] SNP EIF3C [GeneSNPs - Utah] EIF3C] [HGBASE - SRS] HAPMAP EIF3C [HAPMAP] HGMD EIF3C Genetic EIF3C Association CDC HuGE EIF3C General knowledge Family EIF3C [UCSC Family Browser] Browser SOURCE NM_001037808 SOURCE NM_003752 SMD Hs.567374 SAGE Hs.567374 GO translation initiation factor activity [Amigo] translation initiation factor activity GO cytosol [Amigo] cytosol eukaryotic translation initiation factor 3 complex [Amigo] eukaryotic translation initiation GO factor 3 complex GO regulation of translational initiation [Amigo] regulation of translational initiation PubGene EIF3C TreeFam EIF3C CTD 8663 [Comparative ToxicoGenomics Database] Other databases Probes Probe EIF3C Related clones (RZPD - Berlin) PubMed PubMed 21 Pubmed reference(s) in Entrez Bibliography Conservation and diversity of eukaryotic translation initiation factor eIF3. Asano K, Kinzy TG, Merrick WC, Hershey JW The Journal of biological chemistry. 1997 ; 272 (2) : 1101-1109. PMID 8995409

Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q. Loftus BJ, Kim UJ, Sneddon VP, Kalush F, Brandon R, Fuhrmann J, Mason T, Crosby ML, Barnstead

Atlas Genet Cytogenet Oncol Haematol 2008; 6 800 M, Cronin L, Deslattes Mays A, Cao Y, Xu RX, Kang HL, Mitchell S, Eichler EE, Harris PC, Venter JC, Adams MD Genomics. 1999 ; 60 (3) : 295-308. PMID 10493829

Eukaryotic initiation factor 3 p110 mRNA is overexpressed in testicular seminomas. Rothe M, Ko Y, Albers P, Wernert N The American journal of pathology. 2000 ; 157 (5) : 1597-1604. PMID 11073819

Arabidopsis eIF3e (INT-6) associates with both eIF3c and the COP9 signalosome subunit CSN7. Yahalom A, Kim TH, Winter E, Karniol B, von Arnim AG, Chamovitz DA The Journal of biological chemistry. 2001 ; 276 (1) : 334-340. PMID 11029466

A method for the rapid construction of cRNA standard curves in quantitative real-time reverse transcription polymerase chain reaction. Fronhoffs S, Totzke G, Stier S, Wernert N, Rothe M, Bruning T, Koch B, Sachinidis A, Vetter H, Ko Y Molecular and cellular probes. 2002 ; 16 (2) : 99-110. PMID 12030760

The yeast eukaryotic initiation factor 4G (eIF4G) HEAT domain interacts with eIF1 and eIF5 and is involved in stringent AUG selection. He H, von der Haar T, Singh CR, Ii M, Li B, Hinnebusch AG, McCarthy JE, Asano K Molecular and cellular biology. 2003 ; 23 (15) : 5431-5445. PMID 12861028

Induction and mode of action of the viral stress-inducible murine proteins, P56 and P54. Terenzi F, Pal S, Sen GC Virology. 2005 ; 340 (1) : 116-124. PMID 16023166 eIF3: a versatile scaffold for translation initiation complexes. Hinnebusch AG Trends in biochemical sciences. 2006 ; 31 (10) : 553-562. PMID 16920360

Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (eIF3c). Scoles DR, Yong WH, Qin Y, Wawrowsky K, Pulst SM Human molecular genetics. 2006 ; 15 (7) : 1059-1070. PMID 16497727

Individual overexpression of five subunits of human translation initiation factor eIF3 promotes malignant transformation of immortal fibroblast cells. Zhang L, Pan X, Hershey JW The Journal of biological chemistry. 2007 ; 282 (8) : 5790-5800. PMID 17170115

The merlin interacting proteins reveal multiple targets for NF2 therapy. Scoles DR Biochimica et biophysica acta. 2008 ; 1785 (1) : 32-54. PMID 17980164

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

Search in all EBI NCBI

Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2008; 6 801 Written 02-2008 Daniel R Scoles Division of Neurology, CSMC Burns and Allen Research Institute, Cedars- Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 9, USA Citation This paper should be referenced as such : Scoles Daniel R . EIF3C (eukaryotic translation initiation factor 3, subunit C). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/EIF3CID44187ch16p11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 802 Atlas of Genetics and Cytogenetics in Oncology and Haematology

ELAC2 (elaC homolog 2 (E. coli))

Identity Other names HPC2 TRZ1 (tRNaseZL) HGNC ELAC2 Location 17p11.2 Location_base_pair Starts at 12836427 and ends at 12862084 bp from pter ( according to hg18- Mar_2006). Local_order Telomeric to HS3ST3A1 and centromeric to KIAA0672. Note There is a human paralog of this gene on called ELAC1 that is homologous to the C-terminal half of ELAC2. DNA/RNA Note Ubiquitously expressed in a variety of tissues, tumors and developmental stages. Description The genomic size of ELAC2 gene is about 25.6 kb representing a mRNA of 2966 bp with 26 exons. Transcription There is no evidence of alternative splicing of the transcript. Pseudogene No known pseudogenes. Protein Description ELAC2 gene encodes a protein of 826 amino acids. Orthologs are found in Eukaryotes including M. musculus, R. norvegicus, C. elegans, D. melanogaster, S. cerevisiae, S. pombe and A. thaliana. Expression Not determined. Localisation Not determined. But is implicated in nucleus upon overexpression in cell lines. Yeast ortholog (TRZ1p) is detected in cytosol, nucleus and mitochondria via large-scale analysis with GFP tagged gene product. Function ELAC2 has tRNA processing activity as detected by in vitro biochemistry assays. The N-terminus of ELAC2 is required for the Rnase 65 activity. The C-terminus (481-826 aa) of ELAC2, which is homologous to ELAC1, possesses tRNA 3' processing endoribonuclease acitivity (tRNaseZ). Overexpressed ELAC2 binds gamma-tubulin complex and is involved in cell cycle regulation. ELAC2 has also been shown to potentiate TGF-beta-induced growth arrest of prostate cells via over-expression upon transfection and down-regulation via siRNA. Mutations Germinal One pedigree-specific insertion/frameshift, 1641insG, resulting in frameshift after L547, and leading to termination after the miscoding of 67 residues. Four missense variants, S217L, A541T, E622V and R781H. Somatic Not determined. Implicated in Entity Prostate Cancer Note TGF-beta signaling mediated growth arrest via physical interactions with Smad2 / Smad3 and FAST-1, and potentiation of Smad2-driven (ARE)2-Luciferease reporter activity. Also implicated in RNA processing. Disease Hereditary prostate cancer and sporadic prostate cancer. External links Nomenclature HGNC ELAC2 14198 Entrez_Gene ELAC2 60528 elaC homolog 2 (E. coli) Cards Atlas ELAC2ID40437ch17p11 GeneCards ELAC2

Atlas Genet Cytogenet Oncol Haematol 2008; 6 803 Ensembl ENSG00000006744 [Gene_View] ELAC2 [Vega] Genatlas ELAC2 Genomic and cartography ELAC2 - 17p11.2 chr17:12836427-12862084 - 17p11.2 [Description] (hg18- GoldenPath Mar_2006) Ensembl ELAC2 - 17p11.2 [CytoView] NCBI Mapview OMIM 176807 Disease map [OMIM] OMIM 605367 Disease map [OMIM] HomoloGene ELAC2 Gene and transcription Genbank AF304370 [ ENTREZ ] Genbank AK001392 [ ENTREZ ] Genbank AK074244 [ ENTREZ ] Genbank AK094012 [ ENTREZ ] Genbank AK094333 [ ENTREZ ] RefSeq NM_018127 [ SRS ] NM_018127 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq AC_000149 [ SRS ] AC_000149 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010718 [ SRS ] NT_010718 [ ENTREZ ] RefSeq NW_001838403 [ SRS ] NW_001838403 [ ENTREZ ] RefSeq NW_926584 [ SRS ] NW_926584 [ ENTREZ ] CCDS ELAC2 CCDS - NCBI AceView ELAC2 AceView - NCBI Unigene Hs.434232 [ SRS ] Hs.434232 [ NCBI ] Fast-db 4465 (alternative variants) Protein : pattern, domain, 3D structure Q9BQ52 [ SRS] Q9BQ52 [ EXPASY ] Q9BQ52 [ INTERPRO ] Q9BQ52 SwissProt [ UNIPROT ] Q9BQ52 [ VarSplice FASTA ] Interpro IPR001279 Blactmase-like [ SRS ] IPR001279 Blactmase-like [ EBI ] CluSTr Q9BQ52 PF00753 Lactamase_B [ SRS ] PF00753 Lactamase_B [ Sanger ] pfam00753 Pfam [ NCBI-CDD ] Blocks Q9BQ52 HPRD 05641 Protein Interaction databases DIP Q9BQ52 IntAct Q9BQ52 Polymorphism : SNP, mutations, diseases OMIM 176807 [ map ] OMIM 605367 [ map ] GENETests 176807 GENETests 605367 SNP ELAC2 [dbSNP-NCBI] SNP NM_018127 [SNP-NCI] SNP ELAC2 [GeneSNPs - Utah] ELAC2] [HGBASE - SRS] HAPMAP ELAC2 [HAPMAP] HGMD ELAC2 Genetic ELAC2 Association CDC HuGE ELAC2 General knowledge Family ELAC2 [UCSC Family Browser]

Atlas Genet Cytogenet Oncol Haematol 2008; 6 804 Browser SOURCE NM_018127 SMD Hs.434232 SAGE Hs.434232 3.1.26.11 [ Enzyme-Expasy ] 3.1.26.11 [ Enzyme-SRS ] 3.1.26.11 [ IntEnz- Enzyme EBI ] 3.1.26.11 [ BRENDA ] 3.1.26.11 [ KEGG ] GO endonuclease activity [Amigo] endonuclease activity GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO tRNA processing [Amigo] tRNA processing GO ion binding [Amigo] zinc ion binding GO hydrolase activity [Amigo] hydrolase activity GO metal ion binding [Amigo] metal ion binding PubGene ELAC2 TreeFam ELAC2 CTD 60528 [Comparative ToxicoGenomics Database] Other databases Probes Probe ELAC2 Related clones (RZPD - Berlin) PubMed PubMed 37 Pubmed reference(s) in Entrez Bibliography ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer. Rokman A, Ikonen T, Mononen N, Autio V, Matikainen MP, Koivisto PA, Tammela TL, Kallioniemi OP, Schleutker J Cancer research. 2001 ; 61 (16) : 6038-6041. PMID 11507049

Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls. Suarez BK, Gerhard DS, Lin J, Haberer B, Nguyen L, Kesterson NK, Catalona WJ Cancer research. 2001 ; 61 (13) : 4982-4984. PMID 11431329

A candidate prostate cancer susceptibility gene at chromosome 17p. Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P, Desrochers M, Dumont M, Farnham JM, Frank D, Frye C, Ghaffari S, Gupte JS, Hu R, Iliev D, Janecki T, Kort EN, Laity KE, Leavitt A, Leblanc G, McArthur-Morrison J, Pederson A, Penn B, Peterson KT, Reid JE, Richards S, Schroeder M, Smith R, Snyder SC, Swedlund B, Swensen J, Thomas A, Tranchant M, Woodland AM, Labrie F, Skolnick MH, Neuhausen S, Rommens J, Cannon- Albright LA Nature genetics. 2001 ; 27 (2) : 172-180. PMID 11175785

Role of HPC2/ELAC2 in hereditary prostate cancer. Wang L, McDonnell SK, Elkins DA, Slager SL, Christensen E, Marks AF, Cunningham JM, Peterson BJ, Jacobsen SJ, Cerhan JR, Blute ML, Schaid DJ, Thibodeau SN Cancer research. 2001 ; 61 (17) : 6494-6499. PMID 11522646

Association of common missense changes in ELAC2 ( HPC2) with prostate cancer in a Japanese case-control series. Fujiwara H, Emi M, Nagai H, Nishimura T, Konishi N, Kubota Y, Ichikawa T, Takahashi S, Shuin T, Habuchi T, Ogawa O, Inoue K, Skolnick MH, Swensen J, Camp NJ, Tavtigian SV Journal of human genetics. 2002 ; 47 (12) : 641-648. PMID 12522685

Assigning function to yeast proteins by integration of technologies.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 805 Hazbun TR, Malmstrom L, Anderson S, Graczyk BJ, Fox B, Riffle M, Sundin BA, Aranda JD, McDonald WH, Chiu CH, Snydsman BE, Bradley P, Muller EG, Fields S, Baker D, Yates JR 3rd, Davis TN Molecular cell. 2003 ; 12 (6) : 1353-1365. PMID 14690591

Global analysis of protein localization in budding yeast. Huh WK, Falvo JV, Gerke LC, Carroll AS, Howson RW, Weissman JS, O'Shea EK Nature. 2003 ; 425 (6959) : 686-691. PMID 14562095

The product of the candidate prostate cancer susceptibility gene ELAC2 interacts with the gamma-tubulin complex. Korver W, Guevara C, Chen Y, Neuteboom S, Bookstein R, Tavtigian S, Lees E International journal of cancer. Journal international du cancer. 2003 ; 104 (3) : 283-288. PMID 12569551

A candidate prostate cancer susceptibility gene encodes tRNA 3' processing endoribonuclease. Takaku H, Minagawa A, Takagi M, Nashimoto M Nucleic acids research. 2003 ; 31 (9) : 2272-2278. PMID 12711671

The N-terminal half-domain of the long form of tRNase Z is required for the RNase 65 activity. Takaku H, Minagawa A, Takagi M, Nashimoto M Nucleic acids research. 2004 ; 32 (15) : 4429-4438. PMID 15317868

Characterization of TRZ1, a yeast homolog of the human candidate prostate cancer susceptibility gene ELAC2 encoding tRNase Z. Chen Y, Beck A, Davenport C, Chen Y, Shattuck D, Tavtigian SV BMC molecular biology. 2005 ; 6 (1) : page 12. PMID 15892892

ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-beta/Smad- induced growth arrest of prostate cells. Noda D, Itoh S, Watanabe Y, Inamitsu M, Dennler S, Itoh F, Koike S, Danielpour D, ten Dijke P, Kato M Oncogene. 2006 ; 25 (41) : 5591-5600. PMID 16636667

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Yang Chen, Sean Tavtigian, Donna Shattuck Myriad Genetics, Inc., 320 Wakara Way, Salt Lake City, UT 84108, USA Citation This paper should be referenced as such : Chen Y, Tavtigian S, Shattuck D . ELAC2 (elaC homolog 2 (E. coli)). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/ELAC2ID40437ch17p11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 806 Atlas of Genetics and Cytogenetics in Oncology and Haematology

FOXM1 (forkhead box M1)

Identity Other names FKHL16 FOXM1B HFH-11 HFH11 HNF-3 INS-1 MPHOSPH2 MPP-2 MPP2 PIG29 TGT3 TRIDENT HGNC FOXM1 Location 12p13 Location_base_pair Starts at 2837110 and ends at 2856564 bp from pter ( according to hg18- Mar_2006). DNA/RNA

Description The gene spans 25 kb and contains 10 exons. Transcription 3.4-3.6 kb mRNA; Differential splicing of exons Va (A1) and VIIa (A2) gives rise to 3 classes of transcripts, which encode 3 different protein isoforms: FoxM1A, containing both alternative exons; FoxM1B, containing none of the alternative exons and FoxM1C, containing only exon Va. Protein

Atlas Genet Cytogenet Oncol Haematol 2008; 6 807

hFoxM1C Description FoxM1 belongs to a large family of forkhead transcription factors. FoxM1 protein contains 3 main regions: the N-terminal Repressor Domain (NRD). This region is followed by a conserved DNA Binding Domain called Forkhead or winged-helix domain (FKH). The C-terminal region harbors the Transcativation Domain (TAD) with several activating Cyclin-Cdk-dependent phosphorylation sites. Expression FoxM1 is specifically expressed in proliferating cells. Expression is negatively regulated in quiescent or terminally-differentiated cells. Both expression and transcriptional activity of FoxM1 are tightly regulated during the cell cycle. Increase in FoxM1 expression levels is initiated at the onset of S-phase and continues throughout G2- phase and Mitosis. During G1 phase, FoxM1 activity is inhibited through several mechanisms, including interaction with the cell cycle inhibitory pocket protein pRb, and through inhibition by the N-terminal auto-repressor domain of FoxM1 itself. The cell cycle-inhibitory p19ARF can also bind the C-terminal transactivation domain of FoxM1 and inactivate its transcriptional activity by targeting FoxM1 protein to the nucleolus. Transcriptional activation of FoxM1 correlates with increased phosphorylation of the protein. It occurs specifically during G2-phase of the cell cycle through direct phosphorylation of the C-terminal transactivation domain (TAD) mediated by G2-Cyclin- dependent kinases (Cdks). Cyclin-Cdk-dependent phosphorylation of the C-terminal region of FoxM1 is required to relieve auto-inhibition exerted by the N-terminal repressor domain (NRD). In addition, Cdk-dependent phosphorylation of the C-terminal TAD serves to recruit transcriptional co-activators such as the histone deacetylase p300/CREB binding protein (p300/CBP). FoxM1 transcriptional activity also requires the presence of appropriate mitogenic signals involving the Raf/MEK/MAPK signaling pathway. Localisation Nuclear, but can be detected in the cytoplasm upon inhibition of Raf/MEK/MAPK signaling. FoxM1 can also be targeted to the nucleolus by p19ARF. Function FoxM1 acts as a transcriptional activator of the G2-M-specific gene cluster in mammalian cells. Homology Homology with other Forkhead transcription factors in the FKH DNA Binding Domain. Implicated in Entity Cancer Disease FoxM1 is commonly upregulated in human aggressive carcinomas originating from prostate, breast, lung, ovary, colon, pancreas, stomach, bladder, liver and kidney. FoxM1 promotes tumor progression of prostate carcinomas and lung adenocarcinomas. FoxM1 expression and activity are significantly elevated in basal cell carcinoma (BCC) skin tumors and FoxM1 expression in malignant gliomas correlates with disease staging. FoxM1 contributes to cellular transformation by the high-risk human papillomavirus-16 (HPV-16) E7 protein. Conditional deletion of the FoxM1 gene in mice reduces proliferation of lung tumors and renders hepatocytes resistant to tumor development. Down-regulation of FoxM1 reduces the invasiveness of glioma cells and decreases cell migration and cell invasion in pancreatic cancer cells.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 808 Cytogenetics Amplifications of the 12p13 chromosomal band, comprising the FoxM1 gene, have been reported in numerous tumors such as cervical squamous cell carcinomas, breast adenocarcinomas, nasopharyngeal carcinomas and head and neck squamous cell carcinomas. Entity Ageing Disease FoxM1 expression is affected (low) in cells from patients with progeria and FoxM1- deficient cells senesce prematurely. Inversely, increased levels of FoxM1B in regenerating liver of old transgenic mice elevate hepatocyte proliferation to levels similar to those observed in young regenerating mouse liver. External links Nomenclature HGNC FOXM1 3818 Entrez_Gene FOXM1 2305 forkhead box M1 Cards Atlas FOXM1ID40631ch12p13 GeneCards FOXM1 Ensembl ENSG00000111206 [Gene_View] FOXM1 [Vega] Genatlas FOXM1 Genomic and cartography GoldenPath FOXM1 - 12p13 chr12:2837110-2856564 - 12p13 [Description] (hg18-Mar_2006) Ensembl FOXM1 - 12p13 [CytoView] NCBI Mapview OMIM 602341 Disease map [OMIM] HomoloGene FOXM1 Gene and transcription Genbank AK291206 [ ENTREZ ] Genbank AK313845 [ ENTREZ ] Genbank AY542306 [ ENTREZ ] Genbank BC006192 [ ENTREZ ] Genbank BC006529 [ ENTREZ ] RefSeq NM_021953 [ SRS ] NM_021953 [ ENTREZ ] RefSeq NM_202002 [ SRS ] NM_202002 [ ENTREZ ] RefSeq NM_202003 [ SRS ] NM_202003 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq AC_000144 [ SRS ] AC_000144 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_009759 [ SRS ] NT_009759 [ ENTREZ ] RefSeq NW_001838049 [ SRS ] NW_001838049 [ ENTREZ ] RefSeq NW_925295 [ SRS ] NW_925295 [ ENTREZ ] CCDS FOXM1 CCDS - NCBI AceView FOXM1 AceView - NCBI Unigene Hs.239 [ SRS ] Hs.239 [ NCBI ] Fast-db 519 (alternative variants) Protein : pattern, domain, 3D structure Q08050 [ SRS] Q08050 [ EXPASY ] Q08050 [ INTERPRO ] Q08050 [ UNIPROT SwissProt ] Q08050 [ VarSplice FASTA ] Prosite PS00657 FORK_HEAD_1 [ SRS ] PS00657 FORK_HEAD_1 [ Expasy ] Prosite PS00658 FORK_HEAD_2 [ SRS ] PS00658 FORK_HEAD_2 [ Expasy ] Prosite PS50039 FORK_HEAD_3 [ SRS ] PS50039 FORK_HEAD_3 [ Expasy ] Interpro IPR001766 TF_Fork_head [ SRS ] IPR001766 TF_Fork_head [ EBI ] Interpro IPR011991 Wing_hlx_DNA_bd [ SRS ] IPR011991 Wing_hlx_DNA_bd [ EBI ] CluSTr Q08050 PF00250 Fork_head [ SRS ] PF00250 Fork_head [ Sanger ] pfam00250 [ NCBI- Pfam CDD ]

Atlas Genet Cytogenet Oncol Haematol 2008; 6 809 Smart SM00339 FH [EMBL] Prodom PD000425 TF_Fork_head[INRA-Toulouse] Q08050 FOXM1_HUMAN [ Domain structure ] Q08050 FOXM1_HUMAN Prodom [ sequences sharing at least 1 domain ] Blocks Q08050 HPRD 03823 Protein Interaction databases DIP Q08050 IntAct Q08050 Polymorphism : SNP, mutations, diseases OMIM 602341 [ map ] GENETests 602341 SNP FOXM1 [dbSNP-NCBI] SNP NM_021953 [SNP-NCI] SNP NM_202002 [SNP-NCI] SNP NM_202003 [SNP-NCI] SNP FOXM1 [GeneSNPs - Utah] FOXM1] [HGBASE - SRS] HAPMAP FOXM1 [HAPMAP] COSMIC FOXM1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD FOXM1 Genetic FOXM1 Association CDC HuGE FOXM1 General knowledge Family FOXM1 [UCSC Family Browser] Browser SOURCE NM_021953 SOURCE NM_202002 SOURCE NM_202003 SMD Hs.239 SAGE Hs.239 GO transcription factor activity [Amigo] transcription factor activity GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO sequence-specific DNA binding [Amigo] sequence-specific DNA binding PubGene FOXM1 TreeFam FOXM1 CTD 2305 [Comparative ToxicoGenomics Database] Other databases Probes Probe FOXM1 Related clones (RZPD - Berlin) PubMed PubMed 30 Pubmed reference(s) in Entrez Bibliography The winged-helix transcription factor Trident is expressed in cycling cells. Korver W, Roose J, Clevers H Nucleic acids research. 1997 ; 25 (9) : 1715-1719. PMID 9108152

The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization. Korver W, Roose J, Heinen K, Weghuis DO, de Bruijn D, van Kessel AG, Clevers H

Atlas Genet Cytogenet Oncol Haematol 2008; 6 810 Genomics. 1997 ; 46 (3) : 435-442. PMID 9441747

Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues. Ye H, Kelly TF, Samadani U, Lim L, Rubio S, Overdier DG, Roebuck KA, Costa RH Molecular and cellular biology. 1997 ; 17 (3) : 1626-1641. PMID 9032290

Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation. Luscher-Firzlaff JM, Westendorf JM, Zwicker J, Burkhardt H, Henriksson M, Muller R, Pirollet F, Luscher B Oncogene. 1999 ; 18 (41) : 5620-5630. PMID 10523841

Mitotic misregulation and human aging. Ly DH, Lockhart DJ, Lerner RA, Schultz PG Science (New York, N.Y.). 2000 ; 287 (5462) : 2486-2492. PMID 10741968

Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver. Wang X, Quail E, Hung NJ, Tan Y, Ye H, Costa RH Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (20) : 11468-11473. PMID 11572993

FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG Cancer research. 2002 ; 62 (16) : 4773-4780. PMID 12183437

Increased hepatic Forkhead Box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27Kip1 protein levels and increased Cdc25B expression. Wang X, Krupczak-Hollis K, Tan Y, Dennewitz MB, Adami GR, Costa RH The Journal of biological chemistry. 2002 ; 277 (46) : 44310-44316. PMID 12221098

Growth hormone stimulates proliferation of old-aged regenerating liver through forkhead box m1b. Krupczak-Hollis K, Wang X, Dennewitz MB, Costa RH Hepatology (Baltimore, Md.). 2003 ; 38 (6) : 1552-1562. PMID 14647066

Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH Genes & development. 2004 ; 18 (7) : 830-850. PMID 15082532

Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Major ML, Lepe R, Costa RH Molecular and cellular biology. 2004 ; 24 (7) : 2649-2661. PMID 15024056

Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 811 Pilarsky C, Wenzig M, Specht T, Saeger HD, Grutzmann R Neoplasia (New York, N.Y.). 2004 ; 6 (6) : 744-750. PMID 15720800

FoxM1 is required for execution of the mitotic programme and chromosome stability. Laoukili J, Kooistra MR, Bras A, Kauw J, Kerkhoven RM, Morrison A, Clevers H, Medema RH Nature cell biology. 2005 ; 7 (2) : 126-136. PMID 15654331

Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c. Ma RY, Tong TH, Cheung AM, Tsang AC, Leung WY, Yao KM Journal of cell science. 2005 ; 118 (Pt 4) : 795-806. PMID 15671063

Conventional and array-based comparative genomic hybridization analysis of nasopharyngeal carcinomas from the Mediterranean area. Rodriguez S, Khabir A, Keryer C, Perrot C, Drira M, Ghorbel A, Jlidi R, Bernheim A, Valent A, Busson P Cancer genetics and cytogenetics. 2005 ; 157 (2) : 140-147. PMID 15721635

Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, Tan Y, Ackerson T, Costa RH Molecular and cellular biology. 2005 ; 25 (24) : 10875-10894. PMID 16314512

Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ, Kalinichenko VV, Lyubimov A, Costa RH Cancer research. 2006 ; 66 (3) : 1712-1720. PMID 16452231

The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV, Major ML, Gusarova GA, Yoder HM, Costa RH, Kalinichenko VV Cancer research. 2006 ; 66 (4) : 2153-2161. PMID 16489016

FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S Cancer research. 2006 ; 66 (7) : 3593-3602. PMID 16585184

Despite its strong transactivation domain, transcription factor FOXM1c is kept almost inactive by two different inhibitory domains. Wierstra I, Alves J Biological chemistry. 2006 ; 387 (7) : 963-976. PMID 16913846

FoxM1: at the crossroads of ageing and cancer. Laoukili J, Stahl M, Medema RH Biochimica et biophysica acta. 2007 ; 1775 (1) : 92-102. PMID 17014965

An N-terminal inhibitory domain modulates activity of FoxM1 during cell cycle.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 812 Park HJ, Wang Z, Costa RH, Tyner A, Lau LF, Raychaudhuri P Oncogene. 2008 ; 27 (12) : 1696-1704. PMID 17891172

Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Tan Y, Raychaudhuri P, Costa RH Molecular and cellular biology. 2007 ; 27 (3) : 1007-1016. PMID 17101782

Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. Wang Z, Banerjee S, Kong D, Li Y, Sarkar FH Cancer research. 2007 ; 67 (17) : 8293-8300. PMID 17804744

FOXM1, a typical proliferation-associated transcription factor. Wierstra I, Alves J Biological chemistry. 2007 ; 388 (12) : 1257-1274. PMID 18020943

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Jamila Laoukili, Monica Alvarez Fernandez, René H Medema Department of Human Genetics, Academic Medical Center, Amsterdam, The Netherlands (JL); Department of Medical Oncology, University Medical Center Utrecht, The Netherlands (MAF, RHM) Citation This paper should be referenced as such : Laoukili J, Alvarez Fernandez M, Medema RH . FOXM1 (forkhead box M1). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/FOXM1ID40631ch12p13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 813 Atlas of Genetics and Cytogenetics in Oncology and Haematology

PTCH2 (patched homolog 2 (Drosophila))

Identity Other names PTC2 Patched 2 Patched homolog 2 HGNC PTCH2 Location 1p34.1 Location_base_pair Starts at 45060674 and ends at 45081203 bp from pter ( according to hg18- Mar_2006). Tel-PLK3-LOC343521-LOC149478-PTCH2-EIF2B3-LOC728887- LOC128192- Local_order Cen DNA/RNA Description 23 exons, approximately 20 kb of genomic sequence. The last exon is exon 22 due to the presence of exons 12A and 12B. Transcription Altrenative splice variants, skipping of exons 9 and 10 - maintenance of reading frame, skipping of exon 9 - maintenance of reading frame, skipping of exon 21- change of reading frame. Alternative 3' end - termination within intron 21. Protein Description Putative 12 transmembrane protein, similar to PTCH1. Receptor of Hedgehog ligands but can not transduce signal activity as PTCH1 does. Expression Mainly testis and skin, generally weaker than PTCH1, dependent on Hedgehog signaling activation, as in PTCH1. However, in PTCH1 the up-regulation of gene expression due to signaling activation results in a negative feedback loop due to inhibition of the activity of the transmenbrane protein, Smoothened, but this does not appear to be the case for PTCH2. Localisation Cellular membranes. Function Receptor of Hedgehog ligands but lacks the strong capacity of PTCH1 to inhibit the signaling molecule Smoothened, which, through a series of intracellular events, activates the GLI family of transcription factors. Thus, while PTCH1 regulates Smoothened activity depending on Hedgehog ligand binding, PTCH2 is not. This is despite the fact that the three mammalian Hedgehog ligands Sonic, Desert and Indian Hedgehog have similar affinity for both PTCH1 and PTCH2. The expression of the PTCH2 receptor and the Desert Hedgehog ligand in the testis, as well as the requirement of Desert Hedgehog in testicular development has led to the proposal that PTCH2 may mediate the Desert Hedgehog effects in that tissue and could act as a tumor suppressor in germ cell tumors, as these are frequently deleted in 1p33-34. However, no PTCH2 mutations have been identified in such tumors and knock-out mouse models of PTCH2 have not revealed any testicular phenotype. Homology Homolog to PTCH1. Mouse, Chicken and Zebrafish have both PTCH homologs but Drosophila only one. Mutations Germinal None described Somatic Only two cases reported : - Medulloblastomas, 2bp deletion in exon 8 - germline DNA not checked. - Basal Cell Carcinoma, nucleotide change in intron 20, five bases from 5' splice junction. Implicated in Entity Various cancers Note There are no genetic diseases or tumors where the role of PTCH2 has been clearly demonstrated by the unambiguous detection of PTCH2 mutations that disrupt the protein function.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 814 The various suggestions of a possible role of PTCH2 in tumor development are generally circumstantial and are mostly based on chromosomal deletions that encompass the PTCH2 genomic region. The strongest evidence that PTCH2 hay have a role in tumor development comes from knock-out mouse model systems. Thus while Ptch2(-/-) mice have no obvious phenotype and do not develop tumors, if they are crossed with Ptch1 (+/-) heterozygotes, then the resulting Ptch2(-/-)Ptch1(+/-) mice developed at a higher incidence typical Ptch1(+/-) tumors such as medulloblastomas and rhabdomyosarcomas, suggesting genetic interactions between Ptch2 and Ptch1. A possible role of PTCH2 in testicular development, acting as a Desert Hedgehog receptor has been suggested. Overexpression of PTCH2 in basal cell carcinomas cannot compensate for mutated PTCH1 implying distinct roles of the two homologs. This can be rationalized by the very weak capacity of PTCH2 relative to PTCH1 in inhibiting the signaling molecule Smoothened. Additionally, based mostly on chromosomal deletion in the 1p32-34 region where the PTCH2 gene resides, a role in neurofibromas, pituitary tumors, medulloblastomas and meningiomas has been proposed. Also, PTCH2 is implicated in thymus, dental, prostate, ovary, and bone tissue development, as PTCH2 expression has been detected in these tissues. In a mouse model, deletions of exons 5 to 17 in both Ptch2 alleles did not result in any obvious phenotype. However in the context of Ptch1+/- mice, this deletion of Ptch2 resulted in higher incidence and broader spectrum of tumor formation. In another mouse model of Ptch2, with a targeted insertion in exon 6 that would results in premature termination, the resulting homozygous mice were characterized with alopecia and epidermal hyperplasia. External links Nomenclature HGNC PTCH2 9586 Entrez_Gene PTCH2 8643 patched homolog 2 (Drosophila) Cards Atlas PTCH2ID41892ch1p34 GeneCards PTCH2 Ensembl ENSG00000117425 [Gene_View] PTCH2 [Vega] Genatlas PTCH2 Genomic and cartography PTCH2 - 1p34.1 chr1:45060674-45081203 - 1p34.1 [Description] (hg18- GoldenPath Mar_2006) Ensembl PTCH2 - 1p34.1 [CytoView] NCBI Mapview OMIM 155255 Disease map [OMIM] OMIM 603673 Disease map [OMIM] OMIM 605462 Disease map [OMIM] HomoloGene PTCH2 Gene and transcription Genbank AF087651 [ ENTREZ ] Genbank AF091501 [ ENTREZ ] Genbank AF119569 [ ENTREZ ] Genbank AK307168 [ ENTREZ ] Genbank AY358555 [ ENTREZ ] RefSeq NM_003738 [ SRS ] NM_003738 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_032977 [ SRS ] NT_032977 [ ENTREZ ] RefSeq NW_001838578 [ SRS ] NW_001838578 [ ENTREZ ] RefSeq NW_921351 [ SRS ] NW_921351 [ ENTREZ ] CCDS PTCH2 CCDS - NCBI

Atlas Genet Cytogenet Oncol Haematol 2008; 6 815 AceView PTCH2 AceView - NCBI Unigene Hs.591497 [ SRS ] Hs.591497 [ NCBI ] Fast-db 15523 (alternative variants) Protein : pattern, domain, 3D structure Q5JR97 [ SRS] Q5JR97 [ EXPASY ] Q5JR97 [ INTERPRO ] Q5JR97 SwissProt [ UNIPROT ] Q5JR97 [ VarSplice FASTA ] Interpro IPR003392 Patched [ SRS ] IPR003392 Patched [ EBI ] CluSTr Q5JR97 Pfam PF02460 Patched [ SRS ] PF02460 Patched [ Sanger ] pfam02460 [ NCBI-CDD ] Blocks Q5JR97 HPRD 04722 Protein Interaction databases DIP Q5JR97 IntAct Q5JR97 Polymorphism : SNP, mutations, diseases OMIM 155255 [ map ] OMIM 603673 [ map ] OMIM 605462 [ map ] GENETests 155255 GENETests 603673 GENETests 605462 SNP PTCH2 [dbSNP-NCBI] SNP NM_003738 [SNP-NCI] SNP PTCH2 [GeneSNPs - Utah] PTCH2] [HGBASE - SRS] HAPMAP PTCH2 [HAPMAP] COSMIC PTCH2 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PTCH2 Genetic PTCH2 Association CDC HuGE PTCH2 General knowledge Family PTCH2 [UCSC Family Browser] Browser SOURCE NM_003738 SMD Hs.591497 SAGE Hs.591497 GO integral to plasma membrane [Amigo] integral to plasma membrane GO protein complex assembly [Amigo] protein complex assembly GO spermatogenesis [Amigo] spermatogenesis GO hedgehog receptor activity [Amigo] hedgehog receptor activity GO epidermis development [Amigo] epidermis development GO membrane [Amigo] membrane KEGG Hedgehog signaling pathway PubGene PTCH2 TreeFam PTCH2 CTD 8643 [Comparative ToxicoGenomics Database] Other databases Probes Probe PTCH2 Related clones (RZPD - Berlin) PubMed PubMed 7 Pubmed reference(s) in Entrez Bibliography Characterization of two patched receptors for the vertebrate hedgehog protein family. Carpenter D, Stone DM, Brush J, Ryan A, Armanini M, Frantz G, Rosenthal A, de Sauvage FJ

Atlas Genet Cytogenet Oncol Haematol 2008; 6 816 Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (23) : 13630-13634. PMID 9811851

Overlapping and non-overlapping Ptch2 expression with Shh during mouse embryogenesis. Motoyama J, Heng H, Crackower MA, Takabatake T, Takeshima K, Tsui LC, Hui C Mechanisms of development. 1998 ; 78 (1-2) : 81-84. PMID 9858693

Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog. Motoyama J, Takabatake T, Takeshima K, Hui C Nature genetics. 1998 ; 18 (2) : 104-106. PMID 9462734

Characterisation of a second patched gene in the zebrafish Danio rerio and the differential response of patched genes to Hedgehog signalling. Lewis KE, Concordet JP, Ingham PW Developmental biology. 1999 ; 208 (1) : 14-29. PMID 10075838

Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32. Smyth I, Narang MA, Evans T, Heimann C, Nakamura Y, Chenevix-Trench G, Pietsch T, Wicking C, Wainwright BJ Human molecular genetics. 1999 ; 8 (2) : 291-297. PMID 9931336

PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas. Zaphiropoulos PG, Unden AB, Rahnama F, Hollingsworth RE, Toftgard R Cancer research. 1999 ; 59 (4) : 787-792. PMID 10029063

Development of stratum intermedium and its role as a Sonic hedgehog-signaling structure during odontogenesis. Koyama E, Wu C, Shimo T, Iwamoto M, Ohmori T, Kurisu K, Ookura T, Bashir MM, Abrams WR, Tucker T, Pacifici M Developmental dynamics : an official publication of the American Association of Anatomists. 2001 ; 222 (2) : 178-191. PMID 11668596

Ptc1 and Ptc2 transcripts provide distinct readouts of Hedgehog signaling activity during chick embryogenesis. Pearse RV 2nd, Vogan KJ, Tabin CJ Developmental biology. 2001 ; 239 (1) : 15-29. PMID 11784016

Suppression of hair follicle development inhibits induction of sonic hedgehog, patched, and patched-2 in hair germs in mice. Yamago G, Takata Y, Furuta I, Urase K, Momoi T, Huh N Archives of dermatological research. 2001 ; 293 (9) : 435-441. PMID 11758785

Genomic structure and refined chromosomal localization of the mouse Ptch2 gene. Frohlich L, Liu Z, Beier DR, Lanske B Cytogenetic and genome research. 2002 ; 97 (1-2) : 106-110. PMID 12438747

A possible paracrine hedgehog signalling pathway in neurofibromas from patients with neurofibromatosis type 1.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 817 Endo H, Utani A, Matsumoto F, Kuroki T, Yoshimoto S, Ichinose M, Shinkai H The British journal of dermatology. 2003 ; 148 (2) : 337-341. PMID 12588389

A molecular fingerprint for medulloblastoma. Lee Y, Miller HL, Jensen P, Hernan R, Connelly M, Wetmore C, Zindy F, Roussel MF, Curran T, Gilbertson RJ, McKinnon PJ Cancer research. 2003 ; 63 (17) : 5428-5437. PMID 14500378

Expression of hedgehog proteins in the human thymus. Sacedon R, Varas A, Hernandez-Lopez C, Gutierrez-deFrias C, Crompton T, Zapata AG, Vicente A The journal of histochemistry and cytochemistry. 2003 ; 51 (11) : 1557-1566. PMID 14566027

Inhibition of epithelial ductal branching in the prostate by sonic hedgehog is indirectly mediated by stromal cells. Wang BE, Shou J, Ross S, Koeppen H, De Sauvage FJ, Gao WQ The Journal of biological chemistry. 2003 ; 278 (20) : 18506-18513. PMID 12626524

Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR. Levy P, Vidaud D, Leroy K, Laurendeau I, Wechsler J, Bolasco G, Parfait B, Wolkenstein P, Vidaud M, Bieche I Molecular cancer. 2004 ; 3 : page 20. PMID 15255999

Distinct roles of PTCH2 splice variants in Hedgehog signalling. Rahnama F, Toftgard R, Zaphiropoulos PG The Biochemical journal. 2004 ; 378 (Pt 2) : 325-334. PMID 14613484

Genomic annotation of the meningioma tumor suppressor locus on chromosome 1p34. Sulman EP, White PS, Brodeur GM Oncogene. 2004 ; 23 (4) : 1014-1020. PMID 14749765

Molecular abnormalities in pediatric embryonal brain tumors--analysis of loss of heterozygosity on 1, 5, 9, 10, 11, 16, 17 and 22. Zakrzewska M, Rieske P, Debiec-Rychter M, Zakrzewski K, Polis L, Fiks T, Liberski PP Clinical neuropathology. 2004 ; 23 (5) : 209-217. PMID 15581023

The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway. Koudijs MJ, den Broeder MJ, Keijser A, Wienholds E, Houwing S, van Rooijen EM, Geisler R, van Eeden FJ PLoS genetics. 2005 ; 1 (2) : page e19. PMID 16121254

Expression patterns of hedgehog signaling peptides in naturally acquired equine osteochondrosis. Semevolos SA, Strassheim ML, Haupt JL, Nixon AJ Journal of orthopaedic research. 2005 ; 23 (5) : 1152-1159. PMID 16140195

Expression and function of sonic hedgehog pathway components in pituitary adenomas: evidence for a direct role in hormone secretion and cell proliferation. Vila G, Theodoropoulou M, Stalla J, Tonn JC, Losa M, Renner U, Stalla GK, Paez-Pereda M

Atlas Genet Cytogenet Oncol Haematol 2008; 6 818 The Journal of clinical endocrinology and metabolism. 2005 ; 90 (12) : 6687-6694. PMID 16159933

Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells. Wijgerde M, Ooms M, Hoogerbrugge JW, Grootegoed JA Endocrinology. 2005 ; 146 (8) : 3558-3566. PMID 15878962

Desert hedgehog-patched 2 expression in peripheral nerves during Wallerian degeneration and regeneration. Bajestan SN, Umehara F, Shirahama Y, Itoh K, Sharghi-Namini S, Jessen KR, Mirsky R, Osame M Journal of neurobiology. 2006 ; 66 (3) : 243-255. PMID 16329124

Patched2 modulates tumorigenesis in patched1 heterozygous mice. Lee Y, Miller HL, Russell HR, Boyd K, Curran T, McKinnon PJ Cancer research. 2006 ; 66 (14) : 6964-6971. PMID 16849540

Sonic hedgehog signaling is important in tooth root development. Nakatomi M, Morita I, Eto K, Ota MS Journal of dental research. 2006 ; 85 (5) : 427-431. PMID 16632755

Mice with a targeted mutation of patched2 are viable but develop alopecia and epidermal hyperplasia. Nieuwenhuis E, Motoyama J, Barnfield PC, Yoshikawa Y, Zhang X, Mo R, Crackower MA, Hui CC Molecular and cellular biology. 2006 ; 26 (17) : 6609-6622. PMID 16914743

Lack of Rb and p53 delays cerebellar development and predisposes to large cell anaplastic medulloblastoma through amplification of N-Myc and Ptch2. Shakhova O, Leung C, van Montfort E, Berns A, Marino S Cancer research. 2006 ; 66 (10) : 5190-5200. PMID 16707443

Expression of hedgehog signalling components in adult mouse testis. Szczepny A, Hime GR, Loveland KL Developmental dynamics. 2006 ; 235 (11) : 3063-3070. PMID 16958114

Gene expression analysis of the hedgehog signaling cascade in the chick midbrain and spinal cord. Aglyamova GV, Agarwala S Developmental dynamics. 2007 ; 236 (5) : 1363-1373. PMID 17436280

Transcriptome analysis of differentiating spermatogonia stimulated with kit ligand. Rossi P, Lolicato F, Grimaldi P, Dolci S, Di Sauro A, Filipponi D, Geremia R Gene expression patterns : GEP. 2008 ; 8 (2) : 58-70. PMID 18036996

The hedgehog signaling pathway in the mouse ovary. Russell MC, Cowan RG, Harman RM, Walker AL, Quirk SM Biology of reproduction. 2007 ; 77 (2) : 226-236. PMID 17392501

Sonic and desert hedgehog signaling in human fetal prostate development. Zhu G, Zhau HE, He H, Zhang L, Shehata B, Wang X, Cerwinka WH, Elmore J, He D

Atlas Genet Cytogenet Oncol Haematol 2008; 6 819 The Prostate. 2007 ; 67 (6) : 674-684. PMID 17342747

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Peter Zaphiropoulos Department of Biosciences and Nutrition, Karolinska Institute, 14157 Huddinge, Sweden Citation This paper should be referenced as such : Zaphiropoulos P . PTCH2 (patched homolog 2 (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/PTCH2ID41892ch1p34.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 820 Atlas of Genetics and Cytogenetics in Oncology and Haematology

PTPN21 (protein tyrosine phosphatase, non-receptor type 21)

Identity Other names PTPD1 PTPRL10 HGNC PTPN21 Location 14q31.3 Location_base_pair Starts at 88001875 and ends at 88090876 bp from pter ( according to hg18- Mar_2006). DNA/RNA

Transcription cDNA approximately 6.2 kb; at nucleotide 333-335 ATG of transcription initiation sites. Pseudogene No Protein

Description PTPD1 is a protein of 130 kDa composed 1174 amino acids. It is constituted by an N-terminal sequence homologous to the Four-point-one Ezrin- Radixin-Moesin (FERM domain) protein family; a C-terminal catalytic domain (PTP) with the essential cysteine residue at position 1108; two putative SH3 domain binding domains (residues 565-574 and 334-343); an acidic region in the residues 712-722; two highly conserved SH2 binding motifs (Y158ESQ and Y217GEE) within the FERm domain that mediate interaction with src tyrosine kinase. Expression PTPD1 is widely expressed in a variety of tissues including placenta, lung, kidney, colon, skeletal muscle, and in most cell lines (HEK293, fibroblast, MCF-7; T82; B16). Localisation PTPD1 localizes at the outer mitochondrial membrane, the plasma membrane, Golgi apparatus, endoplasmic reticulum, actin filaments and adhesion plaques. Function PTPD1 is member of non-receptor tyrosine phosphatases that binds to- and activates src tyrosine kinase. PTPD1/src complex up-regulates epidermal growth factor receptor (EGFR) phosphorylation and increases ERK 1 / ERK 2 signaling in response to EGF. PTPD1 forms a stable complex with actin, src tyrosine kinase and FAK (Focal Adhesion Kinase). PTPD1 regulates FAK signalling and actin cytoskeleton remodelling, and promotes cell scattering and migration. Mitochondrial PTPD1 in complex with AKAP121 and src is required for efficient maintenance of mitochondrial membrane potential and oxidative ATP synthesis. PTPD1 has been also implicated in the regulation of the Tec family kinases and activation of Stat3 signaling pathway. PTPD1 Interactors: KIF1C kinesin family member 1C, BMX non-receptor tyrosine kinase, Src v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian), TEC tyrosine kinase implicated in the signaling pathways of hematopoietic and antigen receptors, FAK tyrosine kinase of focal adhesion, Actin filaments Homology PTPD1 belongs to the same family of tyrosine phosphatase PTPH1 and PTPMEG1. Implicated in Entity Sporadic colorectal cancer. Note PTPD1 is overexpressed in MIN (microsatellite instability pathway) colorectal cancer cells lines.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 821 External links Nomenclature HGNC PTPN21 9651 Entrez_Gene PTPN21 11099 protein tyrosine phosphatase, non-receptor type 21 Cards Atlas PTPN21ID41916ch14q21 GeneCards PTPN21 Ensembl ENSG00000070778 [Gene_View] PTPN21 [Vega] Genatlas PTPN21 Genomic and cartography PTPN21 - 14q31.3 chr14:88001875-88090876 - 14q31 [Description] (hg18- GoldenPath Mar_2006) Ensembl PTPN21 - 14q31 [CytoView] NCBI Mapview OMIM 603271 Disease map [OMIM] HomoloGene PTPN21 Gene and transcription Genbank AI800682 [ ENTREZ ] Genbank AK310480 [ ENTREZ ] Genbank BC167856 [ ENTREZ ] Genbank BM930068 [ ENTREZ ] Genbank CR593033 [ ENTREZ ] RefSeq NM_007039 [ SRS ] NM_007039 [ ENTREZ ] RefSeq AC_000057 [ SRS ] AC_000057 [ ENTREZ ] RefSeq AC_000146 [ SRS ] AC_000146 [ ENTREZ ] RefSeq NC_000014 [ SRS ] NC_000014 [ ENTREZ ] RefSeq NT_026437 [ SRS ] NT_026437 [ ENTREZ ] RefSeq NW_001838113 [ SRS ] NW_001838113 [ ENTREZ ] RefSeq NW_925561 [ SRS ] NW_925561 [ ENTREZ ] CCDS PTPN21 CCDS - NCBI AceView PTPN21 AceView - NCBI Unigene Hs.437040 [ SRS ] Hs.437040 [ NCBI ] Fast-db 4363 (alternative variants) Protein : pattern, domain, 3D structure Q16825 [ SRS] Q16825 [ EXPASY ] Q16825 [ INTERPRO ] Q16825 [ UNIPROT SwissProt ] Q16825 [ VarSplice FASTA ] Prosite PS00660 FERM_1 [ SRS ] PS00660 FERM_1 [ Expasy ] Prosite PS00661 FERM_2 [ SRS ] PS00661 FERM_2 [ Expasy ] Prosite PS50057 FERM_3 [ SRS ] PS50057 FERM_3 [ Expasy ] PS00383 TYR_PHOSPHATASE_1 [ SRS ] PS00383 TYR_PHOSPHATASE_1 Prosite [ Expasy ] PS50056 TYR_PHOSPHATASE_2 [ SRS ] PS50056 TYR_PHOSPHATASE_2 Prosite [ Expasy ] PS50055 TYR_PHOSPHATASE_PTP [ SRS ] PS50055 TYR_PHOSPHATASE_PTP Prosite [ Expasy ] Interpro IPR000299 Band_4.1_N [ SRS ] IPR000299 Band_4.1_N [ EBI ] IPR014352 FERM/acyl-CoA_bd_prot_3-hlx [ SRS ] IPR014352 FERM/acyl- Interpro CoA_bd_prot_3-hlx [ EBI ] Interpro IPR011993 PH_type [ SRS ] IPR011993 PH_type [ EBI ] Interpro IPR000387 Tyr_Pase [ SRS ] IPR000387 Tyr_Pase [ EBI ] Interpro IPR016130 Tyr_Pase_AS [ SRS ] IPR016130 Tyr_Pase_AS [ EBI ] IPR014392 Tyr_Pase_non-rcpt_typ-14/21 [ SRS ] IPR014392 Tyr_Pase_non- Interpro rcpt_typ-14/21 [ EBI ] Interpro IPR000242 Tyr_Pase_rcpt/non-rcpt [ SRS ] IPR000242 Tyr_Pase_rcpt/non-rcpt [ EBI

Atlas Genet Cytogenet Oncol Haematol 2008; 6 822 ] CluSTr Q16825 Pfam PF00373 Band_41 [ SRS ] PF00373 Band_41 [ Sanger ] pfam00373 [ NCBI-CDD ] PF00102 Y_phosphatase [ SRS ] PF00102 Y_phosphatase [ Sanger ] pfam00102 [ Pfam NCBI-CDD ] Smart SM00295 B41 [EMBL] Smart SM00194 PTPc [EMBL] Blocks Q16825 HPRD 04468 Protein Interaction databases DIP Q16825 IntAct Q16825 Polymorphism : SNP, mutations, diseases OMIM 603271 [ map ] GENETests 603271 SNP PTPN21 [dbSNP-NCBI] SNP NM_007039 [SNP-NCI] SNP PTPN21 [GeneSNPs - Utah] PTPN21] [HGBASE - SRS] HAPMAP PTPN21 [HAPMAP] COSMIC PTPN21 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PTPN21 Genetic PTPN21 Association CDC HuGE PTPN21 General knowledge Family PTPN21 [UCSC Family Browser] Browser SOURCE NM_007039 SMD Hs.437040 SAGE Hs.437040 3.1.3.48 [ Enzyme-Expasy ] 3.1.3.48 [ Enzyme-SRS ] 3.1.3.48 [ IntEnz- Enzyme EBI ] 3.1.3.48 [ BRENDA ] 3.1.3.48 [ KEGG ] GO protein tyrosine phosphatase activity [Amigo] protein tyrosine phosphatase activity GO structural molecule activity [Amigo] structural molecule activity GO binding [Amigo] binding GO cytoplasm [Amigo] cytoplasm GO cytoskeleton [Amigo] cytoskeleton GO protein amino acid dephosphorylation [Amigo] protein amino acid dephosphorylation GO hydrolase activity [Amigo] hydrolase activity PubGene PTPN21 TreeFam PTPN21 CTD 11099 [Comparative ToxicoGenomics Database] Other databases Probes Probe PTPN21 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in Entrez Bibliography Identification of a novel protein tyrosine phosphatase with sequence homology to the cytoskeletal proteins of the band 4.1 family. L'Abbe D, Banville D, Tong Y, Stocco R, Masson S, Ma S, Fantus G, Shen SH FEBS letters. 1994 ; 356 (2-3) : 351-356. PMID 7805871

Src kinase associates with a member of a distinct subfamily of protein-tyrosine phosphatases

Atlas Genet Cytogenet Oncol Haematol 2008; 6 823 containing an ezrin-like domain. Moller NP, Moller KB, Lammers R, Kharitonenkov A, Sures I, Ullrich A PNAS of the United States of America. 1994 ; 91 (16) : 7477-7481. PMID 7519780

Characterization of KIF1C, a new kinesin-like protein involved in vesicle transport from the Golgi apparatus to the endoplasmic reticulum. Dorner C, Ciossek T, Muller S, Moller PH, Ullrich A, Lammers R The Journal of biological chemistry. 1998 ; 273 (32) : 20267-20275. PMID 9685376

Protein-tyrosine phosphatase D1, a potential regulator and effector for Tec family kinases. Jui HY, Tseng RJ, Wen X, Fang HI, Huang LM, Chen KY, Kung HJ, Ann DK, Shih HM The Journal of biological chemistry. 2000 ; 275 (52) : 41124-41132. PMID 11013262

Gene expression differences between the microsatellite instability (MIN) and chromosomal instability (CIN) phenotypes in colorectal cancer revealed by high-density cDNA array hybridization. Dunican DS, McWilliam P, Tighe O, Parle-McDermott A, Croke DT Oncogene. 2002 ; 21 (20) : 3253-3257. PMID 12082642

Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling. Cardone L, Carlucci A, Affaitati A, Livigni A, DeCristofaro T, Garbi C, Varrone S, Ullrich A, Gottesman ME, Avvedimento EV, Feliciello A Molecular and cellular biology. 2004 ; 24 (11) : 4613-4626. PMID 15143158

Mitochondrial AKAP121 links cAMP and src signaling to oxidative metabolism. Livigni A, Scorziello A, Agnese S, Adornetto A, Carlucci A, Garbi C, Castaldo I, Annunziato L, Avvedimento EV, Feliciello A Molecular biology of the cell. 2006 ; 17 (1) : 263-271. PMID 16251349

Protein-tyrosine Phosphatase PTPD1 Regulates Focal Adhesion Kinase Autophosphorylation and Cell Migration. Carlucci A, Gedressi C, Lignitto L, Nezi L, Villa-Moruzzi E, Avvedimento EV, Gottesman M, Garbi C, Feliciello A The Journal of biological chemistry. 2008 ; 283 (16) : 10919-10929. PMID 18223254

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Antonio Feliciello Dipartimento di Biologia e Patologia Molecolare e Cellulare, Instituto di Endocrinologia ed Oncologia Sperimentale, 80131 Napoli, Italia Citation This paper should be referenced as such : Feliciello A . PTPN21 (protein tyrosine phosphatase, non-receptor type 21). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/PTPN21ID41916ch14q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 824 Atlas of Genetics and Cytogenetics in Oncology and Haematology

S100A13 (S100 calcium binding protein A13)

Identity HGNC S100A13 Location 1q21.3 Location_base_pair Starts at 151857900 and ends at 151873192 bp from pter ( according to hg18- Mar_2006). Local_order Co-localized in a gene cluster with other S100 genes on 1q21.3. DNA/RNA Description The gene contains five exons and four introns; it is composed of a variable 5' untranslated region, a 296 bp coding sequence, a 3' untranslated region and a polyA tail. Transcription The gene has 5 alternatively spliced variants encoding the same protein; the variant 1 represents the longest transcript (951 bp), all the other variants have distinct and shorter 5'UTR as compared to variant 1. Protein

Schematic representation of the domains structure of S100A13 monomer. Description Small homodimeric protein (98 amino-acids, M.W. 11,47 kDa), with 2 Ca2+-binding EF- hands motifs and a positively charged C-terminal region mediating the interaction with specific target molecules. Expression Highly expressed in skeletal muscle, heart, kidney, pancreas, ovary, spleen and small intestine, follicle cells of thyroid; moderate expression in prostate, testis, colon and brain; little expression in thymus, lung, liver and placenta, non detectable expression in leukocytes. Localisation Cytosolic Function It may function in exocytosis, since it is one of the targets of some antiallergic drugs, such as amlexanox and cromolyn, which inhibit degranulation of mast cells; marker of active angiogenesis in some tumours and endometriosis; released with signal peptide- less proteins such as FGF1 and IL-1alpha upon intracellular stress conditions. Homology 68% homology with human S100A14 and 50.5% with human S100A5; 86,7% with mouse S100A13. Implicated in Entity Astrocytic gliomas Disease Astrocytic gliomas are the most common primary brain tumours; they include WHO grade IV tumours, such as glioblastomas with its variants and WHO grade III tumours (anaplastic forms of astrocytoma, oligodendroglioma and oligoastrocytoma). Prognosis Poor for glioblastoma, relatively better for who grade III tumours. Cytogenetics Anaplastic astrocytomas carry gain of or 7q and deletions on chromosomes 6, 9p, 11p, 19q and 22q. Glioblastomas demonstrate deletions of chromosome 10 and allelic losses on 19q and 13q. Oncogenesis Homozigous deletion of CDKN2A, CDKN2B and p14ARF(9p) (9p), negative regulators of cell cycle or amplification of the cyclin-dependent kinase CDK4 are frequent in astrocytoma gr. III and glioblastoma. Glioblastoma and a subset of anaplastic astrocytoma with no abnormality of CDK4 and CDKN2A carries mutation in the retinoblastoma gene (Rb1); p53-pathway is frequently altered and PTEN is mutated in 30-40% of glioblastoma and in astrocytoma with poor prognosis. Astrocytic gliomas generally stain positive for S-100 proteins; S100-A13 is up-regulated in high-grade

Atlas Genet Cytogenet Oncol Haematol 2008; 6 825 gliomas and correlated with microvessel density and tumour grading. Entity Endometriosis Disease Endometriosis is characterized by the presence and proliferation of functional endometrial glands and stroma outside the uterine cavity. It is a multifactorial genetic disorders. Increasing evidence points to the role of angiogenesis in the disease pathogenesis and many angiogenic factors and cytokines such as VEGF-A, FGF1, endoglin and interleukin-1 alpha are up-regulated in endometriotic lesions. S100A13 is over-expressed in endometriotic specimens, particularly in microvascular endothelia. Prognosis It is a chronic and recurrent disease associated with infertility. Entity Lung cancer Disease Lung cancer is the most preventable of all the major forms of cancer since at least 75% of all cases worldwide are due to tobacco smoking. It can be classified into two main groups: small cell lung cancer and non-small cell lung cancer. The latter group is a heterogeneous aggregate of at least 3 distinct histologies including epidermoid or squamous carcinoma, adenocarcinoma and large cell carcinoma with the potential for cure with surgical resection when localized. Small cell lung carcinoma has a greater tendency to be disseminated by the time of diagnosis but is much more responsive to chemotherapy and radiation compared to non-small cell lung cancer. Prognosis Poor; small cell carcinoma has the most aggressive clinical course with median survival of only 2-4 months without treatment. Cytogenetics Loss of heterozigosity in chromosome regions 3p (fragile histidine triad, FHIT, locus), 12p, 13q (Rb1 locus) and 17p (p53 locus). Oncogenesis Inactivation of p16 by promoter hypermethylation is more frequent in squamous cell carcinoma compared with adenocarcinoma and is almost never found in small-cell lung cancer; K-ras mutations are documented only in non- small cell lung tumours particularly adenocarcinoma. Overexpression of myc family members and inactivation of p53, pRb and FHIT are found in all histologic types of lung cancer. S100P and S100A2 may be predictors of distant metastasis and poor survival in non-small cell lung tumours since they are overexpressed in tumours that metastatized during the course of the disease; S100A13 expression correlates with a more invasive phenotype in vitro. External links Nomenclature HGNC S100A13 10490 Entrez_Gene S100A13 6284 S100 calcium binding protein A13 Cards Atlas PAF1ID44202ch19q13 GeneCards S100A13 Ensembl ENSG00000189171 [Gene_View] S100A13 [Vega] Genatlas S100A13 Genomic and cartography S100A13 - 1q21.3 chr1:151857900-151873192 - 1q21 [Description] (hg18- GoldenPath Mar_2006) Ensembl S100A13 - 1q21 [CytoView] NCBI Mapview OMIM 601989 Disease map [OMIM] HomoloGene S100A13 Gene and transcription Genbank AA366085 [ ENTREZ ] Genbank AK097132 [ ENTREZ ] Genbank AY987392 [ ENTREZ ] Genbank BC000632 [ ENTREZ ] Genbank BC068064 [ ENTREZ ] RefSeq NM_001024210 [ SRS ] NM_001024210 [ ENTREZ ] RefSeq NM_001024211 [ SRS ] NM_001024211 [ ENTREZ ] RefSeq NM_001024212 [ SRS ] NM_001024212 [ ENTREZ ] RefSeq NM_001024213 [ SRS ] NM_001024213 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2008; 6 826 RefSeq NM_005979 [ SRS ] NM_005979 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004487 [ SRS ] NT_004487 [ ENTREZ ] RefSeq NW_001838529 [ SRS ] NW_001838529 [ ENTREZ ] RefSeq NW_925683 [ SRS ] NW_925683 [ ENTREZ ] CCDS S100A13 CCDS - NCBI AceView S100A13 AceView - NCBI Unigene Hs.516505 [ SRS ] Hs.516505 [ NCBI ] Fast-db 17315 (alternative variants) Protein : pattern, domain, 3D structure Q99584 [ SRS] Q99584 [ EXPASY ] Q99584 [ INTERPRO ] Q99584 [ UNIPROT SwissProt ] Q99584 [ VarSplice FASTA ] Prosite PS00018 EF_HAND_1 [ SRS ] PS00018 EF_HAND_1 [ Expasy ] Prosite PS50222 EF_HAND_2 [ SRS ] PS50222 EF_HAND_2 [ Expasy ] Prosite PS00303 S100_CABP [ SRS ] PS00303 S100_CABP [ Expasy ] Interpro IPR011992 EF-Hand_type [ SRS ] IPR011992 EF-Hand_type [ EBI ] Interpro IPR002048 EF_hand_Ca_bd [ SRS ] IPR002048 EF_hand_Ca_bd [ EBI ] Interpro IPR001751 S100_Ca_bd [ SRS ] IPR001751 S100_Ca_bd [ EBI ] Interpro IPR013787 S100_Ca_bd_sub [ SRS ] IPR013787 S100_Ca_bd_sub [ EBI ] CluSTr Q99584 Pfam PF01023 S_100 [ SRS ] PF01023 S_100 [ Sanger ] pfam01023 [ NCBI-CDD ] Prodom PD003407 CaBP_S100[INRA-Toulouse] Q99584 S10AD_HUMAN [ Domain structure ] Q99584 S10AD_HUMAN [ sequences Prodom sharing at least 1 domain ] Prodom PD003407[INRA-Toulouse] Q99584 S10AD_HUMAN [ Domain structure ] Q99584 S10AD_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q99584 PDB 1YUR [ SRS ] 1YUR [ PdbSum ], 1YUR [ IMB ] 1YUR [ RSDB ] PDB 1YUS [ SRS ] 1YUS [ PdbSum ], 1YUS [ IMB ] 1YUS [ RSDB ] PDB 1YUT [ SRS ] 1YUT [ PdbSum ], 1YUT [ IMB ] 1YUT [ RSDB ] PDB 1YUU [ SRS ] 1YUU [ PdbSum ], 1YUU [ IMB ] 1YUU [ RSDB ] PDB 2EGD [ SRS ] 2EGD [ PdbSum ], 2EGD [ IMB ] 2EGD [ RSDB ] PDB 2H2K [ SRS ] 2H2K [ PdbSum ], 2H2K [ IMB ] 2H2K [ RSDB ] HPRD 03586 Protein Interaction databases DIP Q99584 IntAct Q99584 Polymorphism : SNP, mutations, diseases OMIM 601989 [ map ] GENETests 601989 SNP S100A13 [dbSNP-NCBI] SNP NM_001024210 [SNP-NCI] SNP NM_001024211 [SNP-NCI] SNP NM_001024212 [SNP-NCI] SNP NM_001024213 [SNP-NCI] SNP NM_005979 [SNP-NCI] SNP S100A13 [GeneSNPs - Utah] S100A13] [HGBASE - SRS] HAPMAP S100A13 [HAPMAP] HGMD S100A13 Genetic S100A13 Association

Atlas Genet Cytogenet Oncol Haematol 2008; 6 827 CDC HuGE S100A13 General knowledge Family S100A13 [UCSC Family Browser] Browser SOURCE NM_001024210 SOURCE NM_001024211 SOURCE NM_001024212 SOURCE NM_001024213 SOURCE NM_005979 SMD Hs.516505 SAGE Hs.516505 GO calcium ion binding [Amigo] calcium ion binding GO cellular_component [Amigo] cellular_component GO cell differentiation [Amigo] cell differentiation PubGene S100A13 TreeFam S100A13 CTD 6284 [Comparative ToxicoGenomics Database] Other databases Probes Probe S100A13 Related clones (RZPD - Berlin) PubMed PubMed 24 Pubmed reference(s) in Entrez Bibliography Characterization of the human and mouse cDNAs coding for S100A13, a new member of the family. Wicki R, Schafer BW, Erne P, Heizmann CW Biochemical and biophysical research communications. 1996 ; 227 (2) : 594-599. PMID 8878558

Three distinct anti-allergic drugs, amlexanox, cromolyn and tranilast, bind to S100A12 and S100A13 of the S100 protein family. Shishibori T, Oyama Y, Matsushita O, Yamashita K, Furuichi H, Okabe A, Maeta H, Hata Y, Kobayashi R The Biochemical journal. 1999 ; 338 ( Pt 3) : 583-589. PMID 10051426

Differential frequencies of p16(INK4a) promoter hypermethylation, p53 mutation, and K-ras mutation in exfoliative material mark the development of lung cancer in symptomatic chronic smokers. Kersting M, Friedl C, Kraus A, Behn M, Pankow W, Schuermann M Journal of clinical oncology. 2000 ; 18 (18) : 3221-3229. PMID 10986054

S100A13. Biochemical characterization and subcellular localization in different cell lines. Ridinger K, Schafer BW, Durussel I, Cox JA, Heizmann CW The Journal of biological chemistry. 2000 ; 275 (12) : 8686-8694. PMID 10722710 p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Kim DH, Nelson HH, Wiencke JK, Zheng S, Christiani DC, Wain JC, Mark EJ, Kelsey KT Cancer research. 2001 ; 61 (8) : 3419-3424. PMID 11309302

Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress. Landriscina M, Bagala C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T The Journal of biological chemistry. 2001 ; 276 (27) : 25549-25557.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 828 PMID 11432880

S100A13 participates in the release of fibroblast growth factor 1 in response to heat shock in vitro. Landriscina M, Soldi R, Bagala C, Micucci I, Bellum S, Tarantini F, Prudovsky I, Maciag T The Journal of biological chemistry. 2001 ; 276 (25) : 22544-22552. PMID 11410600

Molecular genetics of small cell lung carcinoma. Wistuba II, Gazdar AF, Minna JD Seminars in oncology. 2001 ; 28 (2 Suppl 4) : 3-13. PMID 11479891

S100A13 mediates the copper-dependent stress-induced release of IL-1alpha from both human U937 and murine NIH 3T3 cells. Mandinova A, Soldi R, Graziani I, Bagala C, Bellum S, Landriscina M, Tarantini F, Prudovsky I, Maciag T Journal of cell science. 2003 ; 116 (Pt 13) : 2687-2696. PMID 12746488

The non-classical export routes: FGF1 and IL-1alpha point the way. Prudovsky I, Mandinova A, Soldi R, Bagala C, Graziani I, Landriscina M, Tarantini F, Duarte M, Bellum S, Doherty H, Maciag T Journal of cell science. 2003 ; 116 (Pt 24) : 4871-4881. PMID 14625381

Endoglin (cd105) and S100A13 as markers of active angiogenesis in endometriosis. Hayrabedyan S, Kyurkchiev S, Kehayov I Reproductive biology. 2005 ; 5 (1) : 51-67. PMID 15821778

Bacterial infection and semen quality. Sanocka-Maciejewska D, Ciupinska M, Kurpisz M Journal of reproductive immunology. 2005 ; 67 (1-2) : 51-56. PMID 16112738

Interleukin 1alpha and tissue-lytic matrix metalloproteinase-1 are elevated in ectopic endometrium of patients with endometriosis. Hudelist G, Lass H, Keckstein J, Walter I, Wieser F, Wenzl R, Mueller R, Czerwenka K, Kubista E, Singer CF Human reproduction (Oxford, England). 2005 ; 20 (6) : 1695-1701. PMID 15746198

S100A13, a new marker of angiogenesis in human astrocytic gliomas. Landriscina M, Schinzari G, Di Leonardo G, Quirino M, Cassano A, D'Argento E, Lauriola L, Scerrati M, Prudovsky I, Barone C Journal of neuro-oncology. 2006 ; 80 (3) : 251-259. PMID 16773219

Crystal structure study on human S100A13 at 2.0 A resolution. Li M, Zhang PF, Pan XW, Chang WR Biochemical and biophysical research communications. 2007 ; 356 (3) : 616-621. PMID 17374362

Identification of a novel, functional role for S100A13 in invasive lung cancer cell lines. Pierce A, Barron N, Linehan R, Ryan E, O'Driscoll L, Daly C, Clynes M European journal of cancer (Oxford, England : 1990). 2008 ; 44 (1) : 151-159. PMID 18061437

REVIEW articles automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2008; 6 829 Last year publications automatic search in PubMed

Search in all EBI NCBI

Contributor(s) Written 02-2008 Carlo Barone, Cinzia Bagalà, Matteo Landriscina Catholic University of Sacred Heart, Institute of Internal Medicine, Oncology Unit, Largo A. Gemelli 8, 00168 Roma, Itlaly Citation This paper should be referenced as such : Barone C, Bagalà C, Landriscina M . S100A13 (S100 calcium binding protein A13). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/S100A13ID44197ch1q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 830 Atlas of Genetics and Cytogenetics in Oncology and Haematology

TACSTD1 (tumor-associated calcium signal transducer 1)

Identity Other names EpCAM Ep-CAM CD326 CO17-1A EGP EGP40 GA733-2 KSA Ly74 M1S2 M4S1 MIC18 MK-1 TROP1 hEGP-2 HGNC TACSTD1 Location 2p21 Location_base_pair Starts at 47449971 and ends at 47467661 bp from pter ( according to hg18- Mar_2006). DNA/RNA Description The gene is composed of 9 exons and encompasses. Transcription 1.528kb mRNA; 945bp open reading frame from base pairs 179 to 1123, (NM_002354). Pseudogene No pseudogene described so far. Protein Description 314 amino acids (aa); 265 aa extracellular domain, 23 aa transmembrane domain, 26 aa intracellular domain; 34-42kDa glycoprotein; differential glycosylation in tumours vesus normal mucosa (Pauli et al., 2003). Expression Restricted to epithelia; mainly in simple epithelium and basal membrane cells; strong overexpression in malignancies already at the stage of dysplasia (Litvinov et al., 1996). Localisation Plasma membrane; baso-lateral in normal cells; redistribution on entire plasma membrane in vitro and in carcinoma cells. Function Homophilic cell-to-cell adhesion molecule (Litvinov et al., 1994); regulation of cadherin- mediated cell-to-cell adhesion (Litvinov et al., 1997); oncogenic signalling molecule, which is over-expressed in a plethora of carcinomas (Baeuerle and Gires, 2007); induces cell proliferation via induction of the proto-oncogene c-myc (Munz et al., 2004); intracellular domain of TACSTD1 /EpCAM is mandatory and sufficient for induction of c-myc gene expression; inhibition results in decreased proliferation and invasion (Osta et al., 2004); frequent use as a prognostic marker (Went et al., 2006; Spizzo et al., 2006) and therapeutic target (Baeuerle and Gires, 2007; Riethmuller et al., 1994; Schweizer et al., 2002; Amann et al., 2008; Ruf et al., 2007). Homology Retroposon GA733-1; gp50/TROP-2 (Fornaro et al., 1995), single-copy gene localised at chrom 1p32-31 TACSTD2, Accession CAA54801, 323 amino acids, calcium- dependent signalling protein. High homology of TACSTD1/EpCAM to TACSTD2/TROP-2/GA733-1), especially in the extracellular domain including cystein- rich EGF-like domains, conserved region similar to thyroglobulin type I repeat (Thyr I- like repeat). Mutations

Atlas Genet Cytogenet Oncol Haematol 2008; 6 831 Note So far, no mutations of the TACSTD1/epcam gene were described. Implicated in Entity Colon cancer Oncogenesis EpCAM is strongly overexpressed and was used as a molecular target for monoclonal, therapeutic antibody 17-1A (Panorex ©)(Riethmuller et al.,1994) EpCAM, in a complex with claudin-7, CD44 isoforms, and tetraspanins, is involved in colorectal cancer progression (Kuhn et al., 2007). Entity Breast cancer Prognosis Increased expression of EpCAM is a marker for poor prognosis and overall survival of patients suffering from node-positive breast cancer (Spizzo et al., 2004). Oncogenesis EpCAM is strongly overexpressed. Entity Ovarian cancer Prognosis Increased expression of EpCAM is a marker for poor prognosis and overall survival of patients suffering from ovarian cancer (Spizzo et al., 2006). Oncogenesis EpCAM is strongly overexpressed. Entity Renal cancer (RCC) Prognosis Increased expression of EpCAM is a marker for improved prognosis in patients suffering from clear cell RCC and might help to discriminate between chromophobe RCC and oncocytomas (Went et al., 2005). Oncogenesis EpCAM is strongly overexpressed in chromophobe RCC but not in oncocytomas. Entity Head and Neck Squamous Cell carcinomas (HNSCCs) Prognosis Expression of EpCAM is a marker for disseminated tumour cells in HNSCCs (Chaubal et al., 1999). Oncogenesis EpCAM is strongly overexpressed in HNSCCS. Entity Esophagus Squamous Cell carcinomas Prognosis Increased expression of EpCAM is a marker for decreased relapse-free survival (Stoecklein et al., 2006). Oncogenesis EpCAM is strongly overexpressed. Entity Hepatocyte development Note EpCAM is strongly expressed in differentiation hepatocytes and progenitors thereof (Schmelzer et al. 2007; Schmelzer and Reid, 2008). Breakpoints Note No breakpoints described so far. To be noted The gene name TACSTD1, for Tumour-Associated Calcium Signalling Signal Transducer 1, is highly misleading and unappropriate. EpCAM, alias TACSTD1, is in fact a signal-transducing membrane protein (Munz et al., 2004), however it is involved in calcium-independent homophilic cell-to-cell adhesion (Litvinov et al., 1994). We shall therefore propose to use the term epcam for the gene and EpCAM for the protein (Baeuerle and Gires, 2007). The characterisation of the molecular function of EpCAM in carcinoma cells pinpointed a role in signalling and regulation of gene transcription rather than cell-to-cell adhesion (Osta et al., 2004; Munz et al., 2004). With respect to cell adhesion properties of EpCAM literature is even contradictory (Fornaro et al., 1995; Litvinov et al., 1994). More recent work described EpCAM as a marker for tumour-initiating cancer stem cells in a variety of entities including colon (Dalerba et al., 2007), pancreas (Li et al., 2007), and breast carcinomas (Al-Hajj et al. 2003). A symposium on functions and clinical applications of EpCAM was initiated 2006 and will be held every two years. For more details please visit http://www.epcam- symposium.de/. External links Nomenclature HGNC TACSTD1 11529 Entrez_Gene TACSTD1 4072 tumor-associated calcium signal transducer 1 Cards Atlas TACSTD1ID42459ch2p21

Atlas Genet Cytogenet Oncol Haematol 2008; 6 832 GeneCards TACSTD1 Ensembl ENSG00000119888 [Gene_View] TACSTD1 [Vega] Genatlas TACSTD1 Genomic and cartography TACSTD1 - 2p21 chr2:47449971-47467661 + 2p21 [Description] (hg18- GoldenPath Mar_2006) Ensembl TACSTD1 - 2p21 [CytoView] NCBI Mapview OMIM 185535 Disease map [OMIM] HomoloGene TACSTD1 Gene and transcription Genbank AK026585 [ ENTREZ ] Genbank BC014785 [ ENTREZ ] Genbank CR542259 [ ENTREZ ] Genbank CR542283 [ ENTREZ ] Genbank CR593061 [ ENTREZ ] RefSeq NM_002354 [ SRS ] NM_002354 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq AC_000134 [ SRS ] AC_000134 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_022184 [ SRS ] NT_022184 [ ENTREZ ] RefSeq NW_001838769 [ SRS ] NW_001838769 [ ENTREZ ] RefSeq NW_927719 [ SRS ] NW_927719 [ ENTREZ ] CCDS TACSTD1 CCDS - NCBI AceView TACSTD1 AceView - NCBI Unigene Hs.542050 [ SRS ] Hs.542050 [ NCBI ] Fast-db 18037 (alternative variants) Protein : pattern, domain, 3D structure P16422 [ SRS] P16422 [ EXPASY ] P16422 [ INTERPRO ] P16422 SwissProt [ UNIPROT ] P16422 [ VarSplice FASTA ] PS00484 THYROGLOBULIN_1_1 [ SRS ] PS00484 THYROGLOBULIN_1_1 Prosite [ Expasy ] PS51162 THYROGLOBULIN_1_2 [ SRS ] PS51162 THYROGLOBULIN_1_2 Prosite [ Expasy ] Interpro IPR000716 Thyroglobulin_1 [ SRS ] IPR000716 Thyroglobulin_1 [ EBI ] CluSTr P16422 PF00086 Thyroglobulin_1 [ SRS ] PF00086 Thyroglobulin_1 [ Sanger ] pfam00086 Pfam [ NCBI-CDD ] Smart SM00211 TY [EMBL] Blocks P16422 HPRD 01709 Protein Interaction databases DIP P16422 IntAct P16422 Polymorphism : SNP, mutations, diseases OMIM 185535 [ map ] GENETests 185535 SNP TACSTD1 [dbSNP-NCBI] SNP NM_002354 [SNP-NCI] SNP TACSTD1 [GeneSNPs - Utah] TACSTD1] [HGBASE - SRS] HAPMAP TACSTD1 [HAPMAP] HGMD TACSTD1 Genetic TACSTD1 Association

Atlas Genet Cytogenet Oncol Haematol 2008; 6 833 CDC HuGE TACSTD1 General knowledge Family TACSTD1 [UCSC Family Browser] Browser SOURCE NM_002354 SMD Hs.542050 SAGE Hs.542050 GO plasma membrane [Amigo] plasma membrane GO integral to membrane [Amigo] integral to membrane PubGene TACSTD1 TreeFam TACSTD1 CTD 4072 [Comparative ToxicoGenomics Database] Other databases Probes Probe TACSTD1 Related clones (RZPD - Berlin) PubMed PubMed 42 Pubmed reference(s) in Entrez Bibliography Sequence investigation of the major gastrointestinal tumor-associated antigen gene family, GA733. Linnenbach AJ, Wojcierowski J, Wu SA, Pyrc JJ, Ross AH, Dietzschold B, Speicher D, Koprowski H Proceedings of the National Academy of Sciences of the United States of America. 1989 ; 86 (1) : 27- 31. PMID 2911574

Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA. Strnad J, Hamilton AE, Beavers LS, Gamboa GC, Apelgren LD, Taber LD, Sportsman JR, Bumol TF, Sharp JD, Gadski RA Cancer research. 1989 ; 49 (2) : 314-317. PMID 2463074

Phase I clinical comparative study of monoclonal antibody KS1/4 and KS1/4-methotrexate immunconjugate in patients with non-small cell lung carcinoma. Elias DJ, Hirschowitz L, Kline LE, Kroener JF, Dillman RO, Walker LE, Robb JA, Timms RM Cancer research. 1990 ; 50 (13) : 4154-4159. PMID 2162255

Molecular cloning of cDNA for the carcinoma-associated antigen GA733-2. Szala S, Froehlich M, Scollon M, Kasai Y, Steplewski Z, Koprowski H, Linnenbach AJ Proceedings of the National Academy of Sciences of the United States of America. 1990 ; 87 (9) : 3542-3546. PMID 2333300

Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO The Journal of cell biology. 1994 ; 125 (2) : 437-446. PMID 8163559

Carcinoma-associated 38-kD membrane glycoprotein MH 99/KS 1/4 is related to proliferation and age of transformed epithelial cell lines. Schon MP, Schon M, Klein CE, Blume U, Bisson S, Orfanos CE The Journal of investigative dermatology. 1994 ; 102 (6) : 987-991. PMID 8006466

E-cadherin, NCAM, and EpCAM expression in human fetal pancreata. Cirulli V, Ricordi C, Hayek A Transplantation proceedings. 1995 ; 27 (6) : page 3335.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 834 PMID 8539977

Distribution of E-cadherin and Ep-CAM in the human lung during development and after injury. Kasper M, Behrens J, Schuh D, Muller M Histochemistry and cell biology. 1995 ; 103 (4) : 281-286. PMID 7648403

Reduction of EGP-2-positive pulmonary metastases by bispecific-antibody-redirected T cells in an immunocompetent rat model. Kroesen BJ, Helfrich W, Bakker A, Wubbena AS, Bakker H, Kal HB, The TH, de Leij L International journal of cancer. Journal international du cancer. 1995 ; 61 (6) : 812-818. PMID 7790116

Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. Litvinov SV, Balzar M, Winter MJ, Bakker HA, Briaire-de Bruijn IH, Prins F, Fleuren GJ, Warnaar SO The Journal of cell biology. 1997 ; 139 (5) : 1337-1348. PMID 9382878

The biology of the 17-1A antigen (Ep-CAM). Balzar M, Winter MJ, de Boer CJ, Litvinov SV Journal of molecular medicine (Berlin, Germany). 1999 ; 77 (10) : 699-712. PMID 10606205

Ep-CAM overexpression in breast cancer as a predictor of survival. Gastl G, Spizzo G, Obrist P, Dunser M, Mikuz G Lancet. 2000 ; 356 (9246) : 1981-1982. PMID 11130529

The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Munz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O Oncogene. 2004 ; 23 (34) : 5748-5758. PMID 15195135

EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, Cole DJ, Gillanders WE Cancer research. 2004 ; 64 (16) : 5818-5824. PMID 15313925

Profiling of the tetraspanin web of human colon cancer cells. Le Naour F, André M, Greco C, Billard M, Sordat B, Emile JF, Lanza F, Boucheix C, Rubinstein E Molecular & cellular proteomics : MCP. 2006 ; 5 (5) : 845-857. PMID 16467180

EpCAM (CD326) finding its role in cancer. Baeuerle PA, Gires O British journal of cancer. 2007 ; 96 (3) : 417-423. PMID 17211480

Phenotypic characterization of human colorectal cancer stem cells. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (24) : 10158-10163. PMID 17548814

Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M

Atlas Genet Cytogenet Oncol Haematol 2008; 6 835 Nature. 2007 ; 450 (7173) : 1235-1239. PMID 18097410

Identification and expansion of human colon-cancer-initiating cells. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R Nature. 2007 ; 445 (7123) : 111-115. PMID 17122771

Human hepatic stem cells from fetal and postnatal donors. Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL, Moss N, Melhem A, McClelland R, Turner W, Kulik M, Sherwood S, Tallheden T, Cheng N, Furth ME, Reid LM The Journal of experimental medicine. 2007 ; 204 (8) : 1973-1987. PMID 17664288

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Olivier Gires Clinical Cooperation Group Molecular Oncology, Munich Medical Center, Ludwig-Maximilians-University, Marchioninistr. 15, D-81377 Munich, Germany, and HelmholtzZentrum munchen, German Research Center for Environmental Health, Marchioninistr. 25, D-81377 Munich, Germany Citation This paper should be referenced as such : Gires O . TACSTD1 (tumor-associated calcium signal transducer 1). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/TACSTD1ID42459ch2p21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 836 Atlas of Genetics and Cytogenetics in Oncology and Haematology

TNC (tenascin C (hexabrachion))

Identity Other names Cytotactin GMEM GP (150-225) Glioma associated extracellular matrix antigen Hexabrachion J1 Myotendinous antigen Neuronectin TN HGNC TNC Location 9q33.1 Location_base_pair Starts at 116822626 and ends at 116920307 bp from pter ( according to hg18- Mar_2006). DNA/RNA

Table shows the lengths of the exons and introns of human tenascin-C. Description The tenascin-C gene consists of 27 exons spanning 97.63 kb of genomic DNA. Transcription 7271 bp mRNA transcribed on the reverse strand; 6333 bp open reading frame. The transcript starts with a non-coding exon 1 (179 bp) followed by exon 2, which contains the start codon (ATG) for translation initiation. Exon 1 is located 26827 bp upstream of exon 2. Protein

Schematic representation of a monomeric tenascin-C subunit. Description Tenascin-C consists of structural motifs arranged in a linear order. Mammalian tenascin-C proteins contain amino-terminal heptad repeats, 14.5 EGF-like repeats, 8 constant FN III domains, whereas 9 additional FN III domains can be included in a combinatorial manner by alternative splicing, and a carboxyl-terminal fibrinogen globe. A prominent feature of tenascin-C is the assembly into hexamers, so-called hexabrachions. The primary sequence encodes a protein of 2110 amino acids. Amino acids 1-22

Atlas Genet Cytogenet Oncol Haematol 2008; 6 837 represent the secretion signal, amino acids 189-621 constitute the EGF-like repeats, and amino acids 622-1882 account for the FNIII domains. SDS-Page analysis revealed a molecular weight of full-length tenascin-C of 250kDa - 300kDa per subunit under reducing conditions. Alternative splicing within the stretch of FN III domains results in a great number and diversity in tenascin-C isoforms. Expression More than two decades ago, tenascin-C was discovered as an extracellular matrix protein (ECM) enriched in the stroma of gliomas and as a myotendinous antigen. Tenascin-C expression is highly regulated both during development and in the adult. Tenascin-C levels are high during embryogenesis, but almost absent during normal postnatal life with some basal expression detectable in tendons and ligaments only. In adult life, tenascin-C is also expressed within the sub-ventricular zone in the central nervous system, a region that constitutes the neural stem cell niche. A prominent feature of tenascin-C is its re-appearance in response to pathological situations such as infection, inflammation and tissue remodeling. Another striking example of a pathological situation leading to the re-expression of tenascin-C is the onset of tumorigenesis, where tenascin-C is specifically expressed in the activated tumor stroma. Tenascin-C can be induced by various stimuli, such as the pro- and anti- inflammatory cytokines, interleukins, TNFa or IFNg and growth factors such as TGFb , EGF or PDGF. Furthermore, tenascin-C inducing stimuli include mechanical stress, hypoxia, and reactive oxygen species, factors or conditions which also might play a prominent role in tumors. Localisation Extracellular matrix. Function Adhesion: Tenascin-C acts as an anti-adhesive substratum for a large variety of cells. Active inhibition of cell spreading was further confirmed by mixing tenascin-C together with fibronectin, which is a classical adhesion protein. Whereas cells on fibronectin nicely spread, form focal contacts and actin stress fibers, the same cells plated on a mixed fibronectin-tenascin-C substratum are not able to spread and do not form focal contacts and actin cables. Migration: Tenascin-C enhances migration and invasiveness of different cancer cells. Proliferation: Tenascin-C stimulates cancer cell proliferation. Angiogenesis: Tenascin-C is expressed around angiogenic vessels in many tumors and there is evidence that it promotes and regulates angiogenesis in vitro and in vivo. Moreover, in glioma patients, clinical studies revealed an inhibition of tumor angiogenesis by applying antibodies directed against tenascin-C. Homology Tenascin-C belongs to the tenascin family, which is a highly conserved family of large oligomeric extracellular matrix proteins. Vertebrate genomes harbor four tenascin genes, which have been termed tenascin-C, tenascin-XB (TNXB), tenascin-R, and tenascin-W. Mutations Germinal A SNP was identified resulting in an amino acid substitution (Leu1677Ile in the tenascin-C FN III domain D) which strongly associates with adult bronchial asthma. Therefore, this SNP might be an asthma marker and may be important in its pathogenesis. Implicated in Entity Cancer (general) Oncogenesis Tenascin-C is strongly expressed in the stroma of various cancers and has been reported to be associated with the invasive front of tumors. For cancers in the lung, colon, and brain, high tenascin-C expression correlates with poor prognosis, whereas in other cancers no clear correlation between tenascin-C and survival or malignancy exists. In search for new diagnostic or prognostic tumor markers, tenascin-C levels have often been analyzed in sera of cancer patients and its potential value as a biomarker has been evaluated. Although elevated tenascin-C serum levels have been found in certain cancers, it still remains a questionable tumor marker. Tenascin-C levels are scattered over a wide range with many cancer patients having normal tenascin-C concentrations and its expression strongly correlates with inflammation or infection. Entity Breast cancer Oncogenesis By means of in vivo selection and microarray analysis a gene expression signature was identified that mediates breast cancer metastasis to lung. Tenascin-C is one of those

Atlas Genet Cytogenet Oncol Haematol 2008; 6 838 genes that have been found to belong to the lung metastasis signature genes. A recent study identified tenascin-C as a direct target gene for the microRNA miR-335. This microRNA is specifically lost as human breast cancer cells develop metastatic potential. Knockdown of tenascin-C in the highly metastatic LM2 cells (a metastatic derivative of the human breast cancer cell line MDA-MB-231) reduced migration in a trans-well assay and significantly inhibited lung colonization by LM2 cells. External links Nomenclature HGNC TNC 5318 Entrez_Gene TNC 3371 tenascin C Cards Atlas TNCID42597ch9q33 GeneCards TNC Ensembl ENSG00000041982 [Gene_View] TNC [Vega] Genatlas TNC Genomic and cartography TNC - 9q33.1 chr9:116822626-116920307 - 9q32-q34 [Description] (hg18- GoldenPath Mar_2006) Ensembl TNC - 9q32-q34 [CytoView] NCBI Mapview OMIM 187380 Disease map [OMIM] HomoloGene TNC Gene and transcription Genbank AB210038 [ ENTREZ ] Genbank BC151843 [ ENTREZ ] Genbank BP278052 [ ENTREZ ] Genbank BQ575939 [ ENTREZ ] Genbank BQ880861 [ ENTREZ ] RefSeq NM_002160 [ SRS ] NM_002160 [ ENTREZ ] RefSeq AC_000052 [ SRS ] AC_000052 [ ENTREZ ] RefSeq AC_000141 [ SRS ] AC_000141 [ ENTREZ ] RefSeq NC_000009 [ SRS ] NC_000009 [ ENTREZ ] RefSeq NT_008470 [ SRS ] NT_008470 [ ENTREZ ] RefSeq NW_001839236 [ SRS ] NW_001839236 [ ENTREZ ] RefSeq NW_924573 [ SRS ] NW_924573 [ ENTREZ ] CCDS TNC CCDS - NCBI AceView TNC AceView - NCBI Unigene Hs.143250 [ SRS ] Hs.143250 [ NCBI ] Fast-db 13747 (alternative variants) Protein : pattern, domain, 3D structure P24821 [ SRS] P24821 [ EXPASY ] P24821 [ INTERPRO ] P24821 SwissProt [ UNIPROT ] P24821 [ VarSplice FASTA ] Prosite PS00022 EGF_1 [ SRS ] PS00022 EGF_1 [ Expasy ] Prosite PS01186 EGF_2 [ SRS ] PS01186 EGF_2 [ Expasy ] Prosite PS50026 EGF_3 [ SRS ] PS50026 EGF_3 [ Expasy ] Prosite PS50853 FN3 [ SRS ] PS50853 FN3 [ Expasy ] Interpro IPR006210 EGF [ SRS ] IPR006210 EGF [ EBI ] Interpro IPR000742 EGF_3 [ SRS ] IPR000742 EGF_3 [ EBI ] Interpro IPR013111 EGF_extracell [ SRS ] IPR013111 EGF_extracell [ EBI ] Interpro IPR006209 EGF_like [ SRS ] IPR006209 EGF_like [ EBI ] Interpro IPR013032 EGF_like_reg_CS [ SRS ] IPR013032 EGF_like_reg_CS [ EBI ] Interpro IPR002181 Fibrinogen_a/b/g_C [ SRS ] IPR002181 Fibrinogen_a/b/g_C [ EBI ] Interpro IPR014716 Fibrinogen_a/b/g_C_1 [ SRS ] IPR014716 Fibrinogen_a/b/g_C_1 [ EBI ] Interpro IPR008957 Fibronectin_typ-III-like_fold [ SRS ] IPR008957 Fibronectin_typ-III-

Atlas Genet Cytogenet Oncol Haematol 2008; 6 839 like_fold [ EBI ] Interpro IPR003961 FN_III [ SRS ] IPR003961 FN_III [ EBI ] CluSTr P24821 Pfam PF00008 EGF [ SRS ] PF00008 EGF [ Sanger ] pfam00008 [ NCBI-CDD ] Pfam PF07974 EGF_2 [ SRS ] PF07974 EGF_2 [ Sanger ] pfam07974 [ NCBI-CDD ] PF00147 Fibrinogen_C [ SRS ] PF00147 Fibrinogen_C [ Sanger ] pfam00147 Pfam [ NCBI-CDD ] Pfam PF00041 fn3 [ SRS ] PF00041 fn3 [ Sanger ] pfam00041 [ NCBI-CDD ] Smart SM00181 EGF [EMBL] Smart SM00186 FBG [EMBL] Smart SM00060 FN3 [EMBL] Blocks P24821 PDB 1TEN [ SRS ] 1TEN [ PdbSum ], 1TEN [ IMB ] 1TEN [ RSDB ] PDB 2RB8 [ SRS ] 2RB8 [ PdbSum ], 2RB8 [ IMB ] 2RB8 [ RSDB ] PDB 2RBL [ SRS ] 2RBL [ PdbSum ], 2RBL [ IMB ] 2RBL [ RSDB ] HPRD 01756 Protein Interaction databases DIP P24821 IntAct P24821 Polymorphism : SNP, mutations, diseases OMIM 187380 [ map ] GENETests 187380 SNP TNC [dbSNP-NCBI] SNP NM_002160 [SNP-NCI] SNP TNC [GeneSNPs - Utah] TNC] [HGBASE - SRS] HAPMAP TNC [HAPMAP] HGMD TNC Genetic TNC Association CDC HuGE TNC General knowledge Family TNC [UCSC Family Browser] Browser SOURCE NM_002160 SMD Hs.143250 SAGE Hs.143250 GO receptor binding [Amigo] receptor binding GO extracellular region [Amigo] extracellular region GO basement membrane [Amigo] basement membrane GO cell adhesion [Amigo] cell adhesion GO signal transduction [Amigo] signal transduction GO neuromuscular junction development [Amigo] neuromuscular junction development KEGG Cell Communication KEGG Focal adhesion KEGG ECM-receptor interaction PubGene TNC TreeFam TNC CTD 3371 [Comparative ToxicoGenomics Database] Other databases Probes Probe TNC Related clones (RZPD - Berlin) PubMed PubMed 88 Pubmed reference(s) in Entrez Bibliography

Atlas Genet Cytogenet Oncol Haematol 2008; 6 840 Human glioma-mesenchymal extracellular matrix antigen defined by monoclonal antibody. Bourdon MA, Wikstrand CJ, Furthmayr H, Matthews TJ, Bigner DD. Cancer Res. 1983 Jun;43(6):2796-805. PMID 6342760

Chick myotendinous antigen II. A novel extracellular glycoprotein complex consisting of large disulfide-linked subunits. Chiquet M, Fambrough DM. J Cell Biol. 1984 Jun;98(6):1937-46. PMID 6202699

Tenascin interferes with fibronectin action. Chiquet-Ehrismann R, Kalla P, Pearson CA, Beck K, Chiquet M. Cell. 1988 May 6;53(3):383-90. PMID 2452695

Tenascin-C in serum: a questionable tumor marker. Schenk S, Muser J, Vollmer G, Chiquet-Ehrismann R. Int J Cancer. 1995 May 16;61(4):443-9. PMID 7538974

Tenascin-C expression by angiogenic vessels in human astrocytomas and by human brain endothelial cells in vitro. Zagzag D, Friedlander DR, Dosik J, et al. Cancer Res. 1996 Jan 1;56(1):182-9. PMID 8548761

The Tenascin family of ECM Glycoproteins: Structure, Function, and Regulation Durig Embryonic Development and Tissue Remodeling. Jones FS and Jones PL. Dev Dyn. 2000 Jun;218(2):235-59. (REVIEW) PMID 10842355

Tenascins: regulation and putative functions during pathological stress. Chiquet-Ehrismann R, Chiquet M. J Pathol. 2003 Jul;200(4):488-99. (REVIEW) PMID 12845616

Coding SNP in tenascin-C Fn-III-D domain associates with adult asthma. Matsuda A, Hirota T, Akahoshi M, et al. Human Molecular Genetics. 2005 Oct 1;14(19):2779-86. PMID 16115819

Genes that mediate breast cancer metastasis to lung. Minn A, Gupta GP, Siegel PM, et al. Nature. 2005 Jul 28;436(7050):518-24. PMID 16049480

Potential oncogenic action of tenascin-C in tumorigenesis. Orend G. Int J Biochem Cell Biol. 2005 May;37(5):1066-83. (REVIEW) PMID 15743679

Vascular tenascin-C regulates cardiac endothelial phenotype and neovascularization. Ballard VL, Sharma A, Duignan I, et al. Faseb J. 2006 Apr;20(6):717-9. PMID 16461331

Tenascin-C induced signaling in cancer. Orend G and Chiquet-Ehrismann R.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 841 Cancer Lett. 2006 Dec 8;244(2):143-63. (REVIEW) PMID 16632194

Endogenous human microRNAs that suppress breast cancer metastasis. Tavazoie SF, Alarcon C, Oskarsson T, et al. Nature. 2008 Jan 10;451(7175):147-52. PMID 18185580

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Martin Degen, Ruth Chiquet-Ehrismann Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland Citation This paper should be referenced as such : Degen M, Chiquet-Ehrismann R . TNC (tenascin C (hexabrachion)). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/TNCID42597ch9q33.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 842 Atlas of Genetics and Cytogenetics in Oncology and Haematology

TNN (tenascin N)

Identity Other names TN-W TN-N HGNC TNN Location 1q25.1 Location_base_pair Starts at 173303617 and ends at 173383825 bp from pter ( according to hg18- Mar_2006). Local_order tail to tail configuration next to the tenascin-R gene(TNR) DNA/RNA

The distribution of the 19 exons is shown in the upper part, whereas the lengths of exons and introns are indicated in the lower part. Description The tenascin-W gene consists of 19 exons spanning 80.21 kb of genomic DNA. Transcription 5005 bp mRNA transcribed in centromeric to telomeric orientation on the forward strand; 3885 bp open reading frame. The transcript starts with a non-coding exon followed by exon 2, which contains the start codon (ATG) for translation initiation. Exon 1 is located 9448 bp upstream of exon 2. Protein

Schematic representation of human tenascin-W is shown. Description Tenascin-W is built up of different structural motifs arranged in a linear order, namely amino-terminal heptad repeats, 3.5 EGF-like repeats, 9 FN III domains, and a carboxyl- terminal fibrinogen globe. The primary sequence encodes a protein of 1294 amino acids. Amino acids 1-16 represent the secretion signal, amino acids 150-254 constitute the EGF-like repeats, and amino acids 255-1054 account for the FNIII domains. FN III domain number 3 was subject to duplication as indicated by the dark boxes in the schematic representation. Tenascin-W is known to form hexameric structures called hexabrachions. SDS-Page analysis revealed a molecular weight of 160kDa per subunit under reducing

Atlas Genet Cytogenet Oncol Haematol 2008; 6 843 conditions. So far, there is no evidence for alternative splicing. Expression Initially, tenascin-W was identified in zebrafish where it was expressed in migrating cells of sclerotomal and neural crest origin. More recently, tenascin-W was characterized in mouse and chicken during embryogenesis as well as in the adult organism. These studies revealed that tenascin-W, similar to tenascin-C, shows tight regulation during development and in the adult. Immunohistochemistry showed prominent expression in the developing and adult metanephric kidney, developing and adult periosteum around ribs, and transient expression in smooth muscles of the developing gut, often but not always overlapping with tenascin-C expression. Furthermore, tenascin-W is highly expressed in the tumor stroma in different solid tumors. Tenascin-W is most likely produced and secreted by mesenchymal cells such as fibroblasts and osteoblasts. Known stimuli that induce tenascin-W expression include so far tumor necrosis factor alpha (TNFα) and bone morphogenetic protein 2 (BMP2). Localisation Extracellular matrix. Function Adhesion: Tenascin-W is an adhesive substratum for some cells (osteoblasts, fibroblasts), while others cannot attach and spread on tenascin-W. Migration: Tenascin-W stimulates the migratory behavior of cells. Homology Tenascin-W belongs to the tenascin family, which is a highly conserved family of large oligomeric extracellular matrix proteins. Vertebrate genomes harbor four tenascin genes, which have been termed tenascin-C, tenascin-XB (TNXB), tenascin-R, and tenascin-W. Human tenascin-W shows high sequence conservation with mouse tenascin-W. Implicated in Entity Breast cancer Oncogenesis Tenascin-W is highly expressed in a large fraction of breast cancer patients whereas it is not detectable in normal human mammary tissue. Expression in tumors correlated with tumor grade. There is statistically significant higher mean expression of tenascin- W in low-grade tumors (Grade1/Grade2) compared to high-grade tumors (Grade3). Tenascin-W is produced in the stromal compartment, most likely by cancer-associated fibroblasts, which are part of a tumor permissive microenvironment that facilitates tumor cell migration. In vitro, presence of tenascin-W stimulated breast cancer cell migration. Benign tumors as well as carcinomas do express tenascin-W. Furthermore, tenascin-W is elevated in sera of breast cancer patients compared to that of healthy volunteers. Tenascin-W is postulated to be a marker for conversion of the normal physiological stroma to an activated stroma in breast cancer. Entity Colorectal cancer Oncogenesis Tenascin-W is highly expressed in colorectal cancer patients whereas it is not detectable in the normal colon mucosa. Furthermore, mean tenascin-W level in sera of colorectal cancer patients is statistically increased compared to that in sera of healthy volunteers. Follow-up studies of colorectal cancer patients revealed that 4 out of 5 patients who developed tumor recurrence after treatment showed high tenascin-W levels in their sera. Thus, tenascin-W might have prognostic value as a serum tumor marker. External links Nomenclature HGNC TNN 22942 Entrez_Gene TNN 63923 tenascin N Cards Atlas ELAVL1ID44237ch19p13 GeneCards TNN Ensembl ENSG00000120332 [Gene_View] TNN [Vega] Genatlas TNN Genomic and cartography GoldenPath TNN - 1q25.1 chr1:173303617-173383825 + 1q23-q24 [Description] (hg18-

Atlas Genet Cytogenet Oncol Haematol 2008; 6 844 Mar_2006) Ensembl TNN - 1q23-q24 [CytoView] NCBI Mapview HomoloGene TNN Gene and transcription Genbank AK127044 [ ENTREZ ] Genbank AK127654 [ ENTREZ ] Genbank AL049689 [ ENTREZ ] RefSeq NM_022093 [ SRS ] NM_022093 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004487 [ SRS ] NT_004487 [ ENTREZ ] RefSeq NW_001838533 [ SRS ] NW_001838533 [ ENTREZ ] RefSeq NW_926128 [ SRS ] NW_926128 [ ENTREZ ] CCDS TNN CCDS - NCBI AceView TNN AceView - NCBI Unigene Hs.156369 [ SRS ] Hs.156369 [ NCBI ] Fast-db 17591 (alternative variants) Protein : pattern, domain, 3D structure Q9UQP3 [ SRS] Q9UQP3 [ EXPASY ] Q9UQP3 [ INTERPRO ] Q9UQP3 SwissProt [ UNIPROT ] Q9UQP3 [ VarSplice FASTA ] Prosite PS00022 EGF_1 [ SRS ] PS00022 EGF_1 [ Expasy ] Prosite PS01186 EGF_2 [ SRS ] PS01186 EGF_2 [ Expasy ] Prosite PS50026 EGF_3 [ SRS ] PS50026 EGF_3 [ Expasy ] PS00514 FIBRIN_AG_C_DOMAIN [ SRS ] PS00514 FIBRIN_AG_C_DOMAIN Prosite [ Expasy ] Prosite PS50853 FN3 [ SRS ] PS50853 FN3 [ Expasy ] Interpro IPR000742 EGF_3 [ SRS ] IPR000742 EGF_3 [ EBI ] Interpro IPR013111 EGF_extracell [ SRS ] IPR013111 EGF_extracell [ EBI ] Interpro IPR013032 EGF_like_reg_CS [ SRS ] IPR013032 EGF_like_reg_CS [ EBI ] Interpro IPR002181 Fibrinogen_a/b/g_C [ SRS ] IPR002181 Fibrinogen_a/b/g_C [ EBI ] IPR008957 Fibronectin_typ-III-like_fold [ SRS ] IPR008957 Fibronectin_typ-III- Interpro like_fold [ EBI ] Interpro IPR003961 FN_III [ SRS ] IPR003961 FN_III [ EBI ] CluSTr Q9UQP3 Pfam PF07974 EGF_2 [ SRS ] PF07974 EGF_2 [ Sanger ] pfam07974 [ NCBI-CDD ] PF00147 Fibrinogen_C [ SRS ] PF00147 Fibrinogen_C [ Sanger ] pfam00147 Pfam [ NCBI-CDD ] Pfam PF00041 fn3 [ SRS ] PF00041 fn3 [ Sanger ] pfam00041 [ NCBI-CDD ] Smart SM00186 FBG [EMBL] Smart SM00060 FN3 [EMBL] Blocks Q9UQP3 Protein Interaction databases DIP Q9UQP3 IntAct Q9UQP3 Polymorphism : SNP, mutations, diseases SNP TNN [dbSNP-NCBI] SNP NM_022093 [SNP-NCI] SNP TNN [GeneSNPs - Utah] TNN] [HGBASE - SRS] HAPMAP TNN [HAPMAP] HGMD TNN Genetic TNN Association

Atlas Genet Cytogenet Oncol Haematol 2008; 6 845 CDC HuGE TNN General knowledge Family TNN [UCSC Family Browser] Browser SOURCE NM_022093 SMD Hs.156369 SAGE Hs.156369 GO molecular_function [Amigo] molecular_function GO integrin binding [Amigo] integrin binding GO cellular_component [Amigo] cellular_component GO proteinaceous extracellular matrix [Amigo] proteinaceous extracellular matrix GO cell-matrix adhesion [Amigo] cell-matrix adhesion GO signal transduction [Amigo] signal transduction GO axonogenesis [Amigo] axonogenesis GO cell surface [Amigo] cell surface GO cell growth [Amigo] cell growth GO cell migration [Amigo] cell migration GO identical protein binding [Amigo] identical protein binding KEGG Cell Communication KEGG Focal adhesion KEGG ECM-receptor interaction PubGene TNN TreeFam TNN CTD 63923 [Comparative ToxicoGenomics Database] Other databases Probes Probe TNN Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in Entrez Bibliography Zebrafish tenascin-W, a new member of the tenascin family. Weber P, Montag D, Schachner M. J Neurobiol. 1998 Apr;35(1):1-16. PMID 9552162

Murine tenascin-W: a novel mammalian tenascin expressed in kidney and at sites of bone and smooth muscle development. Scherberich A, Tucker RP, Samandari E, Brown-Luedi M, Martin D, Chiquet-Ehrismann R. J Cell Sci. 2004 Feb 1;117(Pt 4):571-81. Epub 2004 Jan 6. PMID 14709716

Tenascin-W is found in malignant mammry tumors, promotes alpha8 integrin-dependent motility and requires p38MAPK activity for BMP-2 and TNF alpha induced expression in vitro. Scherberich A, Tucker RP, Degen M, Brown-Luedi M, Andres AC, Chiquet-Ehrismann R. Oncogene. 2005 Feb 24;24(9):1525-32. PMID 15592496

Avian tenascin-W: expression in smooth muscle and bone, and effects on calvarial cell spreading and adhesion in vitro. Meloty-Kapella C, Degen M, Chiquet-Ehrismann R, Tucker RP. Dev Dyn. 2006 Jun;235(6):1532-42. PMID 16534782

Phylogenetic analysis of the tenascin gene family: evidence of origin early in the chordate lineage. Tucker RP, Drabikowski K, Hess JF, Ferralli J, Chiquet-Ehrismann R, Adams JC. BMC Evol Biol. 2006 Aug 7;6:60.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 846 PMID 16893461

Tenascin-W is a novel marker for activated tumor stroma in low-grade human breast cancer and influences cell behavior. Degen M, Brellier F, Kain R, Ruiz C, Terracciano L, Orend G, Chiquet-Ehrismann R. Canc Res 2007; 67: 9169-9179. PMID 17909022

Tenascin-W, a new marker of cancer stroma, is elevated in sera of colon and breast cancer patients. Degen M, Brellier F, Schenk S, Driscoll R, Zaman K, Stupp R, Tornillo L, Terracciano L, Chiquet- Ehrismann R, Rüegg C, Seelentag W. Int J Cancer in press.

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Martin Degen, Ruth Chiquet-Ehrismann Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland Citation This paper should be referenced as such : Degen M, Chiquet-Ehrismann R . TNN (tenascin N). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/TNNID44209ch1q25.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 847 Atlas of Genetics and Cytogenetics in Oncology and Haematology

VTCN1 (V-set domain containing T cell activation inhibitor 1)

Identity Other names B7H4 B7-H4 B7S1 B7X B7h.5 FLJ22418 PRO1291 RP11-229A19.4 HGNC VTCN1 Location 1p13.1 Location_base_pair Starts at 117487732 and ends at 117555072 bp from pter ( according to hg18- Mar_2006). DNA/RNA Description The VTCN1 (B7-H4) gene located in chromosome 1p13.1, consists of six exons and five introns and the coding region spans 849 bp. The mature protein is coded by the exons 3, 4, and part 5 while exons 1 and 2 encodes a signal peptide. The IgV-IgC domain, comprised of the extracellular region, is coded by exons 3, 4 and parts of 5 (Chen et al., 2003). Transcription B7-H4 mRNA can be detected in many tissues including placenta, kidney, liver, lung, ovary, testis and spleen. There are two transcripts of B7-H4 and both transcripts share complete homology with exons 1 to 5 in the full length B7-H4 gene. The smaller transcript of the two, generated by alternative splicing, lacks part of exon 6 (Chen et al., 2003). Pseudogene A possible B7-H4 pseudogene has a single exon with 94% similar nucleotide sequence identity to the cDNA of B-7H4 and is located in chromosome 20p11.1 (Chen et al., 2003). Protein Description The predicted 282-amino acid B7-H4 protein contains a 2-amino acid intracellular domain, a large hydrophobic type 1 transmembrane domain and an extracellular domain (Prasad et al., 2003). Expression Prasad et al (2003) showed that B7-H4 is expressed in professional antigen presenting cells. Although B7-H4 is overexpressed in several human cancers including ovary, endometrium, lung and kidney, its expression is limited in normal tissues. Shroyer et al (2005) showed that there is a limited focal expression of B7-H4 by immunohistochemistry in several normal human tissues including fallopian tubes, endometrial glands, pancreas, larynx, lung, kidney and urinary bladder. Localisation B7-H4 is localized to the cell surface and cytoplasm of epithelial cells and macrophages. Expression in benign glandular cells (ductal epithelium in breast and pancreas) is localized to the apical cell surface but there is circumferential membranous localization in B7-H4 positive tumor cells. Function Published data shows that B7-H4 functions as a negative regulator of T cell responses and it negatively regulates the T cell immunity by the inhibition of T cell proliferation, cytokine production and cell cycle progression. Prasad et al. (2003) reported that B7S1/B7-H4 is expressed on professional antigen presenting cells, binds to its putative receptor on activated T cells, and inhibits T cell activation and IL2 production. Sica et al (2003) also reported that B7-H4 inhibits T cell activation and the production of both IL2 and IL10. They further showed that B7-H4 inhibits the induction of Cytolytic T Lymphocytes (CTL) in vitro and it also arrests cell cycle of T cells in G0/G1 phase. B7-H4 may also play a role in tumor biology by providing tumors with a protective

Atlas Genet Cytogenet Oncol Haematol 2008; 6 848 mechanism to escape from immune surveillance. Several human cancers such ovary, endometrium, breast, kidney and lung (non small cell) are known to overexpress B-7H4 and the level of B7-H4 expression in these tumors has been correlated to the number of tumor-associated and tumor-infiltrating T cells. Papkoff et al. (2005) found that overexpressed B7-H4 promotes epithelial cell transformation by protecting cells from apoptosis and a siRNA knockout of B7-H4 in tumor cell lines lead to an increased apoptosis. Kryczek et al (2006) reported that primary ovarian tumor cells express exclusively intracellular B7-H4 protein, whereas the majority of ovarian tumor macrophages, but not tumor T cells or blood macrophages, express surface B7-H4, possibly by stimulation with tumor-associated IL6 and IL10. They also showed that B7- H4 expressing tumor macrophages suppressed HER2 specific T-cell proliferation and cytotoxicity. Further, the blocking of B7-H4 expression with specific oligonucleotides improved the tumor-associated antigen T-cell responses. They concluded that B7-H4 expressing tumor macrophages are a suppressive cell population in ovarian cancer and might prove to be a good therapeutic target. Homology B7-H4 shares a 24%-31% homology with other members of the B7 family and has the highest homology with B7H3 with 31% homology (Chen et al., 2003). Implicated in Entity Ovarian Cancer Note Chen et al (2003) first reported the detection of B7-H4 expression in ovarian cancer but not in normal ovarian tissue. Papkoff et al (2005) showed that B7-H4 mRNA and protein are overexpressed in human serous ovarian cancers and breast cancers with relatively little or no expression in normal tissues. Also they described that overexpression of B7- H4 in a human ovarian cancer cell line with little endogenous B7-H4 expression, increased the tumor formation in SCID mice. Shroyer et al (2006) found that B7-H4 is highly over-expressed in primary and metastatic serous, endometrioid, and clear cell carcinomas. In contrast, B7-H4 is not expressed in most mucinous ovarian cancers. Kryczek et al (2006) published that primary ovarian tumor cells express intracellular B7- H4, whereas a fraction of tumor macrophages expressed surface B7-H4. These authors concluded that B7-H4 expression in tumor macrophages, rather than in the ovarian tumor cells, was relevant with regard to the suppression of tumor-associated antigen- specific T cell immunity. Kim et al (2006) showed that elevated levels of B7-H4 can be found in the serum of patients with ovarian cancer and could play a role as a biomarker in ovarian cancer. They also developed a method based on ELISA to detect B7-H4 in the serum. Diamandis (2007) reported B7-H4 expression was low in normal ovaries and in benign tumors while half of early stage and two-thirds of late stage cancers over- expressed B7-H4. Entity Uterine Endometrial Cancer Note Shroyer et al (2007) showed that the proportion and intensity of B7-H4 staining were increased in the progression from normal, hyperplastic and malignant endometrial glandular mucosa. The proportion of B7-H4 positive tumor cells and staining intensity was also higher in high risk tumors than in low risk tumors. The proportion of B7-H4 positive tumor cells was inversely related to the number of CD3-positive and CD8- positive tumor-associated lymphocytes. Entity Breast Cancer Note Shroyer et al (2005) showed that B7-H4 is consistently over-expressed in primary and metastatic ductal and lobular breast cancers and its expression is correlated with a negative progesterone receptor status, negative Her-2/neu status and with a history of neo-adjuvant chemotherapy. There was also a significant association between a high proportion of B7-H4 positive cells in invasive ductal carcinomas and decreased number of tumor infiltrating lymphocytes. B7-H4 immunohistochemical expression was independent of tumor grade, stage or the size of the tumors. Entity Non Small Cell Lung Cancer Note Wang et al (2006) showed that B7-H4 is overexpressed in Non Small Cell Lung Cancer and its overexpression is negatively correlated with tumor infiltrating lymphocytes and positively associated with lymph node metastasis. Entity Renal Cell Cancer (RCC) Note Kwon et al (2006) reported that B7-H4 was overexpressed in 59% of 259 RCC tumor specimens analyzed and that tumor cell B7-H4 expression was associated with adverse

Atlas Genet Cytogenet Oncol Haematol 2008; 6 849 clinical and pathologic features, including constitutional symptoms, tumor necrosis, and advanced tumor size, stage, and grade. Also B7-H4 expression when coupled with B7S1 expression was associated with a poor survival from RCC. Additionally, they noted that tumor vasculature was significantly positive for endothelial B7-H4 expression, compared with the normal adjacent renal tissue vessels. Entity Prostate Cancer Note Allison et al (2007) published that B7x/B7-H4 is overexpressed in human prostate cancer and patients with stronger immunohistochemical B7-H4 expression had higher rates of clinical cancer recurrences and cancer specific deaths. External links Nomenclature HGNC VTCN1 28873 Entrez_Gene VTCN1 79679 V-set domain containing T cell activation inhibitor 1 Cards Atlas ENAHID44148ch1q42 GeneCards VTCN1 Ensembl ENSG00000134258 [Gene_View] VTCN1 [Vega] Genatlas VTCN1 Genomic and cartography VTCN1 - 1p13.1 chr1:117487732-117555072 - 1p12 [Description] (hg18- GoldenPath Mar_2006) Ensembl VTCN1 - 1p12 [CytoView] NCBI Mapview OMIM 608162 Disease map [OMIM] HomoloGene VTCN1 Gene and transcription Genbank AK026071 [ ENTREZ ] Genbank AK225413 [ ENTREZ ] Genbank AK310812 [ ENTREZ ] Genbank AY280972 [ ENTREZ ] Genbank AY346100 [ ENTREZ ] RefSeq NM_024626 [ SRS ] NM_024626 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_019273 [ SRS ] NT_019273 [ ENTREZ ] RefSeq NW_001838594 [ SRS ] NW_001838594 [ ENTREZ ] RefSeq NW_922462 [ SRS ] NW_922462 [ ENTREZ ] CCDS VTCN1 CCDS - NCBI AceView VTCN1 AceView - NCBI Unigene Hs.546434 [ SRS ] Hs.546434 [ NCBI ] Fast-db 17165 (alternative variants) Protein : pattern, domain, 3D structure Q5T2L0 [ SRS] Q5T2L0 [ EXPASY ] Q5T2L0 [ INTERPRO ] Q5T2L0 SwissProt [ UNIPROT ] Q5T2L0 [ VarSplice FASTA ] Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ] Interpro IPR007110 Ig-like [ SRS ] IPR007110 Ig-like [ EBI ] Interpro IPR013783 Ig-like_fold [ SRS ] IPR013783 Ig-like_fold [ EBI ] Interpro IPR003599 Ig_sub [ SRS ] IPR003599 Ig_sub [ EBI ] Interpro IPR013106 Ig_V-set [ SRS ] IPR013106 Ig_V-set [ EBI ] CluSTr Q5T2L0 Pfam PF07686 V-set [ SRS ] PF07686 V-set [ Sanger ] pfam07686 [ NCBI-CDD ] Smart SM00409 IG [EMBL] Blocks Q5T2L0

Atlas Genet Cytogenet Oncol Haematol 2008; 6 850 HPRD 06429 Protein Interaction databases DIP Q5T2L0 IntAct Q5T2L0 Polymorphism : SNP, mutations, diseases OMIM 608162 [ map ] GENETests 608162 SNP VTCN1 [dbSNP-NCBI] SNP NM_024626 [SNP-NCI] SNP VTCN1 [GeneSNPs - Utah] VTCN1] [HGBASE - SRS] HAPMAP VTCN1 [HAPMAP] HGMD VTCN1 Genetic VTCN1 Association CDC HuGE VTCN1 General knowledge Family VTCN1 [UCSC Family Browser] Browser SOURCE NM_024626 SMD Hs.546434 SAGE Hs.546434 GO plasma membrane [Amigo] plasma membrane GO immune response [Amigo] immune response GO integral to membrane [Amigo] integral to membrane PubGene VTCN1 TreeFam VTCN1 CTD 79679 [Comparative ToxicoGenomics Database] Other databases Probes Probe VTCN1 Related clones (RZPD - Berlin) PubMed PubMed 19 Pubmed reference(s) in Entrez Bibliography Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. Choi IH, Zhu G, Sica GL, Strome SE, Cheville JC, Lau JS, Zhu Y, Flies DB, Tamada K, Chen L Journal of immunology (Baltimore, Md. : 1950). 2003 ; 171 (9) : 4650-4654. PMID 14568939

B7S1, a novel B7 family member that negatively regulates T cell activation. Prasad DV, Richards S, Mai XM, Dong C Immunity. 2003 ; 18 (6) : 863-873. PMID 12818166

B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, Chapoval AI, Flies DB, Bajorath J, Chen L Immunity. 2003 ; 18 (6) : 849-861. PMID 12818165

The B7 family of immune-regulatory ligands. Collins M, Ling V, Carreno BM Genome biology. 2005 ; 6 (6) : page 223. PMID 15960813

The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 851 Salceda S, Tang T, Kmet M, Munteanu A, Ghosh M, Macina R, Liu W, Pilkington G, Papkoff J Experimental cell research. 2005 ; 306 (1) : 128-141. PMID 15878339

B7-h4 is highly expressed in ductal and lobular breast cancer. Tringler B, Zhuo S, Pilkington G, Torkko KC, Singh M, Lucia MS, Heinz DE, Papkoff J, Shroyer KR Clinical cancer research. 2005 ; 11 (5) : 1842-1848. PMID 15756008

Differential gene expression profiles between tumor biopsies and short-term primary cultures of ovarian serous carcinomas: identification of novel molecular biomarkers for early diagnosis and therapy. Bignotti E, Tassi RA, Calza S, Ravaggi A, Romani C, Rossi E, Falchetti M, Odicino FE, Pecorelli S, Santin AD Gynecologic oncology. 2006 ; 103 (2) : 405-416. PMID 16725184

B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Krambeck AE, Thompson RH, Dong H, Lohse CM, Park ES, Kuntz SM, Leibovich BC, Blute ML, Cheville JC, Kwon ED Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (27) : 10391-10396. PMID 16798883

Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, Chen L, Zou W Journal of immunology (Baltimore, Md. : 1950). 2006 ; 177 (1) : 40-44. PMID 16785496

B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W The Journal of experimental medicine. 2006 ; 203 (4) : 871-881. PMID 16606666

B7-h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer. Simon I, Zhuo S, Corral L, Diamandis EP, Sarno MJ, Wolfert RL, Kim NW Cancer research. 2006 ; 66 (3) : 1570-1575. PMID 16452214

B7-H3 and B7-H4 expression in non-small-cell lung cancer. Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, Wang X Lung cancer (Amsterdam, Netherlands). 2006 ; 53 (2) : 143-151. PMID 16782226

B7-H4 overexpression in ovarian tumors. Tringler B, Liu W, Corral L, Torkko KC, Enomoto T, Davidson S, Lucia MS, Heinz DE, Papkoff J, Shroyer KR Gynecologic oncology. 2006 ; 100 (1) : 44-52. PMID 16256178

The new B7s: playing a pivotal role in tumor immunity. Flies DB, Chen L Journal of immunotherapy (Hagerstown, Md. : 1997). 2007 ; 30 (3) : 251-260. PMID 17414316

Atlas Genet Cytogenet Oncol Haematol 2008; 6 852 Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zou W Cancer research. 2007 ; 67 (18) : 8900-8905. PMID 17875732

B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration. Miyatake T, Tringler B, Liu W, Liu SH, Papkoff J, Enomoto T, Torkko KC, Dehn DL, Swisher A, Shroyer KR Gynecologic oncology. 2007 ; 106 (1) : 119-127. PMID 17509674

B7-h4 expression in a range of breast pathology: correlation with tumor T-cell infiltration. Mugler KC, Singh M, Tringler B, Torkko KC, Liu W, Papkoff J, Shroyer KR Applied immunohistochemistry & molecular morphology. 2007 ; 15 (4) : 363-370. PMID 18091377

B7-H4 is over-expressed in early-stage ovarian cancer and is independent of CA125 expression. Simon I, Katsaros D, Rigault de la Longrais I, Massobrio M, Scorilas A, Kim NW, Sarno MJ, Wolfert RL, Diamandis EP Gynecologic oncology. 2007 ; 106 (2) : 334-341. PMID 17498784

Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer. Simon I, Liu Y, Krall KL, Urban N, Wolfert RL, Kim NW, McIntosh MW Gynecologic oncology. 2007 ; 106 (1) : 112-118. PMID 17490732

B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Zang X, Thompson RH, Al-Ahmadie HA, Serio AM, Reuter VE, Eastham JA, Scardino PT, Sharma P, Allison JP Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (49) : 19458-19463. PMID 18042703

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

Search in all EBI NCBI

Contributor(s) Written 02-2008 Panduka Samarawardana, Kenneth R Shroyer Department of Pathology, University of Colorado at Denver and Health Sciences Center, (PS); Department of Pathology, Stony Brook University Medical Center, Aurora, CO 80045, USA (KRS) Citation This paper should be referenced as such : Samarawardana P, Shroyer KR . VTCN1 (V-set domain containing T cell activation inhibitor 1). Atlas Genet Cytogenet Oncol Haematol. February 2008 . URL : http://AtlasGeneticsOncology.org/Genes/ © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 853 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(8;12)(q24;q22)

Clinics and Pathology Disease Chronic lymphocytic leukemia (CLL) in blastic transformation Note CLL was diagnosed after bone marrow recovery following intensive chemotherapy for acute lymphoblastic leukemia Epidemiology Only one case to date, 69-year-old female patient Cytogenetics The patient had a primary t(11;14)(q13;q32) in all lymphocytic/lymphoblastic cells. A subpopulation of cells carried in addition a t(8;12)(q24;q22) together with the loss of the normal chromosome 8 and homozygosity for the abnormal der(8). It is likely that the t(11;14) corresponded to the CLL, and the subclone with t(8;12) to the blast population Genes MYC was strongly expressed. The breakpoint on chromosome 8 mapped to the 3' end of the MYC locus Prognosis The patient died 5 months after initial blastic phase Genes involved and Proteins Gene Name MYC Location 8q24 Protein Transcription factor binding to specific DNA sequences, upon dimerization to Max (Max can also form heterodimers with Mad as well as homodimers with itself). Myc/Max complexes activate transcription and promote cell proliferation and transformation. Mad/Max complexes, repress transcription. Gene Name BTG1 Location 12q22 Protein B-cell translocation gene 1 (BTG1) is an anti-proliferative gene; it regulates cell growth and differentiation. BTG1 is strongly expressed in the G0/G1 phases of the cell cycle, and then down-regulated during the G1 phase. Overexpression of BTG1 results in a retardation of cell proliferation. Potentially high-affinity self-reactive B cells are eliminated through the interaction of membrane Ig (mIg) with self-antigens. Anti-IgM upregulates BTG1 and BTG2, resulting in growth inhibition. Engagement of mIg on the cells results in G1 arrest and eventual apoptosis. External links Other t(8;12)(q24;q22) Mitelman database (CGAP - NCBI) database Other t(8;12)(q24;q22) 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 Initial clonal acute lymphoblastic transformation of chronic lymphocytic leukemia with (11;14) and (8;12) chromosome translocations and acquired homozygosity. Archimbaud E, Charrin C, Gentilhomme O, Rimokh R, Guyotat D, Fiere D, Germain D Acta haematologica. 1988 ; 79 (3) : 168-173. PMID 3128040

A chromosome 12 coding region is juxtaposed to the MYC protooncogene locus in a t(8;12) (q24;q22) translocation in a case of B-cell chronic lymphocytic leukemia. Rimokh R, Rouault JP, Wahbi K, Gadoux M, Lafage M, Archimbaud E, Charrin C, Gentilhomme O, Germain D, Samarut J Genes, chromosomes & cancer. 1991 ; 3 (1) : 24-36. PMID 2069907

Atlas Genet Cytogenet Oncol Haematol 2008; 6 854 An anti-proliferative gene BTG1 regulates angiogenesis in vitro. Iwai K, Hirata K, Ishida T, Takeuchi S, Hirase T, Rikitake Y, Kojima Y, Inoue N, Kawashima S, Yokoyama M Biochemical and biophysical research communications. 2004 ; 316 (3) : 628-635. PMID 15033446

Role for Btg1 and Btg2 in growth arrest of WEHI-231 cells through arginine methylation following membrane immunoglobulin engagement. Hata K, Nishijima K, Mizuguchi J Experimental cell research. 2007 ; 313 (11) : 2356-2366. PMID 17466295

Contributor(s) Written 10-2007 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . t(8;12)(q24;q22). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0812q24q22ID2057.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 855 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(7;21)(p22;q22)

Clinics and Pathology Disease Acute myeloid leukemia (AML) Phenotype / M0 AML cell stem origin Epidemiology Only one case to date, a 7 year old boy Evolution The patient relapsed; however, he is still alive, with a bone marrow graft, 10 years after diagnosis. Genes involved and Proteins Gene Name UPS42 Protein USP42 (ubiquitin specific protease 42), belongs to the ubiquitin specific protease family. Ubiquitins are highly conserved proteins. Ubiquitins target proteins for degradation in the proteasome. Some USPs, however, act in the opposite reaction. These ubiquitin specific proteases (cysteine proteases) are also called deubiquitinating . They cleave ubiquitin from ubiquitin-conjugated target proteins and may lead to protein stabilization. Usp42 can cleave ubiquitin from ubiquitinated substrates. Usp42 seems to be a deubiquitinating enzyme. It may play an important role in mouse embryogenesis. Gene Name RUNX1 Location 21q22 Protein Transcription factor (activator) for various hematopoietic-specific genes, which experssion is limited to hematopoetic stem cells, and endothelial cells and mesenchymal cells in the embryo; core binding factor family member which forms heterodimers with CBFB; binds to the core site 5' PyGPyGGTPy 3' of promotors and enhancers Result of the chromosomal anomaly

Hybrid gene

Description 5' RUNX1- 3' UPS42 External links Other t(7;21)(p22;q22) Mitelman database (CGAP - NCBI) database Other t(7;21)(p22;q22) 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 novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42. Paulsson K, Bekassy AN, Olofsson T, Mitelman F, Johansson B, Panagopoulos I Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2006 ; 20 (2) : 224-229. PMID 16357831

The expression of Usp42 during embryogenesis and spermatogenesis in mouse. Kim YK, Kim YS, Yoo KJ, Lee HJ, Lee DR, Yeo CY, Baek KH

Atlas Genet Cytogenet Oncol Haematol 2008; 6 856 Gene expression patterns : GEP. 2007 ; 7 (1-2) : 143-148. PMID 16904385

Contributor(s) Written 10-2007 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . t(7;21)(p22;q22). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0721p22q22ID1449.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 857 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(6;11)(q13;q23)

Clinics and Pathology Disease Acute leukemia Note Only 2 cases to date; one of which was not further described. Phenotype / cell One case was a M4 acute myeloid leukaemia. stem origin Epidemiology The patient was a 14 year old girl Prognosis Survival was 18 months in the only documented case. Cytogenetics Additional anomalies Sole anomaly. Genes involved and Proteins Gene Name SMAP1 Location 6q13 Protein SMAP1 is a GTPase-activating protein (GAP) for Arf6. Vesicle formation requires clathrin, its adaptors, and an enzymatic activity. This is given by small GTPase ADP-ribosylation factors (Arf; there is six Arfs, Arf1, Arf3, Arf2/Arf4, Arf5 and Arf6). Arf switches between a GTP-bound active state (regulated by guanine- nucleotide exchange factor (GEF)) and a GDP-bound inactive state (regulated by GTPase-activating protein (GAP)). Arf6/SMAP1 regulates the clathrin dependent endocytosis of vesicles from the plasma membrane and the recycling of endosome to the plasma membrane. Gene Name MLL Location 11q23 Protein transcriptional regulatory factor; MLL may have yin-yang functions though actions of MLL-N and MLL-C (e.g. desacetylation/acetylation); MLL-N acts as a transcriptional repressor; MLL can be associated with more than 30 proteins, including the core components of the SWI/SNF chromatin remodeling complex and the transcription complex TFIID. MLL binds promotors of HOX genes through acetylation and methylation of histones. MLL is a major regulator of hematopoesis and embryonic development, through regulation of HOX genes expression regulation ( HOXA9 in particular). Result of the chromosomal anomaly

Hybrid gene

Description 5' MLL-3' SMAP1 External links Other database t(6;11)(q13;q23) Mitelman database (CGAP - NCBI) Other database t(6;11)(q13;q23) CancerChromosomes (NCBI) 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 Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants. Harrison CJ, Cuneo A, Clark R, Johansson B, Lafage-Pochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 ; 12 (5) : 811-822. PMID 9593286

Atlas Genet Cytogenet Oncol Haematol 2008; 6 858

Cloning, characterization and chromosome mapping of the human SMAP1 gene. Marcos I, Borrego S, Rodriguez de Cordoba S, Galan JJ, Antinolo G Gene. 2002 ; 292 (1-2) : 167-171. PMID 12119110

A novel GTPase-activating protein for ARF6 directly interacts with clathrin and regulates clathrin-dependent endocytosis. Tanabe K, Torii T, Natsume W, Braesch-Andersen S, Watanabe T, Satake M Molecular biology of the cell. 2005 ; 16 (4) : 1617-1628. PMID 15659652

Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Meyer C, Schneider B, Reichel M, Angermueller S, Strehl S, Schnittger S, Schoch C, Jansen MW, van Dongen JJ, Pieters R, Haas OA, Dingermann T, Klingebiel T, Marschalek R Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (2) : 449-454. PMID 15626757

SMAP2, a novel ARF GTPase-activating protein, interacts with clathrin and clathrin assembly protein and functions on the AP-1-positive early endosome/trans-Golgi network. Natsume W, Tanabe K, Kon S, Yoshida N, Watanabe T, Torii T, Satake M Molecular biology of the cell. 2006 ; 17 (6) : 2592-2603. PMID 16571680

Contributor(s) Written 10-2007 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . t(6;11)(q13;q23). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0611q13q23ID1408.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 859 Atlas of Genetics and Cytogenetics in Oncology and Haematology inv(11)(p15q22) t(11;11)(p15;q22)

Identity Note Only one case of t(11;11) with NUP98-DDX10 fusion has been described; most cases are cases of inv(11) Clinics and Pathology Disease de novo Myelodysplastic syndromes (MDS) and Acute Non Lymphoblastic Leukemias (ANLL), therapy related MDS and ANLL, one case of Chronic Myelogenous Leukemia (CML). Epidemiology Thirteen cases reported to date: six adults and seven children (9M/4F) Cytogenetics

A: inv(11)(p15q22) Q-banding: the derivative chromosomes are on the right of each pair.

B: FISH with NUP98 PAC 1173K1 probe. A split signal indicates pericentric inversion in the der(11). C: Cohybridization of DDX10 centromeric BAC RP11-976P22 (red) and subtelomeric 11p RP11-534I22 probe (green). Probes NUP98: PAC 1173K1; DDX10: RP11-976P22 (centromeric) and RP11-25I9 (telomeric) Additional Sole anomaly in 8 out of 13 cases anomalies Genes involved and Proteins Gene Name NUP98 Location 11p15.5 Protein Nucleoporin 98, a 98 kDa component of the nuclear pore complex involved in nucleo-

Atlas Genet Cytogenet Oncol Haematol 2008; 6 860 cytoplasmic transport. Gene Name DDX10 Location 11q22 Dna / Rna Alternative splicing; 3.2 and 5.0 kb mRNA. Protein Putative DEAD-box RNA helicase involved in ribosome biogenesis. Result of the chromosomal anomaly

Hybrid gene

Description 5' NUP98 - 3' DDX10 Twelve out of 13 cases present exon 14 of NUP98 fused in-frame to exon 7 of DDX10, one case with exon 12 of NUP98 fused in-frame to exon 6 of DDX10.

Fusion Protein

Description It fuses the GLFG repeat domains of NUP98 to the acidic domain of DDX10. External links Other database inv(11)(p15q22) Mitelman database (CGAP - NCBI) Other database t(11;11)(p15;q22) Mitelman database (CGAP - NCBI) Other database t(11;11)(p15;q22) CancerChromosomes (NCBI) 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 The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N, Kaneko Y, Ohki M Blood. 1997 ; 89 (11) : 3936-3944. PMID 9166830

The inv(11)(p15q22) chromosome translocation of therapy-related myelodysplasia with NUP98- DDX10 and DDX10-NUP98 fusion transcripts. Ikeda T, Ikeda K, Sasaki K, Kawakami K, Takahara J International journal of hematology. 1999 ; 69 (3) : 160-164. PMID 10222653

Screening for NUP98 rearrangements in hematopoietic malignancies by fluorescence in situ hybridization. Nebral K, Konig M, Schmidt HH, Lutz D, Sperr WR, Kalwak K, Brugger S, Dworzak MN, Haas OA, Strehl S Haematologica. 2005 ; 90 (6) : 746-752. PMID 15951287

Clonal evolution with inv(11)(p15q22) and NUP98/DDX10 fusion gene in imatinib-resistant chronic myelogenous leukemia. Yamamoto M, Kakihana K, Kurosu T, Murakami N, Miura O Cancer genetics and cytogenetics. 2005 ; 157 (2) : 104-108. PMID 15721630

Inversion (11)(p15q22) with NUP98-DDX10 fusion gene in pediatric acute myeloid leukemia. Morerio C, Acquila M, Rapella A, Tassano E, Rosanda C, Panarello C Cancer genetics and cytogenetics. 2006 ; 171 (2) : 122-125. PMID 17116492

NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogenetique Hematologique.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 861 Romana SP, Radford-Weiss I, Ben Abdelali R, Schluth C, Petit A, Dastugue N, Talmant P, Bilhou- Nabera C, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Andrieu J, Lai JL, Terre C, Rack K, Cornillet-Lefebvre P, Luquet I, Nadal N, Nguyen-Khac F, Perot C, Van den Akker J, Fert-Ferrer S, Cabrol C, Charrin C, Tigaud I, Poirel H, Vekemans M, Bernard OA, Groupe Francophone de Cytogenetique Hematologique, Berger R Leukemia. 2006 ; 20 (4) : 696-706. PMID 16467868

Contributor(s) Written 10-2007 Cristina Morerio, Claudio Panarello Citogenetica Ematoncologica, Dipartimento di Ematologia ed Oncologia Pediatrica, Istituto Giannina Gaslini, Largo G.Gaslini 5, 16147 Genova Quarto, Italy Citation This paper should be referenced as such : Morerio C, Panarello C . inv(11)(p15q22); t(11;11)(p15;q22). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/inv11p15q22ID1116.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 862 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(4;11)(q35;q23)

Clinics and Pathology Disease Acute myeloid leukemia (AML) Epidemiology Only one case to date, a 3 month-old girl with M5 AML. Prognosis No data. Genes involved and Proteins Gene Name SORBS2 Location 4q35.1 Note This gene is better known under the name ArgBP2. Protein From N-term to C-term, the protein contains a sorbin homology (SoHo) domain and three SH3 domains. Adaptor protein. Binds signaling proteins like ABL1 and ABL2, AKT and PAK1, and various cytoskeletal proteins, including vinculin, alpha actinin, spectrin. Role in cytoskeleton organization, lipid rafts, and signaling. Gene Name MLL Location 11q23 Protein Transcription regulator (yin/yang?), regulates, among others, HOX genes expression. -- > Hematopoiesis and embryogenesis regulation. Result of the chromosomal anomaly

Hybrid gene

Description 5' MLL - 3' SORBS2 Transcript Fusion transcript of MLL exon 7 to SORBS2 exon 19; the reciprocal was not detected.

Fusion Protein

Description N-term AT hook and methyl transferase domains from MLL, fused to the third and last C-term SH3 domain of SORBS2. Expression The MLL-SORBS2 hybrid localizes to the nucleus with a punctate pattern characteristic Localisation of MLL chimeric proteins. External links Other database t(4;11)(q35;q23) Mitelman database (CGAP - NCBI) Other database t(4;11)(q35;q23) CancerChromosomes (NCBI) 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 ArgBP2, a multiple Src homology 3 domain-containing, Arg/Abl-interacting protein, is phosphorylated in v-Abl-transformed cells and localized in stress fibers and cardiocyte Z- disks. Wang B, Golemis EA, Kruh GD. J Biol Chem. 1997 Jul 11; 272(28): 17542-50. PMID 921190 nArgBP2, a novel neural member of ponsin/ArgBP2/vinexin family that interacts with synapse- associated protein 90/postsynaptic density-95-associated protein (SAPAP). Kawabe H, Hata Y, Takeuchi M, Ide N, Mizoguchi A, Takai Y. J Biol Chem. 1999 Oct 22; 274(43): 30914-8.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 863 PMID 10521485

The Abl/Arg substrate ArgBP2/nArgBP2 coordinates the function of multiple regulatory mechanisms converging on the actin cytoskeleton. Cestra G, Toomre D, Chang S, De Camilli P. Proc Natl Acad Sci U S A. 2005 Feb 1; 102(5): 1731-6. PMID 15659545

ArgBP2, encoding a negative regulator of ABL, is fused to MLL in a case of infant M5 acute myeloid leukemia involving 4q35 and 11q23. Pession A, Lo Nigro L, Montemurro L, Serravalle S, Fazzina R, Izzi G, Nucifora G, Slany R, Tonelli R. Leukemia. 2006 Jul; 20(7): 1310-3. PMID 16628191

Contributor(s) Written 11-2007 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . t(4;11)(q35;q23). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0411q35q23ID1423.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 864 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(3;8)(q26;q24)

Identity

G-banding, t(3;8)(q26;q24) Clinics and Pathology Disease Acute myeloid leukemia, de novo myelodysplastic syndrome or therapy related myelodysplastic syndrome. Phenotype / Mostly AML FAB-M2 or FAB-M-4 subtype. cell stem origin Etiology Unclear, may be secondary to chemotherapy. Epidemiology 10 cases reported so far in the literature, less than 1% of AML cases. Cytology Acute myeloid leukemia of mostly M2, M4 or M5 FAB subtype or high grade MDS. Marked trilineage dysplasia and megakaryocytic hyperplasia, may be associated with peripheral blood thrombocytosis giving the so-call 3q21q26 syndrome.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 865

Dysplastic myeloid elements.

Increased dysplastic megakaryocytes and increased blasts in the interstitium. Treatment Chemotherapy; May responds to thalidomide or arsenic better than conventional chemotherapy. Evolution Myelodysplastic syndrome progress to acute myeloid leukemia. Prognosis Poor. Cytogenetics Note The breakpoint on 3q26 may lie in EVI1 or MDS1 genes. The breakpoint on 8q24 is distal to the PVT1 gene, a MYC activator gene in mice. The t(3;8) is frequently associated with -7. It also can be an isolated finding. Probes EVI1/MDS1 RP11-115B16, RP11-114D6; Vysis C-MYC; Break-apart distal; Probe (green).

Atlas Genet Cytogenet Oncol Haematol 2008; 6 866 Genes involved and Proteins Gene Name EVI1/MDS1 Location 3q26.2 Note Aberrant EVI1 expression usually occurs in AML, MDS or CML-BC as a result of translocation involving 3q26. The most common ones are inv(3)(q21q26), t(3;3) and t(3;21)(q26;q22). The partner genes of EVI1 are identified as Ribophorin I in inv(3) (q21q26) and t(3;3), AML/MDS1/EAP in t(3;21), and ETV6 in t(3;12), respectively. Others involving t(3;12), t(2;3)(p13;q26), t(3;17)(q26;q22) and t(3;13)(q26;q13-14) are uncommon. Aberrant EVI1 expression also occurs in 10% of acute myeloid leukemia without involving 3q26 and is also correlated with an adverse outcome. 16 exons spanning 64.2 Kb. Transcriptional orientation is from telomere to centromere. Dna / Rna EVI1 gene may be transcribed in different isoform which may have different oncogenic effect. Protein 1051 amino acids; 118335 Da. Nuclear location, contains 10 C2H2-type zinc fingers. Gene Name PVT1/C-MYC (pvt-1 (murine) oncogene homolog, MYC activator) Location 8q24 Note The RNA function of pvt1 is unknown. External links Other database t(3;8)(q26;q24) Mitelman database (CGAP - NCBI) Other database t(3;8)(q26;q24) CancerChromosomes (NCBI) 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 High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel- van de Luytgaarde S, Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Lowenberg B, Delwel R Blood. 2003 ; 101 (3) : 837-845. PMID 12393383

EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F Genes, chromosomes & cancer. 2006 ; 45 (4) : 349-356. PMID 16342172

Aberrant EVI1 expression in acute myeloid leukemias associated with the t(3;8)(q26;q24). Lennon PA, Abruzzo LV, Medeiros LJ, Cromwell C, Zhang X, Yin CC, Kornblau SM, Konopieva M, Lin P Cancer genetics and cytogenetics. 2007 ; 177 (1) : 37-42. PMID 17693189

Contributor(s) Written 11-2007 Pei Lin Department of Hematopathology, Box 72, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA Citation This paper should be referenced as such : Lin P . t(3;8)(q26;q24). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0308q26q24ID1463.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 867 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(1;9)(q24;q34)

Identity

R-banded karyotype showing the t(1;9)(q24;q34) translocation. Clinics and Pathology Disease B-cell acute lymphoblastic leukemia Epidemiology Only 1 case to date, a 11 year old boy Prognosis Complete remission was obtained and a bone marrow transplantation was performed. Cytogenetics Cytogenetics LSI bcr/abl dual extra-signal (ES) color probe (Abbott, Rungis, France) and BAC Molecular Probes.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 868

A: Dual-color FISH using RP11-83J21 (labeled in spectrum orange) and RP11-232M22 (labeled in spectrum green) showing two fusion genes. FISH, fluorescence in situ hybridization. B: Probes. Probes RP11-83J21 (chromosome 9) and RP11-232M22, RP11-928F1, RP11-138P14, RP11- 652E14, RP11-64D9 (). All the probes that were used to find the breakpoint on der(1). Genes involved and Proteins Gene Name ABL1 (Abelson Murine Leukemia Viral Oncogene Homolog 1) Location 9q34 The ABL gene is aproximately 225 kb in size and is expressed as a 7-kb mRNA Dna / Rna transcript, with alternatively spliced first exons, exons 1b and 1a, respectively, spliced to the common exons 2-11. Exon 1b is approximately 200 kb 5-prime of exon 1a. Protein The 145-kD ABL protein is classified as a nonreceptor tyrosine kinase. When the N- terminal region of the ABL protein is encoded by exon 1a, the protein is believed to be localized in the nucleus, while when encoded by exon 1b, the resulting N-terminal glycine would be myristylated and thus postulated to direct that protein to the plasma membrane. Gene Name RCSD1 (RCSD Domain-Containing Protein 1) Location 1q24 Dna / Rna Eyers et al (2005) cloned for the first time the human RCSD1, which they called CAPZIP. A 416-amino acid protein was deduced and they calculated a molecular mass of 44.5 kD. Northern blot analysis resulted in a major 3.4-kb transcript and a minor 7-kb

Atlas Genet Cytogenet Oncol Haematol 2008; 6 869 transcript that is highly expressed in skeletal muscle and weakly in cardiac muscle. CAPZIP is detected in several lymphoid organs, including spleen, thymus, peripheral blood leukocytes, lymph node, and bone marrow. Protein Eyers et al (2005) found many properties of rabbit Capzip. It interacted specifically with the F-actin capping protein CapZ. This protein was phosphorylated by : MAPKAPK2 and SAPK3 (MAPK12), on ser108 by SAPK3 and SAPK4 (MAPK13) and on ser68, ser83, and ser216 by JNK1 alpha-1 (MAPK8) in vitro. This team also found that stress induced by hyperosmotic shock and anisomycin, a protein synthesis inhibitor, stimulated the phosphorylation of CAPZIP in human cell lines and induced the dissociation of CAPZIP from CAPZ in Jurkat human T cells. This phenomenon may regulate the ability of CapZ to remodel actin filament. Result of the chromosomal anomaly

Hybrid gene

Description The 3' region of ABL1 is translocated on the 5' region of RCSD1 on the der(1) and the 3' region of RCSD1 is translocated on the 5' region of ABL1 on der(9). Detection FISH detection.

Fusion Protein

Description The fusion gene is predicted to encode an aberrant tyrosine kinase. Oncogenesis The RCSD1 gene, which codes a protein kinase substrate, CapZIP (CapZ-interacting protein), is found in immune cells, splenocytes and muscle. It is possible that the interaction between CapZIP and CapZ affects the cell ability to remodel actin filament assembly. CapZIP is phosphorylated when cells are exposed to various cellular stresses, which activate the kinase cascade. The interaction between CapZIP and CapZ would be lost when CapZIP is phosphorylated. So, RCSD1 would be involved in the remodeling of the actin cytoskeleton, which is an important step in mitosis. The probable formation of the ABL1-RCSD1 fusion gene could result in an alteration of the cellular function by affecting the cytoskeleton regulation, which could be an important step in leukemogenesis. External links Other database t(1;9)(q24;q34) Mitelman database (CGAP - NCBI) Other database t(1;9)(q24;q34) CancerChromosomes (NCBI) 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 The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Eyers CE, McNeill H, Knebel A, Morrice N, Arthur SJ, Cuenda A, Cohen P The Biochemical journal. 2005 ; 389 (Pt 1) : 127-135. PMID 15850461

A new partner gene fused to ABL1 in a t(1;9)(q24;q34)-associated B-cell acute lymphoblastic leukemia. De Braekeleer E, Douet-Guilbert N, Le Bris MJ, Berthou C, Morel F, De Braekeleer M Leukemia. 2007 ; 21 (10) : 2220-2221. PMID 17541395

Contributor(s) Written 11-2007 Etienne De Braekeleer, Marc De Braekeleer Inserm U613, Laboratoire de Cytogenetique, Faculte de Medecine et des Sciences de la Sante, Universite de Bretagne Occidentale, 22, avenue Camille Desmoulins, CS 93837, F-29238 Brest cedex 3, France

Atlas Genet Cytogenet Oncol Haematol 2008; 6 870 Citation This paper should be referenced as such : De Braekeleer E, De Braekeleer M . t(1;9)(q24;q34). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0109q24q34ID2109.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 871 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(12;13)(p13;q14)

Clinics and Pathology Disease Acute lymphoblastic leukemia (ALL) and myeloid malignancies. Note This translocation is likely to be molecularly heterogeneous. Epidemiology Only one case to date with identification of ETV6 and TTL as genes involved in the translocation : a 46 year-old male patient with ALL (blasts were CD10+/-, CD19+) (Qiao et al., 2003).. Clinics Altogether, 15 cases are available: Pre-B or early pre-B ALL cases, with an unbalanced sex ratio (7M/2F), and a median age of 6 years (range: 2-46), 7 of 9 patients being children (Raimondi et al., 1989; Pui et al., 1991; Raimondi et al., 1991; Chan et al., 1994; Kobayashi et al., 1994; Raimondi et al., 1997; Coignet et al., 1999; Qiao et al., 2003). Myeloid cases: 1 chronic myelomonocytic leukaemia (CMML), 1 chronic myelogenous leukaemia in blast crisis (BC-CML), 1 M3 acute myeloid leukaemia (AML), 1 M0-AML, and 2 treatment related AML (t-AML). In contrast with lymphoid cases, the sex ratio was balanced (3M/3F), and median age was 58 years (range (51-70) (Zitzelsberger et al., 1990; Abeliovich et al., 1993; Fugazza et al., 1997; Tosi et al., 1998; Castro et al., 2000; Temperani et al., 2000). Prognosis The patient with ETV6/TTL hybrid gene attained complete remission, but relapsed and died of refractory disease 4 years after diagnosis. Cytogenetics Additional The t(12;13) accompanied a del(5q) in two (t-AML) cases, del(7q) in one of these two anomalies cases, +8 in one myeloid case, t(9;22)(q34;q11) in the BC-CML case, a PML / RARA hybrid without any apparent t(15;17) in the M3 case, an additional 21 in two ALL cases (+21 once, i(21q) once). The t(12;13) was the sole anomaly in four cases (2 ALL and two AML). Genes involved and Proteins Note ETV6 was found implicated in 4 ALL cases and 1 AML case; most other cases have been published before ETV6/TEL was known. Gene Name ETV6 Location 12p13 Protein HLH domain responsible for hetero- and homodimerization in N-term, and an ETS domain responsible for sequence specific DNA-binding in C-term. Transcriptional regulator; involved in bone marrow hematopoiesis. Gene Name TTL Location 13q14 Protein This gene/protein remains poorly known: there has been no study on it since the princeps paper by Qiao et al (2003). Result of the chromosomal anomaly

Hybrid gene

Description Both reciprocal transcripts, TTL/ETV6 and ETV6/TTL, were detected. ETV6/TTL fusion transcript comprises 5' ETV6 exon 1, fused to TLL exon 9, resulting in a potential 31 amino acids peptid. The other transcript, TTL/ETV6, comprises 5' TTL exons 1 to 5 or to 8a, fused to ETV6 from exon 2. The predicted 530 amino acids fusion protein consists mostly of ETV6 with both HLH and ETS domains, and could have modified transcriptional activities. On the other hand, a loss of function of ETV6 and/or of TTL could play the critical role in

Atlas Genet Cytogenet Oncol Haematol 2008; 6 872 leukemogenesis. External links Other database t(12;13)(p13;q14) Mitelman database (CGAP - NCBI) Other database t(12;13)(p13;q14) CancerChromosomes (NCBI) To be noted Additional cases, WITH charaterization of the genes involved in the translocation, are needed to delineate the epidemiology of this/these rare entity/ies: you are welcome to submit a paper to our Case Report section. Bibliography Childhood acute lymphoblastic leukemia with chromosomal breakpoints at 11q23. Raimondi SC, Peiper SC, Kitchingman GR, Behm FG, Williams DL, Hancock ML, Mirro J Jr. Blood. 1989 May 1; 73(6): 1627-34. PMID 2496771

Cytogenetic and molecular analysis of a "masked" Philadelphia chromosome in chronic and blastic phases of chronic myeloid leukemia. Zitzelsberger H, Bauchinger M, Wilmanns W, Strauss PG. Cancer Genet Cytogenet. 1990 Jul 15; 47(2): 219-25. PMID 2357696

Characterization of childhood acute leukemia with multiple myeloid and lymphoid markers at diagnosis and at relapse. Pui CH, Raimondi SC, Head DR, Schell MJ, Rivera GK, Mirro J Jr, Crist WM, Behm FG. Blood. 1991 Sep 1; 78(5): 1327-37. PMID 1878594

New recurring chromosomal translocations in childhood acute lymphoblastic leukemia. Raimondi SC, Privitera E, Williams DL, Look AT, Behm F, Rivera GK, Crist WM, Pui CH. Blood. 1991 May 1; 77(9): 2016-22. PMID 2018838

Therapy-related myelodysplastic syndrome. Two cytogenetically unrelated abnormal clones in a patient with multiple myeloma. Abeliovich D, Yehuda O, Ben-Neriah S, Matzner Y. Cancer Genet Cytogenet. 1993 Oct 15; 70(2): 117-9. PMID 8242590

Cytogenetics and immunophenotypes of childhood acute lymphoblastic leukemia in Hong Kong. Chan LC, Ha SY, Ching LM, Lee CP, Lau YL, Yuen P, Leung NK. Cancer Genet Cytogenet. 1994 Sep; 76(2): 118-24. PMID 7923060

Clinical significance of chromosome abnormalities in childhood acute lymphoblastic leukemia in Japan. Kobayashi H, Maseki N, Homma C, Sakurai M, Kaneko Y. Leukemia. 1994 Nov; 8(11): 1944-50. PMID 7967740

Duplication of the der(13)t(12;13)(p13;q14) in chronic myelomonocytic leukemia. Fugazza G, Cerri R, Bruzzone R, Patrone F, Sessarego M. Haematologica. 1997 May-Jun; 82(3): 336-7. PMID 9234584

12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia. Raimondi SC, Shurtleff SA, Downing JR, Rubnitz J, Mathew S, Hancock M, Pui CH, Rivera GK, Grosveld GC, Behm FG. Blood. 1997 Dec 1; 90(11): 4559-66. PMID 9373267

Atlas Genet Cytogenet Oncol Haematol 2008; 6 873

Identification of new partner chromosomes involved in fusions with the ETV6 (TEL) gene in hematologic malignancies. Tosi S, Giudici G, Mosna G, Harbott J, Specchia G, Grosveld G, Privitera E, Kearney L, Biondi A, Cazzaniga G. Genes Chromosomes Cancer. 1998 Mar; 21(3): 223-9. PMID 9523197

Myeloid- and lymphoid-specific breakpoint cluster regions in chromosome band 13q14 in acute leukemia. Coignet LJ, Lima CS, Min T, Streubel B, Swansbury J, Telford N, Swanton S, Bowen A, Nagai M, Catovsky D, Fonatsch C, Dyer MJ. Genes Chromosomes Cancer. 1999 Jul; 25(3): 222-9. PMID 10379868

Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms. Castro PD, Liang JC, Nagarajan L. Blood. 2000 Mar 15; 95(6): 2138-43. PMID 10706886

Late-appearing PML/RARalpha fusion transcript with coincidental t(12;13)(p13.2;q14) in acute promyelocytic leukemia lacking the t(15;17) cytogenetic anomaly. Temperani P, Luppi M, Giacobbi F, Medici V, Morselli M, Barozzi P, Marasca R, Torelli G, Emilia G. Cancer Genet Cytogenet. 2000 Jun; 119(2): 121-6. PMID 10867147

Identification of a novel fusion gene, TTL, fused to ETV6 in acute lymphoblastic leukemia with t(12;13)(p13;q14), and its implication in leukemogenesis. Qiao Y, Ogawa S, Hangaishi A, Yuji K, Izutsu K, Kunisato A, Imai Y, Wang L, Hosoya N, Nannya Y, Sato Y, Maki K, Mitani K, Hirai H. Leukemia. 2003 Jun; 17(6): 1112-20. PMID 12764377

Contributor(s) Written 11-2007 Jean-Loup Huret Jean Loup HURET, Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . t(12;13)(p13;q14). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t1213p13q14ID1323.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 874 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Thyroid: Anaplastic (undifferentiated) carcinoma

Identity Note Anaplastic (undifferentiated) carcinoma of the thyroid gland is a highly malignant tumor composed in part or wholly by undifferentiated malignant cells. Clinics and Pathology Epidemiology Anaplastic (undifferentiated) carcinoma of the thyroid gland is uncommon, accounting for less than 5% of all cases of thyroid carcinoma. The average age at diagnosis was 66.5 years, with a female to male ratio of 3.1:1 in one study of 70 cases. Clinics Most patients are euthyroid with a history of a rapidly enlarging neck mass. Sometimes, the tumor presents as a new-onset thyroid enlargement in a patient with longstanding thyroid nodule(s) or as the recurrence of a well-differentiated thyroid carcinoma. Tumor infiltration of surrounding structures results in secondary symptoms (dyspnea, dysphonia, dysphagia). Pathology Tumors are poorly defined, fleshy masses with areas of necrosis and hemorrhage. Microscopically they are composed of anaplastic cells with marked cytologic atypia and high mitotic activity. Tumor necrosis and vascular invasion are common. About one- third of cases of anaplastic thyroid carcinoma (ATC) have coexisting areas of well- differentiated thyroid carcinoma, supporting the hypothesis that ATC arises from well- differentiated thyroid carcinoma. Histologic patterns include spindle, giant and squamoid cell types. Other patterns (e.g. angiomatoid, carcinosarcoma, lymphoepithelioma-like, adenosquamous) have been described. Undifferentiated (anaplastic) carcinoma of the thyroid must be differentiated from other high grade tumors with similar microscopic appearance originating from adjacent structures in the neck (e.g. larynx). Sometimes this distinction is only possible on clinical/anatomical grounds. Immunohistochemically, undifferentiated thyroid carcinoma is generally negative for thyroglobulin and calcitonin. Pankeratin and epithelial membrane antigen (EMA) are positive in about one-half and one-third of cases respectively. Vimentin is positive in about 90%, and epithelial membrane antigen is positive in about 30% of cases. Thyroid transcription factor-1 (TTF-1) staining is present in 0-50% of cases. Although immunostaining is negative for muscle-specific actin, Factor VIII-related antigen, and desmin, these markers can differentiate ATC from some soft tissue sarcomas with which they can be confused.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 875

Anaplastic (undifferentiated) thyroid carcinoma is a highly malignant tumor composed by undifferentiated malignant cells. The inset in the left lower corner shows a magnified view of a cell in metaphase of mitosis. Treatment No effective treatment modalities are currently available. A few patients with resectable disease have been reported to have long-term survival with aggressive multimodal therapy that included surgery, radiation, and chemotherapy. Current clinical practice emphasizes the use of multimodal therapy to achieve local disease control and stabilization of airway patency. Radiotherapy may be hyperfractionated and in combination with chemotherapy. Chemotherapy is usually doxorubicin-based or taxane-based combinations. Preclinical studies using human ATC cell lines show promise that new effective combinations including novel drugs will be found in the future. Prognosis Anaplastic (undifferentiated) carcinomas are highly aggressive neoplasms that are usually widely invasive at presentation. Regional and distant metastases are common, and about 75% of patients have distant metastasis in the course of their disease. Most patients die within 1 year of the diagnosis with a median survival of 3 to 6 months. The 5-year survival rate is around 5%, and the surviving cases are typically small tumors confined to the thyroid amenable to local resection. Cytogenetics Cytogenetics Anaplastic (undifferentiated) carcinoma represents not only morphologically but also in Morphological terms of somatic genetic alterations the extreme malignant form of thyroid cancer and as such it is characterized by complex chromosomal alterations. DNA aneuploidy is present in over 65% of the tumors. Cytogenetics LOH: Allelic loss has been identified at 1q (40%), 9p (58%), 11p (33%), 11q (33%), 17p Molecular (44%), 17q (43%), 19p (36%), 22q (38%). CGH: DNA unbalance can be demonstrated at a variety of chromosomal loci in 80% of undifferentiated carcinomas with a median number of chromosomal losses or gains of 10 per case with abnormal CGH profile. Gains were more common than DNA losses. Loss of chromosomal DNA was identified at 1p, 2q, 4q, 5q, 6q, 8p, 13q, 22q. Specific chromosomal DNA alterations (i.e. 3p13-14+, 5q11-31-, 11q13+) may be associated with the transition from more differentiated phenotypes to ATC. CGH shows frequent gain of 20q, including the UBCH10 gene in 20q13.12, which may also be associated with progression of differentiated thyroid cancers to ATC. Using microarray-based CGH with further fluorescence in situ hybridization (FISH) analysis, the MAP kinase phosphatase-8 (DUSP26) gene, which codes for a phosphatase that inhibits p38-mediated apoptosis, is shown to be amplified in ATC. Genes involved and Proteins Note The genetic mechanisms involved with the development of anaplastic thyroid cancer

Atlas Genet Cytogenet Oncol Haematol 2008; 6 876 are complex. Mutational inactivation of p53 has been identified in 70-80% of anaplastic carcinomas while H-Ras, K-Ras, or N-Ras activating mutations are present in approximately 50% of the cases. BRAF V600E mutation is found in 20% to 25% of cases. PTEN mutations are present in 6%. PIK3CA kinase domain mutations are found in 14%. PIK3CA gene copy amplification is present in 39%. Aberrant Wnt/beta-Catenin signaling appears to be a distinctive feature of ATC since stabilizing mutations and/or aberrant beta-Catenin nuclear localization are present in 80% of ATC. beta-Catenin nuclear localization is accompanied by its cellular redistribution with marked decrease of the beta-Catenin membrane bound fraction. ATC are characterized by increased cell replication and high Ki67/Mib1 proliferation index, loss of the apoptotic protein bcl-2 and of Fas and its ligand (usually highly expressed in well differentiated thyroid tumors), by an increase in the proapoptotic protein Bax, by Cyclin D1 over-expression and conversely by a fall in the CDK inhibitor p27. Transmembrane protein 34 (TMEM34) is down-regulated in ATC. It is not clear whether these changes represent the cause or (more likely) the effect of dysregulated cell differentiation and growth in ATC. Immunohistochemical staining of a tissue microarray of 32 cases of ATC showed the following: beta-catenin (positive in 41% of the cases), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%). Thyroglobulin, Bcl-2, MIB-1, E-cadherin, and p53, beta-catenin, topoisomerase II-alpha, and vascular endothelial growth factor are observed to change during progression from differentiated thyroid cancer to ATC. Bibliography Anaplastic thyroid carcinoma. A study of 70 cases. Carcangiu ML, Steeper T, Zampi G, Rosai J American journal of clinical pathology. 1985 ; 83 (2) : 135-158. PMID 2578727

DNA aneuploidy in anaplastic carcinoma of the thyroid gland. Klemi PJ, Joensuu H, Eerola E American journal of clinical pathology. 1988 ; 89 (2) : 154-159. PMID 3341277

Detection of the H-RAS oncogene in human thyroid anaplastic carcinomas. Stringer BM, Rowson JM, Parkar MH, Seid JM, Hearn PR, Wynford-Thomas D, Ingemansson S, Woodhouse N, Goyns MH Experientia. 1989 ; 45 (4) : 372-376. PMID 2651141

Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Jenkins RB, Hay ID, Herath JF, Schultz CG, Spurbeck JL, Grant CS, Goellner JR, Dewald GW Cancer. 1990 ; 66 (6) : 1213-1220. PMID 2400971

Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Venkatesh YS, Ordonez NG, Schultz PN, Hickey RC, Goepfert H, Samaan NA Cancer. 1990 ; 66 (2) : 321-330. PMID 1695118

Anaplastic thyroid carcinoma. Immunocytochemical study of 32 cases. Ordonez NG, El-Naggar AK, Hickey RC, Samaan NA American journal of clinical pathology. 1991 ; 96 (1) : 15-24. PMID 1712540

Tumors of the thyroid gland. Rosai J, Carcangiu ML, DeLellis RA Atlas of tumor Pathology. 1992.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 877 Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. Donghi R, Longoni A, Pilotti S, Michieli P, Della Porta G, Pierotti MA The Journal of clinical investigation. 1993 ; 91 (4) : 1753-1760. PMID 8473515

High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH, Koeffler HP The Journal of clinical investigation. 1993 ; 91 (1) : 179-184. PMID 8423216

Treatment of 37 patients with anaplastic carcinoma of the thyroid. Kobayashi T, Asakawa H, Umeshita K, Takeda T, Maruyama H, Matsuzuka F, Monden M Head & neck. 1996 ; 18 (1) : 36-41. PMID 8774920

Ras oncogene mutations in thyroid tumors: polymerase chain reaction-restriction-fragment- length polymorphism analysis from paraffin-embedded tissues. Capella G, Matias-Guiu X, Ampudia X, de Leiva A, Perucho M, Prat J Diagnostic molecular pathology. 1996 ; 5 (1) : 45-52. PMID 8919545

DNA copy number changes in thyroid carcinoma. Hemmer S, Wasenius VM, Knuutila S, Franssila K, Joensuu H The American journal of pathology. 1999 ; 154 (5) : 1539-1547. PMID 10329606

N-cadherin-mediated adhesion and aberrant catenin expression in anaplastic thyroid- carcinoma cell lines. Husmark J, Heldin NE, Nilsson M International journal of cancer. 1999 ; 83 (5) : 692-699. PMID 10521809

Downregulation of p27KIP1 and Ki67/Mib1 labeling index support the classification of thyroid carcinoma into prognostically relevant categories. Tallini G, Garcia-Rostan G, Herrero A, Zelterman D, Viale G, Bosari S, Carcangiu ML The American journal of surgical pathology. 1999 ; 23 (6) : 678-685. PMID 10366150

Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Ain KB, Egorin MJ, DeSimone PA Thyroid : official journal of the American Thyroid Association. 2000 ; 10 (7) : 587-594. PMID 10958311

Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. Kitamura Y, Shimizu K, Tanaka S, Ito K, Emi M Genes, chromosomes & cancer. 2000 ; 27 (3) : 244-251. PMID 10679913

Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis. Garcia-Rostan G, Camp RL, Herrero A, Carcangiu ML, Rimm DL, Tallini G The American journal of pathology. 2001 ; 158 (3) : 987-996. PMID 11238046

A phase I pharmacokinetic and translational study of the novel vascular targeting agent

Atlas Genet Cytogenet Oncol Haematol 2008; 6 878 combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Dowlati A, Robertson K, Cooney M, Petros WP, Stratford M, Jesberger J, Rafie N, Overmoyer B, Makkar V, Stambler B, Taylor A, Waas J, Lewin JS, McCrae KR, Remick SC Cancer research. 2002 ; 62 (12) : 3408-3416. PMID 12067983

Genome-wide appraisal of thyroid cancer progression. Wreesmann VB, Ghossein RA, Patel SG, Harris CP, Schnaser EA, Shaha AR, Tuttle RM, Shah JP, Rao PH, Singh B The American journal of pathology. 2002 ; 161 (5) : 1549-1556. PMID 12414503

Phase II study of combretastatin A4 phosphate (CA4P) in patients with advanced anaplastic thyroid carcinoma (ATC). Cooney MM, Savvides P, Agarwala S, Wang D, Flick S, Bergant S, Bhakta S, Lavertu P, Ortiz J, Remick S Journal of Clinical Oncology. 2006 ; 24 : page 300.

Down-regulation of an inhibitor of cell growth, transmembrane protein 34 (TMEM34), in anaplastic thyroid cancer. Akaishi J, Onda M, Okamoto J, Miyamoto S, Nagahama M, Ito K, Yoshida A, Shimizu K Journal of cancer research and clinical oncology. 2007 ; 133 (4) : 213-218. PMID 17072649

A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors. Fury MG, Solit DB, Su YB, Rosen N, Sirotnak FM, Smith RP, Azzoli CG, Gomez JE, Miller VA, Kris MG, Pizzo BA, Henry R, Pfister DG, Rizvi NA Cancer chemotherapy and pharmacology. 2007 ; 59 (4) : 467-475. PMID 16896930

Molecular cytogenetic profiles of novel and established human anaplastic thyroid carcinoma models. Lee JJ, Foukakis T, Hashemi J, Grimelius L, Heldin NE, Wallin G, Rudduck C, Lui WO, Hoog A, Larsson C Thyroid : official journal of the American Thyroid Association. 2007 ; 17 (4) : 289-301. PMID 17465858

Molecular cytogenetic profiles of novel and established human anaplastic thyroid carcinoma models. Lee JJ, Foukakis T, Hashemi J, Grimelius L, Heldin NE, Wallin G, Rudduck C, Lui WO, Hoog A, Larsson C Thyroid : official journal of the American Thyroid Association. 2007 ; 17 (4) : 289-301. PMID 17465858

Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. Santarpia L, El-Naggar AK, Cote GJ, Myers JN, Sherman SI The Journal of clinical endocrinology and metabolism. 2008 ; 93 (1) : 278-284. PMID 17989125

BRAF V600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas. Takano T, Ito Y, Hirokawa M, Yoshida H, Miyauchi A British journal of cancer. 2007 ; 96 (10) : 1549-1553. PMID 17453004

Identification of molecular markers altered during transformation of differentiated into anaplastic thyroid carcinoma.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 879 Wiseman SM, Griffith OL, Deen S, Rajput A, Masoudi H, Gilks B, Goldstein L, Gown A, Jones SJ Archives of surgery (Chicago, Ill. : 1960). 2007 ; 142 (8) : 717-727. PMID 17709725

Anaplastic thyroid carcinoma: expression profile of targets for therapy offers new insights for disease treatment. Wiseman SM, Masoudi H, Niblock P, Turbin D, Rajput A, Hay J, Bugis S, Filipenko D, Huntsman D, Gilks B Annals of surgical oncology. 2007 ; 14 (2) : 719-729. PMID 17115102

A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Yu W, Imoto I, Inoue J, Onda M, Emi M, Inazawa J Oncogene. 2007 ; 26 (8) : 1178-1187. PMID 16924234

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 06-2003 Oluwole Fadare, Giovanni Tallini Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy Updated 11-2007 Sai-Ching Jim Yeung The University of Texas M. D. Anderson Cancer Center, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, Department of Endocrine Neoplasia and Hormonal Disorders, 1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030, USA Citation This paper should be referenced as such : Fadare O, Tallini G . Thyroid: Anaplastic (undifferentiated) carcinoma. Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://AtlasGeneticsOncology.org/Genes/AnaCarciThyroidID5069.html Yeung SCJ . Thyroid: Anaplastic (undifferentiated) carcinoma. Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/AnaCarciThyroidID5069.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 880 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cartilage-hair hypoplasia (CHH)

Identity Other names Metaphyseal chondrodysplasia, McKusick type Inheritance Autosomal rezessive Clinics Note CHH was first described in the Amish, an isolated religious group in the USA by Victor McKusick in 1965. It is a multi-systemic disorder characterized by short stature, blond fine sparse hair, but this may be quite variable, and defective cellular immunity predominantly affecting T-cell mediated responses. Patients may have severe combined immunodeficiency, requiring bone marrow transplantation or they may be asymptomatic. Gastrointestinal dysfunctions are frequently observed such as mal- absorption or Hirschsprung¹s disease. The incidence of CHH in the Amish is 1.5 in 1,000 births, whereas in Finland it is 1 in 18,000 to 23,000 live births. Phenotype and The metaphyses of tubular bones are widened, scalloped and irregularly sclerotic. clinics Delayed ossification and trabeculation of the long bones are also characteristic findings on X-rays. All long bones are affected. The relative length of the humerus, ulna, radius, tibia and fibula decreases rapidly in early childhood and again at puberty. Relatively short and broad phalanges of the hands are observed.

Neoplastic risk A predisposition to certain cancers primarily lymphomas has been reported. Treatment - Disproportionate short stature: Treatment with growth hormone is likely not beneficial in children with CHH. Surgical bone lengthening is occasionally considered. - Orthopedic problems: The lumbar lordosis and ligamentous laxity can cause joint pains of the lower spine, the knees and ankles. - Immunodeficiency: The cellular immunity may be defective whereas the humoral immunity is usually intact. However, there are a few cases that have combined immune

Atlas Genet Cytogenet Oncol Haematol 2008; 6 881 deficiency. - Vaccination: immunization with live vaccines is contraindicated in patients with impaired cellular immunity. - Anemia: Patients with severe anemia (5% of CHH patients) require repeated transfusions. A few cases might need lifelong transfusions and/or bone marrow transplantation. - Gastrointestinal dysfunction: This can present with signs of malabsorption, diarrhea, celiac disease, and failure to thrive. This requires symptomatic treatment. It also may present as Hirschsprung¹s disease that can be surgically corrected. - Malignancies: Patients should be monitored closely, since they have a higher risk of developing lymphomas and leukemias. Prognosis Adult height ranges between 111 and 151 cm in males and between 104 and 137 cm in females. No more than 20% of CHH patients exhibit recurrent and severe infections. These patients show evidence of immune deficiency in vivo and in vitro. Genes involved and Proteins Note CHH is mainly caused by mutations in the RMRP gene, but a Uniparental Disomy of 9p13 has been reported as well in one CHH patient.

Gene Name RMRP (RNA component of Mitochondrial RNA-Processing endoribonuclease) Location 9p13 DNA/RNA Note RMRP is the RNA component of the RNase MRP protein complex. It functions as an RNA and is not translated into a protein.

The RMRP gene is an intronless gene, that is 267 bp long (blue). The promoter region contains a SP1 binding site (violet), an octamer (olive green), a proximal sequence element (PSE) (turquoise) and a TATA box (red). Protein

Atlas Genet Cytogenet Oncol Haematol 2008; 6 882

Expression Strong ubiquitous expression in mouse embryos (E9.5 to E18.5 have been tested) and in adult animals. In bone Rmrp is more strongly expressed in hypertrophic chondrocytes and pericondrium than in the zone of proliferating chondrocytes. There is also very strong expression in the epiphysis. In Xenopus laevis oocytes RMRP is stronger expressed in developmental stages with a higher content of mitochondria. Function The RNase MRP complex is highly conserved among a variety of different species (human, mouse, rat, cow, frog, yeast and plants). Homology The functional analysis of the RNase MRP endoribonuclease is complicated by the fact, that eight proteins are shared by a related ribonucleoprotein complex, called RNase P. RNase P is also a ribonucleprotein endoribonuclease and is mainly involved in rRNA precursor maturation. Mutations Note The most frequently found mutation among CHH patients is a 70 A to G transition mutation with an ancient founder origin established in Finland, a country where the disorder is uncommonly frequent. In fact it is the only mutation found in Amish CHH patients. Over 93 different mutations have been described in CHH patients. These include promoter duplications, triplications and insertions exclusively between the TATA box and the transcription start site. These mutations decrease the RMRP transcription efficiency. Single substitutions are spread out over the entire RMRP transcript. Also small deletions of and insertions in the transcribed region of the gene have been observed as well. These mutations might influence the secondary structure of the RNA, the binding of the proteins to the RNA or the RNA stability. In addition many polymorphisms and rare sequence variants have been observed. This is remarkable considering the very small size of the RMRP gene.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 883 To be noted So far no complete deletion of the entire RMRP gene has been observed. This suggests that complete loss of RMRP function might be incompatible with life. This is also supported by the fact that the knock out in yeast is lethal. Bibliography DWARFISM IN THE AMISH. II. CARTILAGE-HAIR HYPOPLASIA. MCKUSICK VA, ELDRIDGE R, HOSTETLER JA, RUANGWIT U, EGELAND JA Bulletin of the Johns Hopkins Hospital. 1965 ; 116 : 285-326. PMID 14284412

Bone marrow transplantation in cartilage-hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia. Berthet F, Siegrist CA, Ozsahin H, Tuchschmid P, Eich G, Superti-Furga A, Seger RA European journal of pediatrics. 1996 ; 155 (4) : 286-290. PMID 8777921

T cell subsets and T cell function in cartilage-hair hypoplasia. Kooijman R, van der Burgt CJ, Weemaes CM, Haraldsson A, Scholtens EJ, Zegers BJ Scandinavian journal of immunology. 1997 ; 46 (2) : 209-215. PMID 9584003

Uniparental disomy in cartilage-hair hypoplasia. Sulisalo T, Makitie O, Sistonen P, Ridanpaa M, el-Rifai W, Ruuskanen O, de la Chapelle A, Kaitila I European journal of human genetics : EJHG. 1997 ; 5 (1) : 35-42. PMID 9156319

Phalangeal cone-shaped epiphyses of the hand: their natural history, diagnostic sensitivity, and specificity in cartilage hair hypoplasia and the trichorhinophalangeal syndromes I and II. Giedion A Pediatric radiology. 1998 ; 28 (10) : 751-758. PMID 9799296

Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia. Makitie O, Kaitila I, Savilahti E European journal of pediatrics. 1998 ; 157 (10) : 816-820. PMID 9809821

Radiologic changes in infancy in McKusick cartilage hair hypoplasia. Glass RB, Tifft CJ American journal of medical genetics. 1999 ; 86 (4) : 312-315. PMID 10494084

Increased incidence of cancer in patients with cartilage-hair hypoplasia. Makitie O, Pukkala E, Teppo L, Kaitila I The Journal of pediatrics. 1999 ; 134 (3) : 315-318. PMID 10064668

Cartilage-hair hypoplasia syndrome: increased apoptosis of T lymphocytes is associated with altered expression of Fas (CD95), FasL (CD95L), IAP, Bax, and Bcl2. Yel L, Aggarwal S, Gupta S Journal of clinical immunology. 1999 ; 19 (6) : 428-434. PMID 10634217

Anemia in children with cartilage-hair hypoplasia is related to body growth and to the insulin- like growth factor system. Makitie O, Juvonen E, Dunkel L, Kaitila I, Siimes MA The Journal of clinical endocrinology and metabolism. 2000 ; 85 (2) : 563-568. PMID 10690856

Atlas Genet Cytogenet Oncol Haematol 2008; 6 884

[The role of immune deficiency in cartilage-hair hypoplasia] Makitie O, Kaitila I, Pukkala E, Teppo L, Savilahti E Duodecim; laaketieteellinen aikakauskirja. 2000 ; 116 (12) : 1299-1305. PMID 11988965

Deficiency of humoral immunity in cartilage-hair hypoplasia. Makitie O, Kaitila I, Savilahti E The Journal of pediatrics. 2000 ; 137 (4) : 487-492. PMID 11035826

Hirschsprung disease associated with severe cartilage-hair hypoplasia. Makitie O, Kaitila I, Rintala R The Journal of pediatrics. 2001 ; 138 (6) : 929-931. PMID 11391344

Impaired spermatogenesis: an unrecognized feature of cartilage-hair hypoplasia. Makitie OM, Tapanainen PJ, Dunkel L, Siimes MA Annals of medicine. 2001 ; 33 (3) : 201-205. PMID 11370774

Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage- hair hypoplasia. Ridanpaa M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, vanVenrooij W, Pruijn G, Salmela R, Rockas S, Makitie O, Kaitila I, de la Chapelle A Cell. 2001 ; 104 (2) : 195-203. PMID 11207361

RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Bonafe L, Schmitt K, Eich G, Giedion A, Superti-Furga A Clinical genetics. 2002 ; 61 (2) : 146-151. PMID 11940090

The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis. Cai T, Aulds J, Gill T, Cerio M, Schmitt ME Genetics. 2002 ; 161 (3) : 1029-1042. PMID 12136008

Hirschsprung's disease in cartilage-hair hypoplasia has poor prognosis. Makitie O, Heikkinen M, Kaitila I, Rintala R Journal of pediatric surgery. 2002 ; 37 (11) : 1585-1588. PMID 12407544

Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP. Ridanpaa M, Sistonen P, Rockas S, Rimoin DL, Makitie O, Kaitila I European journal of human genetics : EJHG. 2002 ; 10 (7) : 439-447. PMID 12107819

RMRP mutations in Japanese patients with cartilage-hair hypoplasia. Nakashima E, Mabuchi A, Kashimada K, Onishi T, Zhang J, Ohashi H, Nishimura G, Ikegawa S American journal of medical genetics. Part A. 2003 ; 123 (3) : 253-256. PMID 14608646

The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases. Ridanpaa M, Jain P, McKusick VA, Francomano CA, Kaitila I American journal of medical genetics. Part C, Seminars in medical genetics. 2003 ; 121 (1) : 81-83.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 885 PMID 12888988

Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease. Ko DC, Milenkovic L, Beier SM, Manuel H, Buchanan J, Scott MP PLoS genetics. 2005 ; 1 (1) : 81-95. PMID 16103921

Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. Hermanns P, Bertuch AA, Bertin TK, Dawson B, Schmitt ME, Shaw C, Zabel B, Lee B Human molecular genetics. 2005 ; 14 (23) : 3723-3740. PMID 16254002

Severely incapacitating mutations in patients with extreme short stature identify RNA- processing endoribonuclease RMRP as an essential cell growth regulator. Thiel CT, Horn D, Zabel B, Ekici AB, Salinas K, Gebhart E, Ruschendorf F, Sticht H, Spranger J, Muller D, Zweier C, Schmitt ME, Reis A, Rauch A American journal of human genetics. 2005 ; 77 (5) : 795-806. PMID 16252239

The natural history of severe anemia in cartilage-hair hypoplasia. Williams MS, Ettinger RS, Hermanns P, Lee B, Carlsson G, Taskinen M, Makitie O American journal of medical genetics. Part A. 2005 ; 138 (1) : 35-40. PMID 16097009

RMRP mutations in cartilage-hair hypoplasia. Hermanns P, Tran A, Munivez E, Carter S, Zabel B, Lee B, Leroy JG American journal of medical genetics. Part A. 2006 ; 140 (19) : 2121-2130. PMID 16838329

Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia. Hirose Y, Nakashima E, Ohashi H, Mochizuki H, Bando Y, Ogata T, Adachi M, Toba E, Nishimura G, Ikegawa S Journal of human genetics. 2006 ; 51 (8) : 706-710. PMID 16832578

A novel RMRP mutation in a Spanish patient with cartilage-hair hypoplasia. Munoz-Robles J, Allende LM, Clemente J, Calleja S, Varela P, Gonzalez L, de Pablos P, Paz E, Morales P Immunobiology. 2006 ; 211 (9) : 753-757. PMID 17015150

RNase MRP RNA and human genetic diseases. Martin AN, Li Y Cell research. 2007 ; 17 (3) : 219-226. PMID 17189938

Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. Thiel CT, Mortier G, Kaitila I, Reis A, Rauch A American journal of human genetics. 2007 ; 81 (3) : 519-529. PMID 17701897

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 10-2007 Pia Hermanns, Brendan Lee Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza Room 635E, Mail

Atlas Genet Cytogenet Oncol Haematol 2008; 6 886 Stop 225, Houston, TX 77030, USA Citation This paper should be referenced as such : Hermanns P, Lee B . Cartilage-hair hypoplasia (CHH). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CartilageHairHypoID10105.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 887 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)

A case of trisomy 8 and loss of the Y-chromosome as secondary aberrations in a ten year old boy with de novo AML FAB M2 and t(16;21)(q24;q22)

Jutta Bradtke, Peter Vorwerk, Jochen Harbott Clinics Age and sex : 10 year(s) old male patient. Previous History : no preleukemia no previous malignant disease no inborn condition of note Organomegaly : hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; no central nervous system involvement Blood WBC : 34 x 109/l; Hb : 8,2 g/dl; platelets : 57 x 109/l; blasts : 92% Bone marrow : 94% Cyto pathology classification Cytology : M2 without Auer rods; Peroxidase (+) esterase (+) Immunophenotype : CD13+, CD33+ Pathology : - Electron microscopy : - Precise diagnosis : ANLL M2 Survival Date of diagnosis: 06-2007 Treatment : AML BFM Protocol (high risk) Complete remission was obtained Treatment related death : - Relapse : - Status : Alive 09-2007 Karyotype Sample : Bone Marrow ; culture time : two cultures 48 hours ; banding : GTG-Banding Results : 46,X,-Y,+8,t(16;21)(q24;q22) Other molecular studies technics : FISH evaluation for AML1 rearrangement and trisomy 8 was performed on abnormal metaphases after 48h of cultivation with the LSI AML1/ETO Dual Color Probe (Abbott Molecular/Vysis, Inc.). results : ish +8(ETO x 3),der(16)t(16;21)(dimAML1+),der(21)t(16;21)(dimAML1+)

Atlas Genet Cytogenet Oncol Haematol 2008; 6 888 GTG-banded chromosomes which are representing the trisomy 8 and the t(16;21).

DAPI stained and inverted metaphase which shows three signals for ETO (red) and three signals for AML1 (green, one signal splitted). Comments The t(16;21)(q24;q22) is a rare aberration in AML with 16 cases described in the Mitelman-database and it is extreme rare in children (only two cases published). Most of these 16 cases are classified to the FAB M2 subtype and a trisomy 8 was seen as a recurrent secondary aberration of t(16;21). Loss of one sex chromosome as a secondary aberration of t(16;21) has not been described yet. This is to our knowledge the first case of an AML with t(16;21)(q24;q22), trisomy 8 and loss of the Y-chromosome. The specific aberration for AML M2 is the t(8;21)(q22;q22), which shows often a loss of one sex chromosome (seen in 50% of the cases) and in 10% a trisomy 8 as secondary aberrations (Huret, 1997). Maybe the t(16;21)(q24;q21) is a rare equivalent of the t(8;21), because 1) the same gene RUNX1, located on (21)(q22), is involved and has similar genes as translocation partners: RUNX1T1 (ETO) in the t(8;21) and CBFA2T3 in the t(16;21); both are coding for ETO proteins, 2) the t(16;21) occurs often in cases with the same AML M2 morphology, and 3) patients with t(16;21) show the same additional chromosome anomalies (-Y/+8). While trisomy 8 is quite frequent in various leukemias the

Atlas Genet Cytogenet Oncol Haematol 2008; 6 889 loss of the Y chromosome is a very specific secondary aberration of the t(8;21). This is the second described case of a de novo AML M2 with t(16;21)(q24;q22) in childhood AML (Jeandidier E et al., 2006). Internal links Atlas Card t(16;21)(q24;q22) t(16;21)(q24;q22) in therapy-related acute myelogenous leukemia arising from Case Report myelodysplastic syndrome A new case of t(16;21)(q24;q22) in a secondary AML-M2 following breast cancer Case Report therapy Bibliography Cytogenetics of childhood acute nonlymphocytic leukemia. Raimondi SC, Kalwinsky DK, Hayashi Y, Behm FG, Mirro J Jr, Williams DL Cancer genetics and cytogenetics. 1989 ; 40 (1) : 13-27. PMID 2758395

Secondary acute myeloblastic leukemia with t(16;21) (q24;q22). involving the AML1 gene. Berger R, Le Coniat M, Romana SP, Jonveaux P Hematology and cell therapy. 1996 ; 38 (2) : 183-186. PMID 8932000

AML1/MTG16 fusion gene from a t(16;21)(q24;q22) translocation in treatment-induced leukemia after breast cancer. La Starza R, Sambani C, Crescenzi B, Matteucci C, Martelli MF, Mecucci C Haematologica. 2001 ; 86 (2) : 212-213. PMID 11224496

A pediatric case of secondary leukemia associated with t(16;21)(q24;q22) exhibiting the chimeric AML1-MTG16 gene. Kondoh K, Nakata Y, Furuta T, Hosoda F, Gamou T, Kurosawa Y, Kinoshita A, Ohki M, Tomita Y, Mori T Leukemia & lymphoma. 2002 ; 43 (2) : 415-420. PMID 11999578

Metaphase fluorescence in situ hybridization (FISH) in the follow-up of 60 patients with haemopoietic malignancies. Nylund SJ, Ruutu T, Saarinen U, Knuutila S British journal of haematology. 1994 ; 88 (4) : 778-783. PMID 7819102

Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin's disease and non-Hodgkin's lymphoma. Traweek ST, Slovak ML, Nademanee AP, Brynes RK, Niland JC, Forman SJ Blood. 1994 ; 84 (3) : 957-963. PMID 8043877

A recurrent translocation, t(16;21)(q24;q22), associated with acute myelogenous leukemia: identification by fluorescence in situ hybridization. Shimada M, Ohtsuka E, Shimizu T, Matsumoto T, Matsushita K, Tanimoto F, Kajii T Cancer genetics and cytogenetics. 1997 ; 96 (2) : 102-105. PMID 9216714

A case of therapy-related acute myeloblastic leukemia with t(16;21)(q24;q22) after chemotherapy with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and the alkylating agent, cyclophosphamide. Takeda K, Shinohara K, Kameda N, Ariyoshi K International journal of hematology. 1998 ; 67 (2) : 179-186. PMID 9631585

AML1-MTG16 fusion gene in therapy-related acute leukemia with t(16;21)(q24;q22): two new cases.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 890 Salomon-Nguyen F, Busson-Le Coniat M, Lafage Pochitaloff M, Mozziconacci J, Berger R, Bernard OA Leukemia. 2000 ; 14 (9) : 1704-1705. PMID 10995019

Abnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Francais de Cytogenetique Hematologique. Jeandidier E, Dastugue N, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Herens C, Michaux L, Verellen-Dumoulin C, Talmant P, Cornillet-Lefebvre P, Luquet I, Charrin C, Barin C, Collonge-Rame MA, Perot C, Van den Akker J, Gregoire MJ, Jonveaux P, Baranger L, Eclache-Saudreau V, Pages MP, Cabrol C, Terre C, Groupe Francais de Cytogenetique Hematologique (GFCH), Berger R Cancer genetics and cytogenetics. 2006 ; 166 (1) : 1-11. PMID 16616106

A patient with de novo AML M1 and t(16;21) with karyotype evolution. Zatkova A, Fonatsch C, Sperr WR, Valent P Leukemia research. 2007 ; 31 (9) : 1319-1321. PMID 17126398 t(8;21)(q22;q22). Huret JL Atlas Genet Cytogenet Oncol Haematol..

Contributor(s) Written 11-2007 Jutta Bradtke, Peter Vorwerk, Jochen Harbott Citation This paper should be referenced as such : Bradtke J, Vorwerk P, Harbott J . A case of trisomy 8 and loss of the Y-chromosome as secondary aberrations in a ten year old boy with de novo AML FAB M2 and t(16;21)(q24;q22). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Reports/1621BradtkeID100031.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 891 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Evolution

*

I. Cuvier and the fixism theory (1769-1832)

II. Lamarck and the transformism theory (1744-1829)

III. Darwin and the Evolution (1809-1882)

III.1. The inferences of the Darwin theory French III.2. The implications of the Darwin theory

III.3. After Darwin

IV. Population Genetics

IV.1. Hypothesis

IV.2. Role of diverse factors (evolutionary forces) on the allele frequency variation through generations

*

I. Cuvier and the fixism theory (1769-1832)

• Fixism and Creationism. Until the 19th century in Occident, the most largely believed theory was fixism. The species always are what they have been since their creation. They are fixe and never change because the world has been created by God. This theory is similar to creationism.

II. Lamarck and the transformism theory (1744-1829)

• In contact with nature the organisms acquire capacities to become more and more complex. • Nature generates circumstances that forces organisms to change to be adapted to their environment (these circumstances are called the Lamarckian factors). • The transformism or the assertion of a principle of change.

1. The compared morpho-anatomy and the palaeontology show that the organisation of the living organisms follows a scale of complexity. 2. "Time and circumstances" are at the origin of the gradually change observed in the fossil series. 3. This gradual transformation indicates a relationship between related species.

III. Darwin and the Theory of Evolution (1809-1882)

III.1. The inferences of Darwin theory

1. Environmental resources are limited for an increasing number of individuals.

Atlas Genet Cytogenet Oncol Haematol 2008; 6 892 2. The survival is not due to random, but depends on the hereditary constitution of the individuals. 3. The natural selection that takes effect on the countless successive generations is the beginning of a slow and continuous change of populations.

III.2. The implications of the Darwin theory

4. Refutation of Fixism. 5. Refutation of Essentialism. 6. Refutation of Creationism. 7. Refutation of Anthropocentrism. 8. A classification based on genealogy.

III.3. After Darwin

9. The non-inheritance of acquired characters (Weismann 1883). 10. The genetic foundations of heredity. 11. The population genetics.

IV. Population Genetics

IV.1. Hypothesis

o Does a genetic polymorphism exist in natural populations? o Which models are able to describe the allele frequencies in these populations? o Which natural selections modify these allele frequencies?

IV.2. Role of diverse factors (evolutionary forces) on the allele frequencies variation through generations

IV.2.1. Hardy-Weinberg Model (basic model)

. Random mating (gametes and individuals): the panmictic hypothesis. . No mutation or migration. . No selection. . Population of infinite size.

Under these conditions the allele frequencies do not vary.

IV.2.2. Impact of Consanguinity

. Mating occurs according to the lineage with for consequence the existence of common ancestor(s). . Mating occurs between related. In this case, their descendants are consanguineous. . The consanguinity increases the probability to constitute homozygous genotypes. . Repeated consanguine mating leads to the homogenisation of populations and therfore to the no maintenance of the genetic polymorphism.

IV.2.3. Impact of Genetic drift

. The genetic drift leads to a homogenisation of populations and therefore not to the maintenance of the genetic polymorphism.

IV.2.4. Impact of selection

Atlas Genet Cytogenet Oncol Haematol 2008; 6 893 The differential selection between phenotypes (and thus between genotypes) leads to the fixation of an advantaged allele, if the selective value of the homozygous for this allele is higher than any of the others genotypes or it leads to the maintenance of a genetic polymorphism, if the selective value of the heterozygous is higher than the others genotypes.

IV.2.5. Combine impact of the genetic drift and mutations: The neutral theory of evolution

. Mr Motoo Kimura (1924 - 1994) proposes a model in which the different mutations have no differential impact on the survival of the bearer. The mutations are selectively neutral. . These mutations occur randomly and disappear more or less quickly depending on the action of genetic drift, according to the population size which is always constant (N individuals, 2N gametes). . No selection --> the alleles are selectively neutral. . Mutations: the neutral mutation rate (µ) (for a locus and by generation, it is 10- 5- 10-6). . Model: with an infinite number of alleles. . These results are based on several hypothesis:

* Constant accumulation of mutations (molecular clock hypothesis). * There are as many alleles lost by genetic drift as new alleles produce by mutation (equilibrium mutation drift). * The process of fixation can be extremely long (4N generations). * 4N = the average time for a new neutral allele to replace the former. Then, the time for this allele to be fixed is of 4N generations (N the population size) (coalescence time). * 1/µ = the substitution time for a new neutral allele to replace the former (in number of generations). * The fixations are probably concentrated when the specie is constituted of few individuals (as in its beginning) during the process of speciation.

IV.2.6. The new synthesis theory of evolution or the evolutionary synthesis It was elaborated in the 40-50’s and it modifies and improves Darwin theory.

It is Theodosius Dobzhansky (1900-1975), (naturalist then geneticist) who revised the evolutionism. In his book "Genetics and the Origin of Species", he

Atlas Genet Cytogenet Oncol Haematol 2008; 6 894 considers that under the action of natural selection, all the evolutionary phenomena are the result of change in the gene frequency within the line.

Gradual evolution is explained by the interactions between mutations and recombination through the screen of natural selection.

Contributor(s) Written 03-2008 Robert Kalmes Institut de Recherche sur la Biologie de l'Insecte, IRBI - CNRS - ESA 6035, Av. Monge, F-37200 Tours, France Citation This paper should be referenced as such : Kalmes R . Evolution. Atlas Genet Cytogenet Oncol Haematol. March 2008 . URL : http://AtlasGeneticsOncology.org/Educ/EvolutionID30026ES.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 6 895