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The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

Staff Mohammad Ahmad, Mélanie Arsaban, Marie-Christine Jacquemot-Perbal, Vanessa Le Berre, Anne Malo, Carol Moreau, Catherine Morel-Pair, Laurent Rassinoux, Alain Zasadzinski. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008.

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Jean-Loup Huret (Poitiers, France) Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section Alessandro Beghini (Milan, Italy) Genes Section Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections Judith Bovée (Leiden, The Netherlands) Solid Tumours Section Vasantha Brito-Babapulle (London, UK) Leukaemia Section Charles Buys (Groningen, The Netherlands) Deep Insights Section Anne Marie Capodano (Marseille, France) Solid Tumours Section Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections Antonio Cuneo (Ferrara, Italy) Leukaemia Section Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section Brigitte Debuire (Villejuif, France) Deep Insights Section François Desangles (Paris, France) Leukaemia / Solid Tumours Sections Enric Domingo-Villanueva (London, UK) Solid Tumours Section Ayse Erson (Ankara, Turkey) Solid Tumours Section Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections Anne Hagemeijer (Leuven, Belgium) Deep Insights Section Nyla Heerema (Colombus, Ohio) Leukaemia Section Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections Sakari Knuutila (Helsinki, Finland) Deep Insights Section Lidia Larizza (Milano, Italy) Solid Tumours Section Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section Edmond Ma (Hong Kong, China) Leukaemia Section Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section Fredrik Mertens (Lund, Sweden) Solid Tumours Section Konstantin Miller (Hannover, Germany) Education Section Felix Mitelman (Lund, Sweden) Deep Insights Section Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section Mariano Rocchi (Bari, Italy) Genes Section Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section Albert Schinzel (Schwerzenbach, Switzerland) Education Section Clelia Storlazzi (Bari, Italy) Genes Section Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections Dan Van Dyke (Rochester, Minnesota) Education Section Roberta Vanni (Montserrato, Italy) Solid Tumours Section Franck Viguié (Paris, France) Leukaemia Section José Luis Vizmanos (Pamplona, Spain) Leukaemia Section Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections

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Volume 17, Number 11, November 2013

Table of contents

Gene Section

ITGA6 (integrin, alpha 6) 731 Young Hwa Soung, Jun Chung MITF (microphthalmia-associated transcription factor) 735 Nicole D Riddle, Paul Zhang PHOX2B (paired-like homeobox 2b) 740 Tiziana Bachetti, Isabella Ceccherini SGOL1 (shugoshin-like 1 (S. pombe)) 746 Tomoaki Kahyo, Haruhiko Sugimura CXCL5 (chemokine (C-X-C motif) ligand 5) 749 Anna A Bulysheva, W Andrew Yeudall MIR211 (microRNA 211) 753 Amir Avan, Mina Maftouh, Godefridus J Peters, Elisa Giovannetti SRD5A2 (steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)) 757 Nelson LS Tang, Chen Di Liao SSX2 (synovial sarcoma, X breakpoint 2) 759 Josiane Eid, Christina Garcia, Andrea Frump

Leukaemia Section t(6;9)(p23;q34) DEK/NUP214 766 Jean-Loup Huret t(6;7)(p25.3;q32.3) DUSP22/FRA7H 770 Sarah H Johnson, George Vasmatzis, Andrew L Feldman

Solid Tumour Section

Fallopian tube tumors: an overview 773 Roland Gregor Stein, Joachim Diessner, Arnd Hönig, Jörg Wischhusen, Johannes Dietl

Cancer Prone Disease Section

Familial Juvenile Polyposis Syndrome 788 Scott K Sherman, James R Howe

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) Atlas of Genetics and Cytogenetics

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Deep Insight Section

Premature Chromosome Condensation (PCC): Tools in chromosome and cytogenetic research 791 Eisuke Gotoh

Case Report Section

Homogeneously Staining Region (HSR) harboring CMYC amplification in a patient with primary plasma cell leukemia 799 Nusrat F Pathan, Margarita Palutke, Anwar N Mohamed

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Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) Atlas of Genetics and Cytogenetics

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Gene Section Review

ITGA6 (integrin, alpha 6) Young Hwa Soung, Jun Chung Louisiana State University Health Sciences Center - Shreveport, Dept of Biochemistry and Molecular Biology, 1501 Kings Highway PO Box 33932, Shreveport, LA 71130-3932, USA (YHS, JC)

Published in Atlas Database: April 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/ITGA6ID41007ch2q31.html DOI: 10.4267/2042/51810 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Transcription The ITGA6 gene has 2 transcript variants encoding two Other names: CD49f, ITGA6B, VLA-6 different isoforms. HGNC (Hugo): ITGA6 Transcript variant 1 (NCBI Accession Location: 2q31.1 NM_001079818) encodes the longer isoform a (NP_001073286) comprised of 25 exons. DNA/RNA Transcript variant 2 (NCBI Accession NM_000210.2) encodes the shorter isoform b (NP_000201) comprised Description of 26 exons which has a distinct C-terminus with an ITGA6 (Gene ID: 3655) is located on chromosome 2 at alterative coding exon compared to isoform a. 2q31.1. Pseudogene Gene ranges from 173292314 to 173371181 on the plus There are no known pseudogenes. strand with a total length of 78870 bp.

Figure 1. Schematic diagram of ITGA6 location on chromosome 2. Chromosome 2 is represented with banding pattern. ITGA6 is located at 31.1 and ranges from 173292314 to 173371181 on reverse strand. The region surrounding ITGA6 is enlarged. Genes are represented by arrows in the direction of transcription.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 731 ITGA6 (integrin, alpha 6) Soung YH, Chung J

Protein Homology Mouse, rat and human homologs of ITGA6 share Note greater than 90% amino acid identity. The integrin alpha6 gene encodes for a protein of 10733 amino acid residues (NP_000201), with a Mutations molecular mass of 119,467 kDa (P23229; UniProKB). It contains a signal peptide, extracellular domain, Note transmembrane domain and a cytoplasmic domain. A homozyous 1-bp deletion mutation (791delC) have Description been identified in an infant with epidermolysis bullosa with pyloric atresia and esophageal stenosis (Ruzzi et The integrin alpha 6subunit consists of a heavy and a al., 1997). light chain linked by a disulfide bond. It forms heterodimers with beta-1 or beta-4 integrin subunits to Implicated in make α6β1 integrin or α6β4 integrin. Expression Glioblastoma multiforme α6β4 integrin is widely expressed in epithelia and in a Note few other cell types such as thymocytes, fibloblasts, Lathia et al identified integrin α6 as a hallmark of and Schwann cells. α6β1 integrin is expressed in glioblastoma stem cells (GSCs) (Lathia et al., 2010). In platelets, leukocytes and many epithelial cells. this study, authors find that integrin α6 is co-expressed with conventional GSC markers such as CD15 and Localisation CD133, and localized to the perivascular compartment. Cell surface and hemidesmosome (Sonnenberg et al., However, integrin α6 expression enriches for GSCs 1991; Alt et al., 2001; Geuijen and Sonnenberg, 2002). lacking CD133 expression. Combining expression of Function both CD133 and integrin α6 led to higher enrichment of GSCs than CD133 alone did. shRNA mediated Both α6β1 integrin and α6β4 integrin are receptors for knockdown of integrin α6 expression results in a the laminin family of extracellular matrix proteins. reduction of GSC phenotype such as GSC self renewal α6β4 integrin in epithelial cells plays an essential role and tumor formation. The results suggest that integrin in strengthening and stabilizing the skin tissue through α6 is a promising target for antiglioblastoma therapy. the formation of hemidesmosome (Dowling et al., 1996; Nievers et al., 1999; Sterk et al., 2000). α6β1 Disease integrin contributes to the formation of organs and Glioblastoma Multiforme (GBM) is the most common tissues before birth (Georges-Labouesse et al., 1996; and malignant primary brain tumor with poor prognosis Niculescu et al., 2011). In malignant carcinoma cells, (Singh et al., 2004). both of these integrins serve as signaling receptors that Upon diagonosis, 5 year survival rate is less the 3%. triggers signaling cascades that enhance survival, GBM is almost incurable because it is cellular invasion and metastasis (reviewed in Mercurio et al., heterogeneous and GBM mass invade functional brain 2001). area, which makes impossible for the surgeons to totally remove the cancer tissues.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 732 ITGA6 (integrin, alpha 6) Soung YH, Chung J

Also, it is resistant to the radiation and other cleavage of integrin α6 in uPA induced manner treatments (Stupp et al., 2005). Recently, Integrin α6 (Rabinovitz et al., 1995; Demetriou et al., 2004; garnered a lot of attention as potential candidate for Pawar., 2007; Ports et al., 2009). effective glioblastoma therapeutic target due to its high Disease expression in neural stem cells and ability to interact It is the form of cancer that develops in a gland in the with laminin (Lathia et al., 2010). male reproductive system. Breast cancer While a majority of prostate cancer grow slowly, some Note cases of aggressive prostate cancer involve metastasis to the bones and lymph nodes. Both α6β1 integrin and α6β4 integrin contribute to Prostate cancer usually occurs in older men. survival of breast carcinoma cells under stress No early symptoms are reported in many cases of conditions (Chung et al., 2002; Chung and Mercurio, prostate cancer, but some patients may experience 2004) through upregulation of VEGF expression, either urinary symptoms and discomfort. at the level of transcription or translation. The α6β4 Treatment options include surgery, chemotherapy, integrin dependent translation of VEGF derives from crytherapy, hormonal therapy, and/or radiation. the ability of this integrin to stimulate AKT/mTOR pathway (Chung et al., 2002). Under hypoxic Epidermolysis bullosa letalis with condition, the α6β1 integrin is required for pyloric atresia (EB-PA) transcriptional activation of VEGF via HIF-1 (Chung et Note al., 2004). α6β4 integrin is implicated in invasion and EB-PA is a rare autosomal recessive genetic disease metastasis of breast carcinoma cells via activation of with a poor progonosis. PI3K/AKT pathway when it is mobilized from It represents frequently lethal, epidermolysis bullosa hemidesmosome into leading edges (Lipscomb et al., with variable involvement of skin, nails, mucosa. 2005). EB-PA is caused by defects in ITGA6. Disease The mutations in the genes encoding two subunit It is the most common cancer among women and the polypeptides of the α6β4 integrin (ITGA 6 and ITGA4) second leading cause of cancer deaths of women in US. have been reported in the patients with EB-PA (Chung Breast cancer is 100 times more common in women and Uitto, 2010). than in men. Despite of its mortality, it is mostly Disease curable disease when it is detected at early stages. Mucocutaneous fragility, aplasia cutis congenita, and Microarray gene expression analysis defines four gastrointestinal atresia are common symptoms that distinct sub-types of breast cancer, including hormone affects the pylorus. receptor (HR) positive luminal A and B, human epidermal growth receptor 2 (HER2/neu)-enriched and basal-like breast cancer (BLBC) (Perou et al., 2000). References BLBC represent 17% to 37% of all breast cancers and Sonnenberg A, Calafat J, Janssen H, Daams H, van der Raaij- is one of the most aggressive breast cancer sub-types Helmer LM, Falcioni R, Kennel SJ, Aplin JD, Baker J, Loizidou with poor prognosis (Irvin and Carey, 2008). M. Integrin alpha 6/beta 4 complex is located in Expression of α6β4 integrin significantly correlates hemidesmosomes, suggesting a major role in epidermal cell- basement membrane adhesion. J Cell Biol. 1991 with BLBC (Lu et al., 2008). May;113(4):907-17 Prognosis Friedrichs K, Ruiz P, Franke F, Gille I, Terpe HJ, Imhof BA. High expression of integrin α6 in women with breast High expression level of alpha 6 integrin in human breast cancer significantly correlated with reduced survival carcinoma is correlated with reduced survival. Cancer Res. times (Friedrich et al., 1995; Chung and Mercurio, 1995 Feb 15;55(4):901-6 2004). Rabinovitz I, Nagle RB, Cress AE. Integrin alpha 6 expression Co-expression of α6β4 integrin and laminin in breast in human prostate carcinoma cells is associated with a tumors has been correlated with poor prognosis migratory and invasive phenotype in vitro and in vivo. Clin Exp Metastasis. 1995 Nov;13(6):481-91 (Tagliabue et al., 1998). Co-expression of both α6β4 integrin and Net1 (RhoA- Dowling J, Yu QC, Fuchs E. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J specific guanine nucleotide exchange factor) is Cell Biol. 1996 Jul;134(2):559-72 correlated with a high risk of distant metastasis in patients with hormone receptor-positive tumors Georges-Labouesse E, Messaddeq N, Yehia G, Cadalbert L, Dierich A, Le Meur M. Absence of integrin alpha 6 leads to (Gilcrease et al., 2009). epidermolysis bullosa and neonatal death in mice. Nat Genet. Prostate cancer 1996 Jul;13(3):370-3 Note Ruzzi L, Gagnoux-Palacios L, Pinola M, Belli S, Meneguzzi G, D'Alessio M, Zambruno G. A homozygous mutation in the Integrin α6β1 contributes to migration and invasion of integrin alpha6 gene in junctional epidermolysis bullosa with protsate cancer cells through cell surface pyloric atresia. J Clin Invest. 1997 Jun 15;99(12):2826-31

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 733 ITGA6 (integrin, alpha 6) Soung YH, Chung J

Tagliabue E, Ghirelli C, Squicciarini P, Aiello P, Colnaghi MI, Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Ménard S. Prognostic value of alpha 6 beta 4 integrin Henkelman RM, Cusimano MD, Dirks PB. Identification of expression in breast carcinomas is affected by laminin human brain tumour initiating cells. Nature. 2004 Nov production from tumor cells. Clin Cancer Res. 1998 18;432(7015):396-401 Feb;4(2):407-10 Lipscomb EA, Mercurio AM. Mobilization and activation of a Nievers MG, Schaapveld RQ, Sonnenberg A. Biology and signaling competent alpha6beta4integrin underlies its function of hemidesmosomes. Matrix Biol. 1999 Feb;18(1):5-17 contribution to carcinoma progression. Cancer Metastasis Rev. 2005 Sep;24(3):413-23 Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Børresen-Dale AL, Brown PO, Botstein D. Molecular portraits Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, of human breast tumours. Nature. 2000 Aug Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. 17;406(6797):747-52 Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96 Sterk LM, Geuijen CA, Oomen LC, Calafat J, Janssen H, Sonnenberg A. The tetraspan molecule CD151, a novel Pawar SC, Demetriou MC, Nagle RB, Bowden GT, Cress AE. constituent of hemidesmosomes, associates with the integrin Integrin alpha6 cleavage: a novel modification to modulate cell alpha6beta4 and may regulate the spatial organization of migration. Exp Cell Res. 2007 Apr 1;313(6):1080-9 hemidesmosomes. J Cell Biol. 2000 May 15;149(4):969-82 Irvin WJ Jr, Carey LA. What is triple-negative breast cancer? Alt A, Ohba M, Li L et al.. Protein kinase Cdelta-mediated Eur J Cancer. 2008 Dec;44(18):2799-805 phosphorylation of alpha6beta4 is associated with reduced integrin localization to the hemidesmosome and decreased Lu S, Simin K, Khan A, Mercurio AM. Analysis of integrin beta4 keratinocyte attachment. Cancer Res. 2001 Jun 1;61(11):4591- expression in human breast cancer: association with basal-like 8 tumors and prognostic significance. Clin Cancer Res. 2008 Feb 15;14(4):1050-8 Mariotti A, Kedeshian PA, Dans M, Curatola AM, Gagnoux- Palacios L, Giancotti FG. EGF-R signaling through Fyn kinase Gilcrease MZ, Kilpatrick SK, Woodward WA, Zhou X, Nicolas disrupts the function of integrin alpha6beta4 at MM, Corley LJ, Fuller GN, Tucker SL, Diaz LK, Buchholz TA, hemidesmosomes: role in epithelial cell migration and Frost JA. Coexpression of alpha6beta4 integrin and guanine carcinoma invasion. J Cell Biol. 2001 Oct 29;155(3):447-58 nucleotide exchange factor Net1 identifies node-positive breast cancer patients at high risk for distant metastasis. Cancer Mercurio AM, Rabinovitz I, Shaw LM. The alpha 6 beta 4 Epidemiol Biomarkers Prev. 2009 Jan;18(1):80-6 integrin and epithelial cell migration. Curr Opin Cell Biol. 2001 Oct;13(5):541-5 Ports MO, Nagle RB, Pond GD, Cress AE. Extracellular engagement of alpha6 integrin inhibited urokinase-type Chung J, Bachelder RE, Lipscomb EA, Shaw LM, Mercurio plasminogen activator-mediated cleavage and delayed human AM. Integrin (alpha 6 beta 4) regulation of eIF-4E activity and prostate bone metastasis. Cancer Res. 2009 Jun VEGF translation: a survival mechanism for carcinoma cells. J 15;69(12):5007-14 Cell Biol. 2002 Jul 8;158(1):165-74 Chung HJ, Uitto J. Epidermolysis bullosa with pyloric atresia. Geuijen CA, Sonnenberg A. Dynamics of the alpha6beta4 Dermatol Clin. 2010 Jan;28(1):43-54 integrin in keratinocytes. Mol Biol Cell. 2002 Nov;13(11):3845- 58 Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macswords J, Wu Q, Vasanji A, McLendon RE, Hjelmeland Chung J, Mercurio AM. Contributions of the alpha6 integrins to AB, Rich JN. Integrin alpha 6 regulates glioblastoma stem breast carcinoma survival and progression. Mol Cells. 2004 cells. Cell Stem Cell. 2010 May 7;6(5):421-32 Apr 30;17(2):203-9 Niculescu C, Ganguli-Indra G, Pfister V, Dupé V, Messaddeq Chung J, Yoon S, Datta K, Bachelder RE, Mercurio AM. N, De Arcangelis A, Georges-Labouesse E. Conditional Hypoxia-induced vascular endothelial growth factor ablation of integrin alpha-6 in mouse epidermis leads to skin transcription and protection from apoptosis are dependent on fragility and inflammation. Eur J Cell Biol. 2011 Feb-Mar;90(2- alpha6beta1 integrin in breast carcinoma cells. Cancer Res. 3):270-7 2004 Jul 15;64(14):4711-6 This article should be referenced as such: Demetriou MC, Pennington ME, Nagle RB, Cress AE. Extracellular alpha 6 integrin cleavage by urokinase-type Soung YH, Chung J. ITGA6 (integrin, alpha 6). Atlas Genet plasminogen activator in human prostate cancer. Exp Cell Res. Cytogenet Oncol Haematol. 2013; 17(11):731-734. 2004 Apr 1;294(2):550-8

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Gene Section Review

MITF (microphthalmia-associated transcription factor) Nicole D Riddle, Paul Zhang Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA (NDR), Department of Pathology, University of Pennsylvania Health System, Philadelphia, PA, USA (PZ)

Published in Atlas Database: April 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/MITFID44193ch3p13.html DOI: 10.4267/2042/51811 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Exon 1 is variable and the domains within it are the Identity transactivation domain (TAD) and the beta-helix-loop- Other names: CMM8, MI, WS2, WS2A, bHLHe32 helix-zipper (B-HLH-Zip). Location: 3p14.1 Some isoforms are specific for certain cells types, i.e. M: melanocytes, MC: mast cells (Levy et al., 2006). Local order: The MITF gene is located between the genes PDHB (telomeric) and PROK2 (centromeric). Protein Note: Total size: 228903 bps. MITF has 18 transcripts and encodes a transcription Description factor that contains both a helix-loop-helix structure as 526 aa, 58795 Da. well as a leucine zipper. Regulates the differentiation and development of Target genes: MITF has been shown to recognize the melanocytes, neural crest-derived cells, retinal E-box (CAYRTG) and M-box (TCAYRTG or epithelium (optic cup-derived retinal pigment CAYRTGA) sequences in the promoter regions of epithelium), mast cells, and osteoclasts (Lin and Fisher, multiple target genes, including ACP5, BCL2, BEST1, 2007; Adijanto et al., 2012). BIRC7, CDK2, CLCN7, DCT, EDNRB, GPNMB, Post translational modifications: GPR143, MC1R, MLANA, OSTM1, RAB27A, SILV, - Phosphorylation at Ser-405 significantly enhances the SLC45A2, TBX2, TRPM1, TYR and TYRP1 (Hoek et ability to bind the tyrosinase promoter. al., 2008b). - Phosphorylation at Ser-180 and Ser-516 by MAPK and RPS6KA1 activate the transcription factor activity DNA/RNA and promote ubiquitiniation and subsequent degradation. Description - Can be deubiquitinated by USP13, preventing its The gene encompasses 229 kb, and has 9 exons. degradation. Transcription Expression Nine different isoforms have been described for MITF, Found in most human tissues. each with different 5' specificity (MITF -A, -J, -C, - Particularly high quantities in retina, uterus, pineal MC, -E, -H, -D, -B, -M). gland, and adipocytes (biogps.org). All isoforms have exons 2-9 in common, encoding the functional domains of the transcription factors. Localisation Nucleus.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 735 MITF (microphthalmia-associated transcription factor) Riddle ND, Zhang P

Function However, MITF also has anti-proliferative properties by way of inducing cell-cycle arrest by activating A transcription factor that activates the transcription of cyclin-dependent kinase inhibitor 1A and 2A tyrosinase and tyrosinase-related protein 1 (TYRP1), (CDKN1A/p21, CDKN2A/p16) (Carreira et al., 2005; and dopachrome tautomerase (DCT). These are Loercher et al., 2005). enzymes that are specifically expressed in melanocytes It has believed that both depletion and over-expression (Yasumoto et al., 1995). For tyrosinase, MITF binds to inhibit proliferation whereas normal levels promote a symmetrical DNA sequence found in the promoter proliferation (Kido et al., 2009). region: a restricted subset of E-box motives containing MITF also has important roles in osteoclast and mast canonical CATGTG sequence flanked by a 5' cell development and function. thymidine (Aksan and Goding, 1998). In osteoclasts it activates transcription of functional The regulation of the DCT promoter is even more proteins tartrate-resistant alkaline phosphatase (TRAP), complex and involves other proteins like CREB and cathepsin K, OSCAR, e-cadherin, OSTM1 and CLCN7 SOX10; and PAX3 has an inhibitory effect on DCT (Meadows et al., 2007). activation by MITF (Bertolotto et al., 1998; Ludwig et In mast cells MITF activates the transcription of mast al., 2004; Lang et al., 2005). cell proteases 2,4,5,6, and 9, granzyme B, tryptophan Not only does MITF activate genes involved in melanin hydroxylase, and kit, all important for differentiation synthesis, it also activates the transcription of genes and function (Kitamura et al., 2006). involved in melanosome structure (PMEL17, MART- Up-stream regulation: LysRS-Ap4A-MITF signaling 1), biogenesis (ocular albinism type 1 gene), and pathway (Lee et al., 2004); Wnt signaling pathway transport (RAB27A) (Du et al., 2003; Vetrini et al., (Takeda et al., 2000); alpha melanocyte-stimulating 2004; Chiaverini et al., 2008). Also, MITF activates the hormone signaling pathway (Bertolotto et al., 1998). transcription of the melanocortin 1 receptor gene which encodes a melanocyte-stimulating hormone receptor Homology normally present on the plasma membrane of High homology to TFE genes (TFE3, TFEB, TFEC, melanocytes: this binding is the first step in the etc.) and the myc family of bHLH transcription factors hormonal regulation of pigmentation (Vachtenheim and (Dickson et al., 2011). Borovansky, 2010). In addition, MITF plays a role in apoptosis through several target genes, showing importance of MITF in Mutations melanocyte development and survival. Note MITF controls the transcription of BCL-2, and known The MITF promoter is partially regulated by certain inhibitor of apoptosis (McGill et al., 2002). Therefore, transcription factors such as PAX3, SOX10, LEF- MITF mutation may explain the reduced number of 1/TCF and CREB during development. melanocytes in certain disorders (Samija et al., 2010). Mutations affecting the MITF and the MITF pathway MITF also induces transcription of melanoma- lead to pigmentary and auditory defects (Cimadamore inhibitor-of-apoptosis (BIRC7, ML-IAP) (Dynek et al., et al., 2012; Pierrat et al., 2012). 2008). Furthermore, it regulates a receptor for hepatocyte growth factor (MET), whose activation Germinal inhibits melanocyte apoptosis (Beuret et al., 2007). Mutations in the MITF at germline will lead to MITF also plays a role in melanocyte proliferation by syndromes with pigmentary and/or auditory defects. regulating several genes involved in the cell-cycle: Mutations in MITF are also known to give a cyclin-dependant kinase 2 (CDK2), transcription factor predisposition to certain cancers, including melanoma TBX2, and Dia1 protein (Diaph1). and renal cell carcinoma (Bertolotto et al., 2011). These promote cell-cycle progression, prevent Heterozygous mutations lead to auditory/pigmentary senescence and cell-cycle arrest, and increase cellular syndromes such as Waardenburg type 2 and Tietz proliferation, respectively (Du et al., 2004; Carreira et syndrome (Lin and Fisher, 2007). al., 2005; Carreira et al., 2006).

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 736 MITF (microphthalmia-associated transcription factor) Riddle ND, Zhang P

Associated with Von Hippel-Lindau syndrome: a rare, Implicated in autosomal dominant disease predisposing to clear cell Melanoma renal cell carcinoma, as well as hemangioblastomas, pheochromocytomas, pancreatic cysts and Note neuroendocrine tumors, endolymphatic sac tumors, and A malignant neoplasm of melanocytes, arising either a general increase risk in cancer; results from mutation from pre-existing benign nevi or de novo and occurring of the VHL tumor suppressor gene on chromosome 3p. most commonly on the skin, but may occur in other A subset of renal cell carcinomas, more common in locations. children, are associated with TFE3 mutations, a There have been linkage and genome wide association member of the microphthalmia (MIT) family, closely studies (GWAS) studies that have shown no evidence related to MITF. to implicate MITF in melanoma (Gillanders et al., Recent studies have shown that the same MITF 2003; Bishop et al., 2009). However, MITF has been mutation associated with increased risk of melanoma shown to be mutated in a subset of melanomas and (E318K) also leads to increased risk of renal cell overexpressed in others (Garraway et al., 2005; Cronin carcinoma (Bertolotto et al., 2011). However, it is et al., 2009). This raises the possibility of MITF's unclear at this time the role that MITF in particular involved despite the lack of prior evidence for germline plays in renal tumors. It may be that this mutation leads risk. Indeed, individuals with a specific MITF mutation to disrupted interaction with TFE3. Or it is possible that (E318K) have a 5-fold increase risk of developing mechanisms are similar to that of melanoma, however, melanoma (Yokoyama et al., 2011). MITF MITF is not associated with normal kidney function in amplification has also been associated with decreased the same way that it is in normal melanocyte function. survival and chemoresistance (Gallaway et al., 2005). Research is ongoing in this area. It is postulated the MITF may be a lineage specific oncogene in melanoma, particularly in the subset with Waardenburg syndrome CDKN2A mutations (Garraway and Sellers, 2006; Note Bennett, 2008). This hypothesis is supported by A group of autosomal dominant inherited conditions research that has shown that all melanoma cell lines that involve deafness and lack of pigment of the hair, that had MITF gene amplifications also had CDKN2A skin, and/or eyes. There are 4 main types of WS, 1 and pathway inactivation (Gallaway et al., 2005). MITFs 2 being most common. MITF is the gene associated role as a lineage specific oncogene is also supported by with Waardenburg syndrome 2a (WS2a), characterized its important part in cell growth, survival, growth, and by sensorineural hearing loss and patches of proliferation through BCL2, CDK2, TBX2, ML-IAP depigmentation, with or without ocular albinism. These etc, as described above. features may show variable expression and penetrance. In addition, BRAF mutations (found in ~60% of Some of the mutations are single or multiple amino melanomas) have a two-fold regulation of MITF acid changes that alter the helix-loop-helix or leucine transcription and is believed to keep MITF at zipper motif. There are other mutations that create a appropriate levels promoting melanoma cell shortened, non-functional version of MITF. It is proliferation and survival. believed that all of these mutations disrupt the Supporting this theory is the fact that pure up- formation of the dimers necessary for proper function regulation of MITF inhibits melanoma cell proliferation and development; thereby there is an insufficient and re-expression reduces tumorigenecity in vivo concentration of the MITF protein within the cytoplasm (Wellbrock and Marais, 2005). for normal function (haploinsufficiency). Also, as And MITF expression by immunohistochemistry has described above, MITF regulates BCL-2, ML-IAP, and been shown to decrease with disease progression, and MET. Without adequate amounts of MITF there is be a predictor of overall and disease-free survival (Salti over-apoptosis of melanocytes. This leads to a et al., 2000; Zhuang et al., 2007). decreased number of melanocytes in certain areas of As mentioned above, MITF is not expressed in all the skin, hair, eyes, inner ear, etc (Tachibana, 1997; melanomas. This indicates that there are different Samija et al., 2010). subsets of melanomas which differ in their need of Patients with WS1 will have the addition of MITF for their progression and survival (Salti et al., craniofacial deformities and those with WS3 (Klein- 2000; Miettinen et al., 2001; Granter et al., 2002). Waardenburg syndrome) have limb deformities, both There is also evidences that the role of MITF may are due to mutations in PAX3, which is part of the change within a melanoma during progression (Hoek et MITF pathway, those with WS4 (Waardenburg-Shah al., 2008a). Syndrome) will also have Hirchsprung's syndrome, Renal cell carcinoma associated with mutations in 3 genes: SOX10, endothelin 3, and endothelin receptor B (Tassabehji et Note al., 1995; Widlund and Fisher, 2003). Malignant transformation of the renal parenchyma.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 737 MITF (microphthalmia-associated transcription factor) Riddle ND, Zhang P

Tietz syndrome Granter SR, Weilbaecher KN, Quigley C, Fisher DE. Role for microphthalmia transcription factor in the diagnosis of Note metastatic malignant melanoma. Appl Immunohistochem Mol An autosomal dominant disorder characterized by Morphol. 2002 Mar;10(1):47-51 generalized hypopigmentation (fair skin and light- McGill GG, Horstmann M, Widlund HR, Du J et al.. Bcl2 colored hair) and profound bilateral congenital hearing regulation by the melanocyte master regulator Mitf modulates loss. Penetrance is complete. lineage survival and melanoma cell viability. Cell. 2002 Jun 14;109(6):707-18 The mutation is a change or deletion of a single amino acid in the basic motif region. This resultant altered Du J, Miller AJ, Widlund HR, Horstmann MA, Ramaswamy S, Fisher DE. MLANA/MART1 and SILV/PMEL17/GP100 are protein cannot bind to DNA, thereby affecting the transcriptionally regulated by MITF in melanocytes and development of melanocytes, and therefore, melanin melanoma. Am J Pathol. 2003 Jul;163(1):333-43 production (Smith et al., 2000). The mechanism is Gillanders E, Juo SH, Holland EA, Jones M et al.. Localization similar to Waardenburg syndrome, but more severe. In of a novel melanoma susceptibility locus to 1p22. Am J Hum a heterozygote the abnormal protein cannot dimerise Genet. 2003 Aug;73(2):301-13 effectively even with a normal allele product, i.e. even Widlund HR, Fisher DE. Microphthalamia-associated the normal allele does not function. This concept is transcription factor: a critical regulator of pigment cell referred to as a dominant negative. There is effectively development and survival. Oncogene. 2003 May no normal MITF available (Smith et al., 2000). 19;22(20):3035-41 Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, References Huber WE, Nishimura EK, Golub TR, Fisher DE. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific Tassabehji M, Newton VE, Liu XZ, Brady A, Donnai D, transcriptional regulation by MITF. Cancer Cell. 2004 Krajewska-Walasek M, Murday V, Norman A, Obersztyn E, Dec;6(6):565-76 Reardon W. The mutational spectrum in Waardenburg syndrome. Hum Mol Genet. 1995 Nov;4(11):2131-7 Lee YN, Nechushtan H, Figov N, Razin E. The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of Yasumoto K, Mahalingam H, Suzuki H, Yoshizawa M, MITF activity in FcepsilonRI-activated mast cells. Immunity. Yokoyama K. Transcriptional activation of the melanocyte- 2004 Feb;20(2):145-51 specific genes by the human homolog of the mouse Microphthalmia protein. J Biochem. 1995 Nov;118(5):874-81 Ludwig A, Rehberg S, Wegner M. Melanocyte-specific expression of dopachrome tautomerase is dependent on Tachibana M. Evidence to suggest that expression of MITF synergistic gene activation by the Sox10 and Mitf transcription induces melanocyte differentiation and haploinsufficiency of factors. FEBS Lett. 2004 Jan 2;556(1-3):236-44 MITF causes Waardenburg syndrome type 2A. Pigment Cell Res. 1997 Feb-Apr;10(1-2):25-33 Vetrini F, Auricchio A, Du J, Angeletti B, Fisher DE, Ballabio A, Marigo V. The microphthalmia transcription factor (Mitf) Aksan I, Goding CR. Targeting the microphthalmia basic helix- controls expression of the ocular albinism type 1 gene: link loop-helix-leucine zipper transcription factor to a subset of E- between melanin synthesis and melanosome biogenesis. Mol box elements in vitro and in vivo. Mol Cell Biol. 1998 Cell Biol. 2004 Aug;24(15):6550-9 Dec;18(12):6930-8 Carreira S, Goodall J, Aksan I, La Rocca SA, Galibert MD, Bertolotto C, Buscà R, Abbe P, Bille K, Aberdam E, Ortonne Denat L, Larue L, Goding CR. Mitf cooperates with Rb1 and JP, Ballotti R. Different cis-acting elements are involved in the activates p21Cip1 expression to regulate cell cycle regulation of TRP1 and TRP2 promoter activities by cyclic progression. Nature. 2005 Feb 17;433(7027):764-9 AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia. Mol Cell Biol. 1998 Feb;18(2):694-702 Garraway LA, Widlund HR, Rubin MA, Getz G et al.. Integrative genomic analyses identify MITF as a lineage Salti GI, Manougian T, Farolan M, Shilkaitis A, Majumdar D, survival oncogene amplified in malignant melanoma. Nature. Das Gupta TK. Micropthalmia transcription factor: a new 2005 Jul 7;436(7047):117-22 prognostic marker in intermediate-thickness cutaneous malignant melanoma. Cancer Res. 2000 Sep 15;60(18):5012-6 Lang D, Lu MM, Huang L, Engleka KA, Zhang M, Chu EY, Lipner S, Skoultchi A, Millar SE, Epstein JA. Pax3 functions at Smith SD, Kelley PM, Kenyon JB, Hoover D. Tietz syndrome a nodal point in melanocyte stem cell differentiation. Nature. (hypopigmentation/deafness) caused by mutation of MITF. J 2005 Feb 24;433(7028):884-7 Med Genet. 2000 Jun;37(6):446-8 Loercher AE, Tank EM, Delston RB, Harbour JW. MITF links Takeda K, Yasumoto K, Takada R et al.. Induction of differentiation with cell cycle arrest in melanocytes by melanocyte-specific microphthalmia-associated transcription transcriptional activation of INK4A. J Cell Biol. 2005 Jan factor by Wnt-3a. J Biol Chem. 2000 May 12;275(19):14013-6 3;168(1):35-40 Udono T, Yasumoto K, Takeda K, Amae S, Watanabe K, Saito Vance KW, Carreira S, Brosch G, Goding CR. Tbx2 is H, Fuse N, Tachibana M, Takahashi K, Tamai M, Shibahara S. overexpressed and plays an important role in maintaining Structural organization of the human microphthalmia- proliferation and suppression of senescence in melanomas. associated transcription factor gene containing four alternative Cancer Res. 2005 Mar 15;65(6):2260-8 promoters. Biochim Biophys Acta. 2000 Apr 25;1491(1-3):205- 19 Wellbrock C, Marais R. Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell Miettinen M, Fernandez M, Franssila K, Gatalica Z, Lasota J, proliferation. J Cell Biol. 2005 Aug 29;170(5):703-8 Sarlomo-Rikala M. Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: Carreira S, Goodall J, Denat L, Rodriguez M, Nuciforo P, Hoek comparison with four other melanoma markers. Am J Surg KS, Testori A, Larue L, Goding CR. Mitf regulation of Dia1 Pathol. 2001 Feb;25(2):205-11 controls melanoma proliferation and invasiveness. Genes Dev. 2006 Dec 15;20(24):3426-39

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Garraway LA, Sellers WR. Lineage dependency and lineage- Samuels Y. Frequent mutations in the MITF pathway in survival oncogenes in human cancer. Nat Rev Cancer. 2006 melanoma. Pigment Cell Melanoma Res. 2009 Aug;22(4):435- Aug;6(8):593-602 44 Kitamura Y, Oboki K, Ito A. Molecular mechanisms of mast cell Kido K, Sumimoto H, Asada S, Okada SM, Yaguchi T, development. Immunol Allergy Clin North Am. 2006 Kawamura N, Miyagishi M, Saida T, Kawakami Y. Aug;26(3):387-405; v Simultaneous suppression of MITF and BRAF V600E enhanced inhibition of melanoma cell proliferation. Cancer Sci. Levy C, Khaled M, Fisher DE. MITF: master regulator of 2009 Oct;100(10):1863-9 melanocyte development and melanoma oncogene. Trends Mol Med. 2006 Sep;12(9):406-14 Samija I, Lukac J, Kusic Z.. Microphthalmia-associated transcription factor (MITF) - from Waardenburg syndrome Beuret L, Flori E, Denoyelle C, Bille K, Busca R, Picardo M, genetics to melanoma therapy. Acta Medica Academica Bertolotto C, Ballotti R. Up-regulation of MET expression by 2010;39:175-193 alpha-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and Vachtenheim J, Borovansky J.. "Transcription physiology" of melanoma cells from apoptosis. J Biol Chem. 2007 May pigment formation in melanocytes: central role of MITF. Exp 11;282(19):14140-7 Dermatol. 2010 Jul 1;19(7):617-27. doi: 10.1111/j.1600- 0625.2009.01053.x. Epub 2010 Feb 25. (REVIEW) Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature. 2007 Feb 22;445(7130):843-50 Bertolotto C, Lesueur F, Giuliano S, Strub T et al.. A SUMOylation-defective MITF germline mutation predisposes to Meadows NA, Sharma SM, Faulkner GJ, Ostrowski MC, Hume melanoma and renal carcinoma. Nature. 2011 Oct DA, Cassady AI. The expression of Clcn7 and Ostm1 in 19;480(7375):94-8. doi: 10.1038/nature10539. osteoclasts is coregulated by microphthalmia transcription factor. J Biol Chem. 2007 Jan 19;282(3):1891-904 Dickson BC, Brooks JS, Pasha TL, Zhang PJ.. TFE3 expression in tumors of the microphthalmia-associated Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, transcription factor (MiTF) family. Int J Surg Pathol. 2011 Thompson JF, Hersey P. Mcl-1, Bcl-XL and Stat3 expression Feb;19(1):26-30. doi: 10.1177/1066896909352861. Epub 2010 are associated with progression of melanoma whereas Bcl-2, Feb 16. AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol. 2007 Apr;20(4):416-26 Yokoyama S, Woods SL, Boyle GM et al.. A novel recurrent mutation in MITF predisposes to familial and sporadic Bennett DC. How to make a melanoma: what do we know of melanoma. Nature. 2011 Nov 13;480(7375):99-103. doi: the primary clonal events? Pigment Cell Melanoma Res. 2008 10.1038/nature10630. Feb;21(1):27-38 Adijanto J, Castorino JJ, Wang ZX, Maminishkis A, Grunwald Chiaverini C, Beuret L, Flori E, Busca R, Abbe P, Bille K, GB, Philp NJ.. Microphthalmia-associated transcription factor Bahadoran P, Ortonne JP, Bertolotto C, Ballotti R. (MITF) promotes differentiation of human retinal pigment Microphthalmia-associated transcription factor regulates epithelium (RPE) by regulating microRNAs-204/211 RAB27A gene expression and controls melanosome transport. expression. J Biol Chem. 2012 Jun 8;287(24):20491-503. doi: J Biol Chem. 2008 May 2;283(18):12635-42 10.1074/jbc.M112.354761. Epub 2012 Apr 20. Dynek JN, Chan SM, Liu J, Zha J, Fairbrother WJ, Vucic D. Cimadamore F, Shah M, Amador-Arjona A, Navarro-Peran E, Microphthalmia-associated transcription factor is a critical Chen C, Huang CT, Terskikh AV.. SOX2 modulates levels of transcriptional regulator of melanoma inhibitor of apoptosis in MITF in normal human melanocytes, and melanoma lines in melanomas. Cancer Res. 2008 May 1;68(9):3124-32 vitro. Pigment Cell Melanoma Res. 2012 Jul;25(4):533-6. doi: Hoek KS, Eichhoff OM, Schlegel NC, Döbbeling U, Kobert N, 10.1111/j.1755-148X.2012.01012.x. Schaerer L, Hemmi S, Dummer R. In vivo switching of human Genovese G, Ghosh P, Li H, Rettino A, Sioletic S, Cittadini A, melanoma cells between proliferative and invasive states. Sgambato A.. The tumor suppressor HINT1 regulates MITF Cancer Res. 2008a Feb 1;68(3):650-6 and beta-catenin transcriptional activity in melanoma cells. Cell Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius Cycle. 2012 Jun 1;11(11):2206-15. doi: 10.4161/cc.20765. C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Epub 2012 Jun 1. Schepsky A, Dummer R, Steingrimsson E. Novel MITF targets Pierrat MJ, Marsaud V, Mauviel A, Javelaud D.. Expression of identified using a two-step DNA microarray strategy. Pigment microphthalmia-associated transcription factor (MITF), which is Cell Melanoma Res. 2008b Dec;21(6):665-76 critical for melanoma progression, is inhibited by both Watanabe M, Mishima Y, Yamashita I, Park SY, Tame JR, transcription factor GLI2 and transforming growth factor-beta. J Heddle JG. Intersubunit linker length as a modifier of protein Biol Chem. 2012 May 25;287(22):17996-8004. doi: stability: crystal structures and thermostability of mutant TRAP. 10.1074/jbc.M112.358341. Epub 2012 Apr 11. Protein Sci. 2008 Mar;17(3):518-26 This article should be referenced as such: Bishop DT, Demenais F, Iles MM, Harland M et al.. Genome- wide association study identifies three loci associated with Riddle ND, Zhang P. MITF (microphthalmia-associated melanoma risk. Nat Genet. 2009 Aug;41(8):920-5 transcription factor). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11):735-739. Cronin JC, Wunderlich J, Loftus SK, Prickett TD, Wei X, Ridd K, Vemula S, Burrell AS, Agrawal NS, Lin JC, Banister CE, Buckhaults P, Rosenberg SA, Bastian BC, Pavan WJ,

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 739 Atlas of Genetics and Cytogenetics

in Oncology and Haematology

OPEN ACCESS JOURNAL INIST -CNRS

Gene Section Review

PHOX2B (paired-like homeobox 2b) Tiziana Bachetti, Isabella Ceccherini UOC Medical Genetics, G Gaslini Institute, 16147 Genova, Italy (TB, IC)

Published in Atlas Database: April 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/PHOX2BID126ch4p13.html DOI: 10.4267/2042/51812 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Protein Other names: NBLST2, NBPhox, PMX2B Note HGNC (Hugo): PHOX2B NCBI Reference Sequence: NP_003915.2. Location: 4p13 Description Local order: APBB2 - UCHL1 - LIMCH1 - PHOX2B PHOX2B protein is 314 aminoacids long. A - TMEM33 - DCAF4L1 - ATP1B1P1 - SLC30A9. homeodomain region spanning exons 1 and 2 (from residue 99 to residue 148) is responsible for the binding DNA/RNA of this transcription factor to target DNA elements. In exon 3 there are two sequences characterized by Note stretches of 9 and 20 alanine residues, encoded by Genomic: NCBI Reference Sequence: NG_008243.1. GC(N) triplets. Their functional role is still unknown. Description Expression The PHOX2B gene is 4888bp long; the coding region PHOX2B is expressed during neural development in (CDS) is 945bp and is composed of 3 exons: exon 1 central autonomic circuits and peripheral neural crest (241bp), exon 2 (188bp), exon 3 (516bp). derivatives, and particularly in the retrotrapezoid Other features: 5'UTR: 361bp; 3'UTR: 1725bp. nucleus, noradrenergic centres and hindbrain (Pattyn et Transcription al., 1997; Dubreuil et al., 2002; Stornetta et al., 2006; mRNA: NCBI Reference Sequence NM_003924.3. The Kang et al., 2007). PHOX2B mRNA is 3218bp long; no alternative splice PHOX2B expression is transcriptionally regulated by site is known. the PHOX2B protein itself, through its direct binding to four promoter elements which give rise to a positive Pseudogene autoregulatory loop (Cargnin et al., 2005). No pseudogene is reported.

Cytogenetic location of PHOX2B on chromosome 4.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 740 PHOX2B (paired-like homeobox 2b) Bachetti T, Ceccherini I

PHOX2B gene structure. Untranslated regions (orange boxes), introns (black lines) and coding regions (blue boxes) are shown.

Representation of the PHOX2B protein. The three exons (blue) are shown, with the number of aminoacids (aa) they code for, in addition to the homeodomain (red) and the polyalanine stretches (yellow). In the upper part of the figure, the first and last aminoacid positions for each of these crucial regions is indicated.

In addition, PHOX2B expression is known to be 100% identical to those of the chimpanzee, rat and regulated at specific sympathetic and enteric nervous mouse, suggesting that the function of PHOX2B is system developmental stages by E2a and Hand2 highly conserved in Mammals. (Hashimoto et al., 2011). Finally, SOX10 (Nagashimada et al., 2012), as well as Mutations PHOX2A and HASH1 (reviewed by Brunet and Pattyn, 2002) have shown a degree of cross-regulation with Germinal respect to PHOX2B. Hoxb1 and Hoxb2 have also Germline PHOX2B mutations are responsible for shown to form a trimer with Pbx1 and Meis 1 to Congenital Central Hypoventilation Syndrome regulate PHOX2B transcription (Samad et al., 2004). (CCHS). The vast majority of mutations is represented by in frame triplet duplications of a sequence stretch Localisation coding for 20 Alanine residues in exon 3, also known PHOX2B is localized within the nuclear compartment. as polyalanine (polyAla) expansions or PARM Function (Polyalanine repeats mutation). The duplication length is variable, starting from 12 bp up to 39 bp, thus PHOX2B is a transcription factor essential for the leading from +4 Ala up to +13 Ala expansions (Amiel development of autonomic neural crest derivatives et al., 2003; Sasaki et al., 2003; Weese-Mayer et al., (Pattyn et al., 1999). 2003; Matera et al., 2004; Trochet et al., 2008a). It controls the development of motoneurons (Pattyn et Ninety percent of constitutive (germinal) mutations al., 2000) and drives a somatic-to-visceral switch in detected in CCHS patients are represented by polyAla cranial sensory pathways (D'Autréaux et al., 2011). expansions. Among these, 75% have arisen de novo PHOX2B regulates the transcriptional expression of while 25% is inherited from one parent (Bachetti et al., several genes: TH (Lo et al., 1999), DBH (Adachi et 2011; Meguro et al., 2012). al., 2000), PHOX2A (Flora et al., 2011), PHOX2B In addition, germline PHOX2B missense, frameshift, itself (Cargnin et al., 2005), RET (Bachetti et al., nonsense non polyAla mutations (NPARMs) have been 2005a), TLX-2 (Borghini et al., 2006), ALK (Bachetti detected in a small fraction of mainly syndromic et al., 2010), SOX10 (Nagashimada et al., 2012), patients characterized by CCHS+other Hand1 (Vincentz et al., 2012), SCG2 (Wen et al., neurocristophaties such as neuroblastoma (NB) and/or 2007), MSX1 (Revet et al., 2008). Hirschsprung's disease (HSCR) (Trochet et al., 2005; CREB-binding protein (CREBBP/CBP) interacts with Matera et al., 2004). A few specific missense PHOX2B PHOX2B and serves as its coactivator to mediate mutations have been detected in isolated NB and/or synergistic trans-activation (Wu et al., 2009). HSCR, as reported in Table 1. Using a yeast two-hybrid screening, TRIM11 was In frame deletions within the polyAla stretch have been isolated as an additional PHOX2B interacting protein identified in healthy subjects, but also in association (Hong et al., 2008). with schizophenia (Toyota et al., 2004). Homology The amino acid sequence of the human PHOX2B is

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 741 PHOX2B (paired-like homeobox 2b) Bachetti T, Ceccherini I

Table 1: NPARMS and PARMS mutations of PHOX2B in human disease. Legend: NB neuroblastoma, TSNS tumor sympathetic nervous system, CCHS congenital central hypoventilation syndrome, LO-CHS late onset central hypoventialtion syndrome, NF1 neurofibromatosis type 1, (?) undetermined associations.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 742 PHOX2B (paired-like homeobox 2b) Bachetti T, Ceccherini I

Localization of mutations within the PHOX2B gene. In the figure some PARMS (yellow) and NPARMS (black) PHOX2B mutations are shown (see also Weese-Mayer et al., 2010).

Somatic Additional dysfunction of the autonomous nervous system, such as HSCR, NB, ocular defects, cardiac No CCHS patient has ever been proven to be a somatic rythm alterations, etc., may be found in association mosaic for PHOX2B mutation; however, somatic and with the especially largest polyAla expansions (Weese- therefore germline mosaicism has been demonstrated in Mayer et al., 2010). a proportion of CCHS parents (Parodi et al., 2008; Bachetti et al., 2011; Bachetti et al., 2013). Disease Somatic PHOX2B mutations have been identified in Congenital Central Hypovention Syndrome (CCHS). NB cell lines and NB tumor samples as reported in the Prognosis Table 1. Congenital central hypoventilation syndrome (CCHS) Note is characterized by alveolar hypoventilation and There is a clear correlation between types of PHOX2B autonomic dysregulation. mutations and clinical manifestations. Indeed, while the It is a life-long, still untreatable disease. vast majority of PHOX2B mutations identified in Oncogenesis isolated Congenital Central Hypoventilation Syndrome Among PARMs, only subjects with the 20/29 and (CCHS) are PARMs (Polyalanine repeats mutation), 20/33 genotypes have been identified to have tumors of those present in HSCR-NB (Hirschsprung's disease- neural crest origin (ganglioneuromas and neuroblastoma) associated CCHS are non-PARMs ganglioneuroblastomas). (NPARM), namely either missense mutations or No children with genotypes 20/24 to 20/28 have been nucleotide deletions/insertions causing frameshifts of identified with tumors of neural crest origin (Weese- the open reading frame. Mayer et al., 2010). Moreover, inherited and de novo missense and frameshift mutations in exons 2 and 3 of the PHOX2B NPARMS: non polyAla repeat gene have been detected in both sporadic (NB) and mutations, either germline or somatic syndromic (NB+CCHS) cases (Weese-Mayer et al., (i.e. missense, nonsense, indels and 2010; Bachetti et al., 2005b), thus suggesting that loss of the stop codon mutations) PHOX2B may play a role in isolated NB pathogenesis. Table 1 reports PHOX2B mutations detected so far, Note with detailed description of the nucleotide and These mutations, listed in Table 1, include missense, aminoacid changes. Associated phenotypes are also nonsense, loss of stop codon and small indels annotated. mutations. Disease Implicated in Neuroblastoma and/or Hirschsprung's disease (either PARMs (from +4 to +13 polyAla sporadic or in association with CCHS). expansions) Neuroblastoma Note Note A correlation between the length of the expanded tract In neuroblastoma cell lines and tumor samples, and the severity of the CCHS phenotype has already PHOX2B expression has turned out to be much higher been reported (Matera et al., 2004; Weese-Mayer et al., than in normal tissues (Longo et al., 2008). Moreover, 2010). LOH in about 10% of the tumors and rare aberrant CpG

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 743 PHOX2B (paired-like homeobox 2b) Bachetti T, Ceccherini I

dinucleotide methylation of 500 bp of PHOX2B Benailly HK, Lapierre JM, Laudier B, Amiel J, Attié T, De promoter region have been reported as NB associated Blois MC, Vekemans M, Romana SP. PMX2B, a new molecular event (De Pontual et al., 2007). candidate gene for Hirschsprung's disease. Clin Genet. 2003 Sep;64(3):204-9 Breakpoints Sasaki A, Kanai M, Kijima K, Akaba K, Hashimoto M, Hasegawa H, Otaki S, Koizumi T, Kusuda S, Ogawa Y, Note Tuchiya K, Yamamoto W, Nakamura T, Hayasaka K. Molecular A 5-Mb deletion at chromosome 4p12-p13 that analysis of congenital central hypoventilation syndrome. Hum included the PHOX2B gene was found in a 16-month- Genet. 2003 Dec;114(1):22-6 old girl with developmental delay, severe hypotonia, Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, facial dysmorphism, and short-segment Hirschsprung Silvestri JM, Curran ME, Marazita ML. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent disease thus suggesting that PHOX2B to early autonomic nervous system embryologic development haploinsufficiency may predispose to colonic and identification of mutations in PHOX2b. Am J Med Genet A. aganglionosis (Benailly et al,. 2003). 2003 Dec 15;123A(3):267-78 Interestingly, other cytogenetic interstitial deletions, Matera I, Bachetti T, Puppo F, Di Duca M, Morandi F, spanning from 0.29 to 2.6 Mb across the PHOX2B Casiraghi GM, Cilio MR, Hennekam R, Hofstra R, Schöber JG, locus, have been detected in patients affected with Ravazzolo R, Ottonello G, Ceccherini I. PHOX2B mutations atypical disorders, apparently sharing a loss of and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both function/haploinsufficiency pathogenic mechanism, congenital and late onset Central Hypoventilation syndrome. J namely apparent-life threatening event including, Med Genet. 2004 May;41(5):373-80 Hirschsprung disease, transient neonatal Mosse YP, Laudenslager M, Khazi D, Carlisle AJ, Winter CL, hypoventilation and dysmorphic features. Rappaport E, Maris JM. Germline PHOX2B mutation in Neuroblastoma did not develop in any of these cases hereditary neuroblastoma. Am J Hum Genet. 2004 (Jennings et al., 2012). Oct;75(4):727-30 Samad OA, Geisen MJ, Caronia G, Varlet I, Zappavigna V, References Ericson J, Goridis C, Rijli FM. Integration of anteroposterior and dorsoventral regulation of Phox2b transcription in cranial Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF. Expression motoneuron progenitors by homeodomain proteins. and interactions of the two closely related homeobox genes Development. 2004 Aug;131(16):4071-83 Phox2a and Phox2b during neurogenesis. Development. 1997 Oct;124(20):4065-75 Toyota T, Yoshitsugu K, Ebihara M, Yamada K, Ohba H, Fukasawa M, Minabe Y, Nakamura K, Sekine Y, Takei N, Lo L, Morin X, Brunet JF, Anderson DJ. Specification of Suzuki K, Itokawa M, Meerabux JM, Iwayama-Shigeno Y, neurotransmitter identity by Phox2 proteins in neural crest Tomaru Y, Shimizu H, Hattori E, Mori N, Yoshikawa T. stem cells. Neuron. 1999 Apr;22(4):693-705 Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Hum Mol Genet. Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF. The 2004 Mar 1;13(5):551-61 homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature. 1999 May van Limpt V, Schramm A, van Lakeman A, Sluis P, Chan A, 27;399(6734):366-70 van Noesel M, Baas F, Caron H, Eggert A, Versteeg R. The Phox2B homeobox gene is mutated in sporadic Adachi M, Browne D, Lewis EJ. Paired-like homeodomain neuroblastomas. Oncogene. 2004 Dec 9;23(57):9280-8 proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta- Bachetti T, Borghini S, Ravazzolo R, Ceccherini I. An in vitro hydroxylase gene transcription. DNA Cell Biol. 2000 approach to test the possible role of candidate factors in the Sep;19(9):539-54 transcriptional regulation of the RET proto-oncogene. Gene Expr. 2005a;12(3):137-49 Pattyn A, Hirsch M, Goridis C, Brunet JF. Control of hindbrain motor neuron differentiation by the homeobox gene Phox2b. Bachetti T, Matera I, Borghini S, Di Duca M, Ravazzolo R, Development. 2000 Apr;127(7):1349-58 Ceccherini I. Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in Flora A, Lucchetti H, Benfante R, Goridis C, Clementi F, congenital central hypoventilation syndrome. Hum Mol Genet. Fornasari D. Sp proteins and Phox2b regulate the expression 2005b Jul 1;14(13):1815-24 of the human Phox2a gene. J Neurosci. 2001 Sep 15;21(18):7037-45 Cargnin F, Flora A, Di Lascio S, Battaglioli E, Longhi R, Clementi F, Fornasari D. PHOX2B regulates its own Brunet JF, Pattyn A. Phox2 genes - from patterning to expression by a transcriptional auto-regulatory mechanism. J connectivity. Curr Opin Genet Dev. 2002 Aug;12(4):435-40 Biol Chem. 2005 Nov 11;280(45):37439-48 Dubreuil V, Hirsch MR, Jouve C, Brunet JF, Goridis C. The role Trochet D, O'Brien LM, Gozal D, Trang H, Nordenskjöld A, of Phox2b in synchronizing pan-neuronal and type-specific Laudier B, Svensson PJ, Uhrig S, Cole T, Niemann S, Munnich aspects of neurogenesis. Development. 2002 A, Gaultier C, Lyonnet S, Amiel J. PHOX2B genotype allows Nov;129(22):5241-53 for prediction of tumor risk in congenital central hypoventilation Amiel J, Laudier B, Attié-Bitach T, Trang H, de Pontual L, syndrome. Am J Hum Genet. 2005 Mar;76(3):421-6 Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Borghini S, Bachetti T, Fava M, Di Duca M, Cargnin F, Vekemans M, Munnich A, Gaultier C, Lyonnet S. Polyalanine Fornasari D, Ravazzolo R, Ceccherini I. The TLX2 homeobox expansion and frameshift mutations of the paired-like gene is a transcriptional target of PHOX2B in neural-crest- homeobox gene PHOX2B in congenital central hypoventilation derived cells. Biochem J. 2006 Apr 15;395(2):355-61 syndrome. Nat Genet. 2003 Apr;33(4):459-61

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 744 PHOX2B (paired-like homeobox 2b) Bachetti T, Ceccherini I

McConville C, Reid S, Baskcomb L, Douglas J, Rahman N. Wu HT, Su YN, Hung CC, Hsieh WS, Wu KJ. Interaction PHOX2B analysis in non-syndromic neuroblastoma cases between PHOX2B and CREBBP mediates synergistic shows novel mutations and genotype-phenotype associations. activation: mechanistic implications of PHOX2B mutants. Hum Am J Med Genet A. 2006 Jun 15;140(12):1297-301 Mutat. 2009 Apr;30(4):655-60 Stornetta RL, Moreira TS, Takakura AC, Kang BJ, Chang DA, Bachetti T, Di Paolo D, Di Lascio S, Mirisola V, Brignole C, West GH, Brunet JF, Mulkey DK, Bayliss DA, Guyenet PG. Bellotti M, Caffa I, Ferraris C, Fiore M, Fornasari D, Chiarle R, Expression of Phox2b by brainstem neurons involved in Borghini S, Pfeffer U, Ponzoni M, Ceccherini I, Perri P. chemosensory integration in the adult rat. J Neurosci. 2006 Oct PHOX2B-mediated regulation of ALK expression: in vitro 4;26(40):10305-14 identification of a functional relationship between two genes involved in neuroblastoma. PLoS One. 2010 Oct 1;5(10) de Pontual L, Trochet D, Bourdeaut F, Thomas S, Etchevers H, Chompret A, Minard V, Valteau D, Brugieres L, Munnich A, Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Delattre O, Lyonnet S, Janoueix-Lerosey I, Amiel J. Loghmanee DA, Trang H. An official ATS clinical policy Methylation-associated PHOX2B gene silencing is a rare event statement: Congenital central hypoventilation syndrome: in human neuroblastoma. Eur J Cancer. 2007 genetic basis, diagnosis, and management. Am J Respir Crit Nov;43(16):2366-72 Care Med. 2010 Mar 15;181(6):626-44 Kang BJ, Chang DA, Mackay DD, West GH, Moreira TS, Bachetti T, Parodi S, Di Duca M, Santamaria G, Ravazzolo R, Takakura AC, Gwilt JM, Guyenet PG, Stornetta RL. Central Ceccherini I. Low amounts of PHOX2B expanded alleles in nervous system distribution of the transcription factor Phox2b asymptomatic parents suggest unsuspected recurrence risk in in the adult rat. J Comp Neurol. 2007 Aug 10;503(5):627-41 congenital central hypoventilation syndrome. J Mol Med (Berl). 2011 May;89(5):505-13 Wen G, Wessel J, Zhou W, Ehret GB, Rao F, Stridsberg M, Mahata SK, Gent PM, Das M, Cooper RS, Chakravarti A, Zhou D'Autréaux F, Coppola E, Hirsch MR, Birchmeier C, Brunet JF. H, Schork NJ, O'connor DT, Hamilton BA. An ancestral variant Homeoprotein Phox2b commands a somatic-to-visceral switch of Secretogranin II confers regulation by PHOX2 transcription in cranial sensory pathways. Proc Natl Acad Sci U S A. 2011 factors and association with hypertension. Hum Mol Genet. Dec 13;108(50):20018-23 2007 Jul 15;16(14):1752-64 Hashimoto Y, Tsutsumi M, Myojin R, Maruta K, Onoda F, Hong SJ, Chae H, Lardaro T, Hong S, Kim KS. Trim11 Tashiro F, Ohtsu M, Murakami Y. Interaction of Hand2 and increases expression of dopamine beta-hydroxylase gene by E2a is important for transcription of Phox2b in sympathetic interacting with Phox2b. Biochem Biophys Res Commun. 2008 nervous system neuron differentiation. Biochem Biophys Res Apr 11;368(3):650-5 Commun. 2011 Apr 29;408(1):38-44 Longo L, Borghini S, Schena F, Parodi S, Albino D, Bachetti T, Jennings LJ, Yu M, Rand CM, Kravis N, Berry-Kravis EM, Da Prato L, Truini M, Gambini C, Tonini GP, Ceccherini I, Perri Patwari PP, Weese-Mayer DE. Variable human phenotype P. PHOX2A and PHOX2B genes are highly co-expressed in associated with novel deletions of the PHOX2B gene. Pediatr human neuroblastoma. Int J Oncol. 2008 Nov;33(5):985-91 Pulmonol. 2012 Feb;47(2):153-61 Parodi S, Bachetti T, Lantieri F, Di Duca M, Santamaria G, Meguro T, Yoshida Y, Hayashi M, Toyota K, Otagiri T, Ottonello G, Matera I, Ravazzolo R, Ceccherini I. Parental Mochizuki N, Kishikawa Y, Sasaki A, Hayasaka K. Inheritance origin and somatic mosaicism of PHOX2B mutations in of polyalanine expansion mutation of PHOX2B in congenital Congenital Central Hypoventilation Syndrome. Hum Mutat. central hypoventilation syndrome. J Hum Genet. 2012 2008 Jan;29(1):206 May;57(5):335-7 Raabe EH, Laudenslager M, Winter C, Wasserman N, Cole K, Nagashimada M, Ohta H, Li C, Nakao K, Uesaka T, Brunet JF, LaQuaglia M, Maris DJ, Mosse YP, Maris JM. Prevalence and Amiel J, Trochet D, Wakayama T, Enomoto H. Autonomic functional consequence of PHOX2B mutations in neurocristopathy-associated mutations in PHOX2B dysregulate neuroblastoma. Oncogene. 2008 Jan 17;27(4):469-76 Sox10 expression. J Clin Invest. 2012 Sep 4;122(9):3145-58 Revet I, Huizenga G, Chan A, Koster J, Volckmann R, van Vincentz JW, VanDusen NJ, Fleming AB, Rubart M, Firulli BA, Sluis P, Øra I, Versteeg R, Geerts D. The MSX1 homeobox Howard MJ, Firulli AB. A Phox2- and Hand2-dependent Hand1 transcription factor is a downstream target of PHOX2B and cis-regulatory element reveals a unique gene dosage activates the Delta-Notch pathway in neuroblastoma. Exp Cell requirement for Hand2 during sympathetic neurogenesis. J Res. 2008 Feb 15;314(4):707-19 Neurosci. 2012 Feb 8;32(6):2110-20 Trochet D, de Pontual L, Estêvao MH, Mathieu Y, Munnich A, Bachetti T, Di Duca M, Monica MD, Grappone L, Scarano G, Feingold J, Goridis C, Lyonnet S, Amiel J. Homozygous Ceccherini I. Recurrence of CCHS associated PHOX2B poly- mutation of the PHOX2B gene in congenital central alanine expansion mutation due to maternal mosaicism. hypoventilation syndrome (Ondine's Curse). Hum Mutat. 2008a Pediatr Pulmonol. 2013 Mar 4; May;29(5):770 Fernández RM, Mathieu Y, Luzón-Toro B, Núñez-Torres R, Trochet D, de Pontual L, Straus C, Gozal D, Trang H, Landrieu González-Meneses A, Antiñolo G, Amiel J, Borrego S. P, Munnich A, Lyonnet S, Gaultier C, Amiel J. PHOX2B Contributions of PHOX2B in the pathogenesis of Hirschsprung germline and somatic mutations in late-onset central disease. PLoS One. 2013;8(1):e54043 hypoventilation syndrome. Am J Respir Crit Care Med. 2008b Apr 15;177(8):906-11 This article should be referenced as such: Trochet D, Mathieu Y, Pontual Ld, Savarirayan R, Munnich A, Bachetti T, Ceccherini I. PHOX2B (paired-like homeobox 2b). Brunet JF, Lyonnet S, Goridis C, Amiel J. In Vitro studies of Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11):740-745. non poly alanine PHOX2B mutations argue against a loss-of- function mechanism for congenital central hypoventilation. Hum Mutat. 2009 Feb;30(2):E421-31

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Gene Section Short Communication

SGOL1 (shugoshin-like 1 (S. pombe)) Tomoaki Kahyo, Haruhiko Sugimura Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan (TK, HS)

Published in Atlas Database: April 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/SGOL1ID50710ch3p24.html DOI: 10.4267/2042/51813 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: NY-BR-85, SGO, Sgo1 Description HGNC (Hugo): SGOL1 The SGOL1 gene is composed of 9 exons and spans Location: 3p24.3 25698 bases. Local order: Telomeric to ZNF385D (zinc finger Transcription protein 385D); centromeric to KAT2B (lysine Transcript variant A2 (NM_001012410) has the longest acetyltransferase 2B). coding sequence and encodes a protein comprised of Note 561 aa. Transcript variant A1 (NM_001012409) lacks The Sgo1 gene was identified in fission yeast as a exon 9 and encodes a protein comprised of 527 aa. factor protecting centromeric Rec8 from degradation Typically, "SGOL1" corresponds to type A1 or A2. during meiosis I, and human Sgo1 homolog, SGOL1, Transcript variant B2 (NM_001012412) lacks a large was identified as a homologue of yeast Sgo1 on proportion of exon 6 and encodes a protein comprised databases (Kitajima et al., 2004). of 309 aa.

Figure 1. Scheme of SGOL1 transcript variants. Exon numbers are shown at the top. Red and yellow boxes indicate exons of CDS and UTR, respectively.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 746 SGOL1 (shugoshin-like 1 (S. pombe)) Kahyo T, Sugimura H

Figure 2. Green, black and red boxes represent an N-terminal conserved coiled-coil region, a P-V-I motif and a C-terminal conserved basic region, respectively. Indicated numbers mean the exon numbers shown at Fig.1. SGOL1-interacting proteins are shown at the bottom.

Transcript B1 (NM_001012411) lacks exon 9 in SGOL1, are detected in breast cancer patients, and the addition to a large proportion of exon 6 and encodes a expression of NY-BR-85 mRNA was detected in protein comprised of 275 aa. several tissues, including thymus and testis (Scanlan et Transcript C2 (NM_138484) skips exon 6 and encodes al., 2001). a protein comprised of 292 aa. Expression of SGOL1 was also detected in the Transcript C1 (NM_001012413) lacks exon 9 in extraction of HeLa addition to exon 6 and encodes a protein comprised of 258 aa. Transcript D1 (NM_001199257) lacks exon 7 cells (Salic et al., 2004; Kitajima et al., 2005) and and exon 8 in addition to a large proportion of exon 6 various human leukemia cell lines (Yang et al., 2013), and encodes a protein comprised of 215 aa. Transcript while the expression of SGOL1 was downregulated in P1 (AB567656) lacks exon 3, resulting in leading to a the colorectal cancers (Iwaizumi et al., 2009). stop codon within exon 4, and encodes a protein comprised of 59 aa. Localisation Furthermore, several transcript variants that have an Nucleus. During prophase and metaphase, SGOL1 alternate 5' UTR exon are also stored in databases localizes to the inner centromere (Salic et al., 2004; (NM_001199251, NM_001199253, NM_001199255, Kitajima et al., 2005). NM_001199252, NM_001199254 and Function NM_001199256). SGOL1 is a crucial factor to protect centromeric Pseudogene cohesin during mitosis and to maintain genomic There are two pseudogenes on chromosome 1 stability in human cells. SGOL1-knockdown caused (PGOHUM00000244068) and chromosome 7 severe mitotic arrest and precocious separation of (PGOHUM00000232695). centromeric cohesion in HeLa cells (Salic et al., 2004; Kitajima et al., 2006) and HCT116 cells, resulting in Protein chromosomal instability (Iwaizumi et al., 2009; Kahyo et al., 2011). Description In addition, SGOL1 was needed for the kinetochore SGOL1 protein (type A2) is a 64.2 kDa protein and has localization of PLK1 and CENP-F in HeLa cells (Salic an N-terminal coiled-coil region, a P-V-I motif and a et al., 2004; Pouwels et al., 2007). C-terminal conserved basic region. Several short isoforms of SGOL1 showed aberrant cell The N-terminal coiled-coil regions are required for the phenotypes including unstable chromatid cohesion interaction with PP2A (Yamagishi et al., 2008) and the (Suzuki et al., 2006; Kahyo et al., 2011). chromosomal passenger complex (CPC) (Tsukahara et These results suggest that the short isoforms of SGOL1 al., 2010) at centromere. function as a negative factor to native SGOL1, and that The P-V-I motif and the C-terminal basic region of abundant expression of the SGOL1 short isoforms can SGOL1 are required for the interaction with HP1 be responsible for chromosomal instability. (heterochromatin protein 1) and phosphorylated histone Homology H2A at centromere, respectively (Yamagishi et al., 2008; Kawashima et al., 2010). The coiled-coil and basic regions of shugoshin or shugoshin-like proteins are highly conserved between Expression different species (Kitajima et al., 2004). SGOL2, a Serum antibodies against NY-BR-85, which encodes paralogue of SGOL1, was required for the PP2A-

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 747 SGOL1 (shugoshin-like 1 (S. pombe)) Kahyo T, Sugimura H

mediated protection of cohesin and the MCAK- Kitajima TS, Kawashima SA, Watanabe Y. The conserved mediated chromosome congression in HeLa cells kinetochore protein shugoshin protects centromeric cohesion during meiosis. Nature. 2004 Feb 5;427(6974):510-7 (Tanno et al., 2010). Salic A, Waters JC, Mitchison TJ. Vertebrate shugoshin links sister centromere cohesion and kinetochore microtubule Mutations stability in mitosis. Cell. 2004 Sep 3;118(5):567-78 Somatic Kitajima TS, Hauf S, Ohsugi M, Yamamoto T, Watanabe Y. Human Bub1 defines the persistent cohesion site along the Losses of heterozygosity at several polymorphic mitotic chromosome by affecting Shugoshin localization. Curr markers in SGOL1 locus (c.416+39_42delGAAA, Biol. 2005 Feb 22;15(4):353-9 c.504A>T and c.1461C>T) were detected in 31.2 % of Kitajima TS, Sakuno T, Ishiguro K, Iemura S, Natsume T, human colorectal cancers (Iwaizumi et al., 2009). Kawashima SA, Watanabe Y. Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature. 2006 May Implicated in 4;441(7089):46-52 Suzuki H, Akiyama N, Tsuji M, Ohashi T, Saito S, Eto Y. Breast cancer Human Shugoshin mediates kinetochore-driven formation of kinetochore microtubules. Cell Cycle. 2006 May;5(10):1094- Note 101 NY-BR-85 is a serologically defined breast cancer Pouwels J, Kukkonen AM, Lan W, Daum JR, Gorbsky GJ, antigen (Scanlan et al., 2001). NY-BR-86 was Stukenberg T, Kallio MJ. Shugoshin 1 plays a central role in overexpressed in 90% of breast cancers. kinetochore assembly and is required for kinetochore targeting Colorectal cancer of Plk1. Cell Cycle. 2007 Jul 1;6(13):1579-85 Yamagishi Y, Sakuno T, Shimura M, Watanabe Y. Note Heterochromatin links to centromeric protection by recruiting The expression of SGOL1 was significantly shugoshin. Nature. 2008 Sep 11;455(7210):251-5 downregulated in the colorectal cancer tissue in Iwaizumi M, Shinmura K, Mori H, Yamada H, Suzuki M, comparison with the paired normal mucosa, and the Kitayama Y, Igarashi H, Nakamura T, Suzuki H, Watanabe Y, tumors in the SGOL1-downregulated group tended to Hishida A, Ikuma M, Sugimura H. Human Sgo1 downregulation be located on the left side of the large bowel, especially leads to chromosomal instability in colorectal cancer. Gut. in the rectum, rather than in the other regions of the 2009 Feb;58(2):249-60 large bowel (Iwaizumi et al., 2009). The mRNA of the Kawashima SA, Yamagishi Y, Honda T, Ishiguro K, Watanabe shortest isoform SGOL1-P1, the overexpression of Y. Phosphorylation of H2A by Bub1 prevents chromosomal instability through localizing shugoshin. Science. 2010 Jan which caused unstable chromatid cohesion in HCT116 8;327(5962):172-7 cells, was detected specifically in colorectal cancer tissues (Kahyo et al., 2011). Tanno Y, Kitajima TS, Honda T, Ando Y, Ishiguro K, Watanabe Y. Phosphorylation of mammalian Sgo2 by Aurora B recruits Oncogenesis PP2A and MCAK to centromeres. Genes Dev. 2010 Oct While Sgo1 homozygous mutant mice (Sgo1 -/-) showed 1;24(19):2169-79 +/- embryonic lethality, Sgo1 heterozygous mice (Sgo1 ) Tsukahara T, Tanno Y, Watanabe Y. Phosphorylation of the showed an increase in formation of colonic aberrant CPC by Cdk1 promotes chromosome bi-orientation. Nature. crypt foci and accelerated development of colon tumors 2010 Oct 7;467(7316):719-23 after exposure to azoxymethane, a colon carcinogen Kahyo T, Iwaizumi M, Shinmura K, Matsuura S, Nakamura T, (Yamada et al., 2012). Watanabe Y, Yamada H, Sugimura H. A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable Hematological malignancies chromatid cohesion. Oncogene. 2011 Nov 3;30(44):4453-63 Note Yamada HY, Yao Y, Wang X, Zhang Y, Huang Y, Dai W, Rao SGOL1 was aberrantly expressed in various human CV. Haploinsufficiency of SGO1 results in deregulated centrosome dynamics, enhanced chromosomal instability and leukemia cell lines and freshly isolated leukemia cells. colon tumorigenesis. Cell Cycle. 2012 Feb 1;11(3):479-88 SGOL1-knockdown suppressed the cell proliferation in Yang J, Ikezoe T, Nishioka C, Yokoyama A. A novel treatment several leukemia cell lines (Yang et al., 2013). strategy targeting shugoshin 1 in hematological malignancies. References Leuk Res. 2013 Jan;37(1):76-82 This article should be referenced as such: Scanlan MJ, Gout I, Gordon CM, Williamson B, Stockert E, Gure AO, Jäger D, Chen YT, Mackay A, O'Hare MJ, Old LJ. Kahyo T, Sugimura H. SGOL1 (shugoshin-like 1 (S. pombe)). Humoral immunity to human breast cancer: antigen definition Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11):746-748. and quantitative analysis of mRNA expression. Cancer Immun. 2001 Mar 30;1:4

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Gene Section Review

CXCL5 (chemokine (C-X-C motif) ligand 5) Anna A Bulysheva, W Andrew Yeudall VCU Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA (AAB, WAY)

Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/CXCL5ID40223ch4q13.html DOI: 10.4267/2042/51814 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

acids. The N-terminal 36 amino acids are removed to Identity generate the mature molecule 78 amino acids in length. Other names: ENA-78, SCYB5 An E-L-R (Glu-Leu-Arg) motif, important for receptor HGNC (Hugo): CXCL5 binding, is found immediately N-terminal to the C-X-C motif (Cys-Val-Cys). Location: 4q13.3 The E-L-R motif is found in pro-angiogenic Local order: On the reverse strand. chemokines (Belperio et al., 2000), while the presence of the C-X-C motif places this protein into the CXC- DNA/RNA chemokine family. CXCL5 has homology to CXCL8 (Walz et al., 1991). Description Expression The CXCL5 gene is located on human chromosome 4 at 4q13.3, starting at position 74861359 and ending at Ubiquitous in adult. position 74864496 on the reverse strand. It consists of 4 Localisation exons. Secreted. Transcription The transcript consists of 2538bp. The coding sequence Function begins at residue 119 and ends at residue 463. The Chemotaxis, neutrophil activation, angiogenesis. mRNA is polyadenylated and is translated to produce a Human CXCL5 is a substrate for several proteases 114 residue polypeptide. (Van den Steen et al., 2003; Dean et al., 2008; Starr et al., 2012). Protein These include matrix metalloprotease MMP-1, MMP-9, MMP-12, and MMP-25 (MT6-MMP), which cleave the Description N-terminal region of the mature (78aa) polypeptide. The full length polypeptide consists of 114 amino

Solid blue boxes - coding regions; patterned boxes - non-coding regions; single lines - intervening (intronic) sequences; start / stop codons and direction of transcription are indicated.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 749 SGOL1 (shugoshin-like 1 (S. pombe)) Kahyo T, Sugimura H

Schematic representation of human CXCL5. C-X-C motif is indicated in red, together with predicted intrachain disulphide bridges; E-L- R motif is indicated in blue.

MMP-12 has been reported to inactivate CXCL5, as it CXCL5 relative to primary tumor cells, as measured by results in cleavage within the ELR motif, as well as microarray and confirmed by quantitative real-time between residues 5 and 6. MMP-25 is also thought to PCR and analysis of conditioned medium (Miyazaki et activate CXCL5 by removing the N-terminal 7 amino al., 2006). Biological consequences of CXCL5 acids from the mature polypeptide, resulting in a 71 overexpression have been investigated in terms of amino acid product (8-78). MMP-9 digests CXCL5 at tumor cell proliferation and motility, both of which are multiple sites: early proteolysis involves the N-terminal reduced if CXCL5 expression is inhibited. region and is thought to potentiate CXCL5 activity, In vivo growth of xenografted tumor cells was whereas later proteolysis (upon extended incubation abrogated when CXCL5 expression was repressed by with the protease) results in CXCL5 inactivation. small hairpin RNA. Homology Gastric cancer IL-8. Conservation of this gene is observed in Oncogenesis chimpanzee, dog and cow. Overexpression of CXCL5 has been found to correlate with late stage gastric cancer and high N stage, Implicated in suggesting a role for CXCL5 in progression of gastric Cancer, pulmonary fibrosis, cancer and nodal metastasis (Park et al., 2007). This was revealed by immunostaining of gastric tumors inflammatory diseases and for CXCL5, as well as enzyme-linked immunosorbent endometriosis assay (ELISA) measurement of serum CXCL5 levels. Note Colorectal cancer CXCL5 is reportedly overexpressed in a number of Oncogenesis human tumors such as head and neck squamous cell Low expression of CXCL5 in a rat model of colorectal carcinoma, gastric, pancreatic, colorectal, prostate and lung cancer as well as in lung tissue of patients with cancer has been reported to increase the tumorigenic potential of cells that would otherwise form a less pulmonary fibrosis. CXCL5 was found to be aggressive type of colon cancer (Speetjens et al., 2008). upregulated in many types of inflammatory conditions. It has also been observed that human patients with low It plays a significant role in inflammation that occurs in CXCL5 levels in their colorectal tumors had a poorer diseases such as acute coronary syndrome, allergy, rheumatoid arthritis, inflammatory bowel disease, prognosis than those with higher expression of CXCL5. pulmonary sarcoidosis, pancreatitis and endometriosis. Pancreatic cancer Oncogenesis Oncogenesis Abnormal expression of CXCL5 has been correlated CXCL5 is secreted by pancreatic cancer cell lines, and with increased tumor cell motility and proliferation in antibody-mediated blockade of the CXCR2 receptor vitro and increased tumorigenicity in vivo. inhibits neovascularization in corneal angiogenesis It is also associated with worse clinical prognosis in assays (Wente et al., 2006). CXCL5 is also several cancer types. overexpressed in pancreatic cancer specimens, and is Head and neck squamous cell linked to poor patient survival (Frick et al., 2008). Blocking CXCR2 with an antibody, or inhibiting carcinoma CXCL5 expression with siRNA, inhibits tumor Oncogenesis xenograft formation. CXCL5 activates signaling It has been reported that metastatic head and neck through AKT-, ERK- and STAT-dependent pathways cancer cells express comparatively high levels of in pancreatic cancer cells (Li et al., 2011).

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 750 CXCL5 (chemokine (C-X-C motif) ligand 5) Bulysheva AA, Yeudall WA

Prostate cancer compared to patients with other forms of arthritis (Koch et al., 1994). Studies of rat adjuvant-induced Oncogenesis arthritis (AIA), as a model for RA, showed elevated Androgen-independent prostate cancers tend to CXCL5 levels in serum with progressive development overexpress CXCL5. It has been reported that CXCL5 of arthritis compared to control animals. Joint overexpression leads to increased cell migration and homogenates also had increased levels of CXCL5 and epithelial-to-mesenchymal transition (Kuo et al., 2011). this correlated with disease progression. Anti-CXCL5 Non-small cell lung cancer antibody treatments prior to the onset of AIA decreased Oncogenesis the severity of the disease (Halloran et al., 1999). The CXCL5 was found to play a role in development of results indicate that CXCL5 plays an important role in non-small cell lung cancer by enhancing tumor the onset and progression of RA. angiogenesis (Arenberg et al., 1998). High expression Inflammatory bowel disease of CXCL5 was correlated with vascularity of tumors. Note Passive immunity against CXCL5 resulted in a Immunohistochemical studies of colonic epithelial cells reduction of tumor growth, vascularity and metastases in normal subjects and patients with inflammatory in vivo, although there was no effect of passive bowel disease showed that CXCL5 is expressed immunity on tumor cell proliferation. predominantly by crypt epithelial cells (Keates et al., Pulmonary fibrosis 1997). CXCL5 production is significantly higher in Note patients with ulcerative colitis, with less intense Analysis of bronchoalveolar lavage (BAL) fluid and expression in Crohn's disease patients. lung tissue from patients with idiopathic pulmonary Pulmonary sarcoidosis fibrosis revealed elevated levels of the angiogenic Note chemokines CXCL5 and CXCL8, together with a Increased levels of CXCL5 were found in the serum relative decrease of angiostatic factors, correlating with and BAL fluid of patients with pulmonary sarcoidosis increased fibrosis of lung tissue (Streiter et al., 2007). compared to normal subjects, as judged by ELISA. Acute coronary syndrome (ACS) BAL levels of CXCL5 were elevated in stage III Note sarcoidosis (Sujiyama et al., 2006). Examination of CXCL5 in inflammation associated Pancreatitis with acute coronary syndrome indicated that a Note polymorphism in CXCL5 (156G>C; rs352046) was Patients with severe acute pancreatitis had significantly linked to a 2.7-fold rise in 3-year mortality (all causes; higher serum levels of CXCL5 compared to individuals C/C genotype only). Mortality was reduced in G/G with mild acute pancreatitis (Shokuhi et al., 2002). genotype individuals by the use of statins. Treatment of Samples from patients with chronic pancreatitis also human umbilical vein endothelial cells (HUVECs) with showed higher expression of CXCL5 than normal atorvastatin in vitro reduced the levels of IL-1β- pancreatic tissues, predominantly in centroacinar ducts induced CXCL5 in a dose-dependent manner (Zineh et of pancreatic lobuli (Saurer et al., 2000). These al., 2008). findings suggest a role for CXCL5 in development and Allergy maintenance of both acute and chronic pancreatitis. Note Endometriosis Activated mast cells have been shown to increase CXCL5 production significantly compared to the level Note of CXCL5 in resting cells. Supernatants from sonicated CXCL5 has also been implicated in the pathogenesis of MC-9 mast cells elicited a significant influx of endometriosis, with elevated levels of CXCL5 found in neutrophils when injected intratracheally in mice. peritoneal fluid of patients with endometriosis When the same supernatants were preincubated with compared to control subjects (Mueller et al., 2003). CXCL5-specific antibodies, neutrophil influx was Further studies showed that glandular cells, stromal dramatically reduced, implicating CXCL5 produced by fibroblasts and peritoneal macrophages were primarily activated mast cells as a critical chemoattractant for responsible for CXCL5 production in patients with neutrophils (Lukacs et al., 1998). endometriosis. Elevated levels of CXCL5 have also been found in the follicular fluid of patients with Rheumatoid arthritis (RA) endometriosis compared to controls (Wunder et al., Note 2006). Together, these studies implicate CXCL5 in the CXCL5 is reported to be significantly elevated in pathogenesis of endometriosis. synovial fluid of patients with rheumatoid arthritis

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 751 SGOL1 (shugoshin-like 1 (S. pombe)) Kahyo T, Sugimura H

and epithelial neutrophil-activating peptide-78 in patients with References pulmonary sarcoidosis. Respirology. 2006 Nov;11(6):708-14 Walz A, Burgener R, Car B, Baggiolini M, Kunkel SL, Strieter Wente MN, Keane MP, Burdick MD, Friess H, Büchler MW, RM. Structure and neutrophil-activating properties of a novel Ceyhan GO, Reber HA, Strieter RM, Hines OJ. Blockade of the inflammatory peptide (ENA-78) with homology to interleukin 8. chemokine receptor CXCR2 inhibits pancreatic cancer cell- J Exp Med. 1991 Dec 1;174(6):1355-62 induced angiogenesis. Cancer Lett. 2006 Sep 28;241(2):221-7 Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Wunder DM, Mueller MD, Birkhäuser MH, Bersinger NA. Burdick MD, Pope RM, Walz A, Strieter RM. Epithelial Increased ENA-78 in the follicular fluid of patients with neutrophil activating peptide-78: a novel chemotactic cytokine endometriosis. Acta Obstet Gynecol Scand. 2006;85(3):336-42 for neutrophils in arthritis. J Clin Invest. 1994 Sep;94(3):1012-8 Park JY, Park KH, Bang S, Kim MH, Lee JE, Gang J, Koh SS, Keates S, Keates AC, Mizoguchi E, Bhan A, Kelly CP. Song SY. CXCL5 overexpression is associated with late stage Enterocytes are the primary source of the chemokine ENA-78 gastric cancer. J Cancer Res Clin Oncol. 2007 in normal colon and ulcerative colitis. Am J Physiol. 1997 Nov;133(11):835-40 Jul;273(1 Pt 1):G75-82 Strieter RM, Gomperts BN, Keane MP. The role of CXC Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Morris SB, chemokines in pulmonary fibrosis. J Clin Invest. 2007 Xue YY, Burdick MD, Glass MC, Iannettoni MD, Strieter RM. Mar;117(3):549-56 Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM. Clin Invest. 1998 Aug 1;102(3):465-72 Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, - Lukacs NW, Hogaboam CM, Kunkel SL, Chensue SW, Burdick 8, and -13 antagonists: potential role of the macrophage in MD, Evanoff HL, Strieter RM. Mast cells produce ENA-78, terminating polymorphonuclear leukocyte influx. Blood. 2008 which can function as a potent neutrophil chemoattractant Oct 15;112(8):3455-64 during allergic airway inflammation. J Leukoc Biol. 1998 Jun;63(6):746-51 Frick VO, Rubie C, Wagner M, Graeber S, Grimm H, Kopp B, Rau BM, Schilling MK. Enhanced ENA-78 and IL-8 expression Halloran MM, Woods JM, Strieter RM, Szekanecz Z, Volin MV, in patients with malignant pancreatic diseases. Pancreatology. Hosaka S, Haines GK 3rd, Kunkel SL, Burdick MD, Walz A, 2008;8(4-5):488-97 Koch AE. The role of an epithelial neutrophil-activating peptide- 78-like protein in rat adjuvant-induced arthritis. J Immunol. Speetjens FM, Kuppen PJ, Sandel MH, Menon AG, Burg D, 1999 Jun 15;162(12):7492-500 van de Velde CJ, Tollenaar RA, de Bont HJ, Nagelkerke JF. Disrupted expression of CXCL5 in colorectal cancer is Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, associated with rapid tumor formation in rats and poor Burdick MD, Strieter RM. CXC chemokines in angiogenesis. J prognosis in patients. Clin Cancer Res. 2008 Apr Leukoc Biol. 2000 Jul;68(1):1-8 15;14(8):2276-84 Saurer L, Reber P, Schaffner T, Büchler MW, Buri C, Kappeler Zineh I, Beitelshees AL, Welder GJ, Hou W, Chegini N, Wu J, A, Walz A, Friess H, Mueller C. Differential expression of Cresci S, Province MA, Spertus JA. Epithelial neutrophil- chemokines in normal pancreas and in chronic pancreatitis. activating peptide (ENA-78), acute coronary syndrome Gastroenterology. 2000 Feb;118(2):356-67 prognosis, and modulatory effect of statins. PLoS One. 2008 Sep 3;3(9):e3117 Shokuhi S, Bhatia M, Christmas S, Sutton R, Neoptolemos JP, Slavin J. Levels of the chemokines growth-related oncogene Kuo PL, Chen YH, Chen TC, Shen KH, Hsu YL. alpha and epithelial neutrophil-activating protein 78 are raised CXCL5/ENA78 increased cell migration and epithelial-to- in patients with severe acute pancreatitis. Br J Surg. 2002 mesenchymal transition of hormone-independent prostate May;89(5):566-72 cancer by early growth response-1/snail signaling pathway. J Cell Physiol. 2011 May;226(5):1224-31 Mueller MD, Mazzucchelli L, Buri C, Lebovic DI, Dreher E, Taylor RN. Epithelial neutrophil-activating peptide 78 Li A, King J, Moro A, Sugi MD, Dawson DW, Kaplan J, Li G, Lu concentrations are elevated in the peritoneal fluid of women X, Strieter RM, Burdick M, Go VL, Reber HA, Eibl G, Hines OJ. with endometriosis. Fertil Steril. 2003 Mar;79 Suppl 1:815-20 Overexpression of CXCL5 is associated with poor survival in patients with pancreatic cancer. Am J Pathol. 2011 Van Den Steen PE, Wuyts A, Husson SJ, Proost P, Van Mar;178(3):1340-9 Damme J, Opdenakker G. Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP- Starr AE, Bellac CL, Dufour A, Goebeler V, Overall CM. 2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and Biochemical characterization and N-terminomics analysis of modulate their physiological activities. Eur J Biochem. 2003 leukolysin, the membrane-type 6 matrix metalloprotease Sep;270(18):3739-49 (MMP25): chemokine and vimentin cleavages enhance cell migration and macrophage phagocytic activities. J Biol Chem. Miyazaki H, Patel V, Wang H, Edmunds RK, Gutkind JS, 2012 Apr 13;287(16):13382-95 Yeudall WA. Down-regulation of CXCL5 inhibits squamous carcinogenesis. Cancer Res. 2006 Apr 15;66(8):4279-84 This article should be referenced as such: Sugiyama K, Mukae H, Ishii H, Kakugawa T, Ishimoto H, Bulysheva AA, Yeudall WA. CXCL5 (chemokine (C-X-C motif) Nakayama S, Shirai R, Fujii T, Mizuta Y, Kohno S. Elevated ligand 5). Atlas Genet Cytogenet Oncol Haematol. 2013; levels of interferon gamma-inducible protein-10 17(11):749-752.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 752 Atlas of Genetics and Cytogenetics

in Oncology and Haematology

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Gene Section Short Communication

MIR211 (microRNA 211) Amir Avan, Mina Maftouh, Godefridus J Peters, Elisa Giovannetti Department of Medical Oncology, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands and Department of New Sciences and Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (AA, MM), Department of Medical Oncology, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands (GJP, EG)

Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/MIR211ID50533ch15q13.html DOI: 10.4267/2042/51815 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

AGCAAAGGGG TGCTCAGTTG TCACTTCCCA Identity CAGCACGGAG) which is cleaved by the Drosha Other names: MIRN211, mir-211 ribonuclease III enzyme into 2 products, hsa-miR-211- HGNC (Hugo): MIR211 5p (26-47 bp) and hsa-miR-211-3p (63-83 bp). This miRNA is further cleaved by the cytoplasmic Location: 15q13.3 Dicer ribonuclease to the mature miR-211 sequence (5'- Local order: Based on Mapviewer, gene flanking miR- UUCCCUUUGUCAUCCUUCGCCU-3') with stem- 211 oriented on 15q13 are: loop shape. - FAN1 (FANCD2/FANCI-associated nuclease 1); In general, the mature miRNA is incorporated into a 15q13.2-q13.3 RNA-induced silencing complex (RISC), that can - MTMR10 (myotubularin related protein 10); 15q13.3 target mRNA through imperfect base pairing, leading - miR-211 (microRNA 211); 15q13.3 to translational inhibition or destabilization of the target - TRPM1 (transient receptor potential cation channel, mRNA. subfamily M, member 1); 15q13.3 - LOC283710; 15q13.3. Pseudogene No reported pseudogenes. DNA/RNA Protein Description Note miR-211 is located in the intron 6 of TRPM1 gene at 15q13, which is transcribed by RNA polymerase II. This miRNA is not translated into amino acids. Transcription Mutations The primary transcript contains of 110 nucleotides (TCACCTGGCC ATGTGACTTG TGGGCTTCCC Note TTTGTCATCC TTCGCCTAGG GCTCTGAGCA No mutations have been reported, while single GGGCAGGGAC nucleotide variations (SNPs) include: rs141424579, rs187960998, rs34520022 and rs140017415.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 753 MIR211 (microRNA 211) Avan A, et al.

Location of miR-211 in chromosome 15q13. This gene is located in the intron 6 of the TRPM1 gene within 31357235-31357344 bp. The mature miR-211 is 22 nucleotides long.

Multivariate analysis revealed that low miR-211 Implicated in expression was an independent factor of poor prognosis Pancreatic cancer (hazard ratio 2.3, P = 0.03). The expression of this miRNA was also assessed by quantitative-PCR in an Note independent cohort of laser-microdissected PDACs Giovannetti and collaborators, recently identified miR- from 60 resected patients treated with the same 211 as a prognostic factor in resected pancreatic ductal gemcitabine regimen, showing the significant adenocarcinoma (PDAC) patients using high- association of miR-211 expression status with both OS throughput microarray analysis of more than 1200 and disease-free-survival (DFS). human miRNAs in PDAC patients classified in short- term overall survivors versus long-term survivors Colorectal cancer (Giovannetti et al., 2012). This study evaluated 26 Note PDAC patients with homogeneous clinicopathological miR-211 has been found to be expressed in colorectal characteristics that underwent resection with curative cancer and a recent study showed that over-expression intent and were treated with standard gemcitabine of miR-211 in the colorectal cancer cell line HCT-116 adjuvant regimen. The miRNA microarray analysis was promotes cellular growth in vitro and in vivo by carried out in 19 samples that passed the RNA quality downregulating the expression level of the CHD5 criterion, including 13 patients with short survival and tumor suppressor gene (Cai et al., 2012). 6 patients with long survival. These results illustrated that patients with low miR-211 expression according to Glioblastoma median value had a significantly shorter median overall Note survival compared to patients with high miR-211 Glioblastoma multiforme (GBM) is the most aggressive expression (OS, 14.8, 95%CI = 13.1-16.5, vs. 25.7 brain tumor with less than one year survival time. Thus, months, 95%CI = 16.2-35.1, log-rank-P = 0.004). there is an urgent need to identify new

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 754 MIR211 (microRNA 211) Avan A, et al.

predictive/prognostic biomarkers that can stroke. Angiopoietin-1 is a vascular strengthening predict/manage the patients at earlier stages. A recent factor which acts a protective factor for pathological study showed that miRNA-211 is downregulated in vascular inflammation and leakage. The rs2507800 GBM, which might be due to aberrant methylation- variant is located in the miR-211-binding site of mediated epigenetic silencing of the miR-211 angiopoietin-1, Cheng and colleagues evaluated the promoter. Asuthkar and collaborators showed that miR- effect of the variant on angiopoietin-1 translation. They 211 has an inhibitory effect on glioma cell invasion and showed that the A allele of rs2507800 inhibited migration via suppression of MMP-9 and angiopoietin-1 translation by facilitating miR-211 demethylation of miR-211 promoter-associated CpG binding. Furthermore they assessed the association of islands, which results in insensitivity of some GBMs to the variant with stroke in 438 stroke patients and 890 radiation and chemotherapy (Asuthkar et al., 2012). controls, and replicated in an independent population of Oral carcinoma 1791 stroke patients and 1843 controls. These results illustrated that the TT genotype (rs2507800) in the 3'- Note UTR of angiopoietin-1 could reduce the risk of stroke High expression of miR-211 has been shown to be by interacting with miR-211 binding (Chen et al., associated with the advanced nodal metastasis, vascular 2010). invasion, and poor prognosis of oral carcinoma. Chang and colleagues demonstrated that enforced miR- Human retinal pigment epithelium 211 expression significantly increased the proliferation, Note migration, and anchorage-independent colony Wang and collaborators identified the critical role of formation of oral carcinoma cells, while it enhanced the miR-211 in maintaining epithelial barrier function and tumorigenicity (Chang et al., 2008). cell physiology in human retinal pigment epithelium. Breast cancer Moreover they found that miR-211 is one of the most highly expressed microRNAs in human retinal pigment Note epithelium. Expression of this miRNA was Expression of 455 miRNAs was evaluated in a highly significantly lower in the NCI60 tumor cell line panel bone metastatic MDA-MB-231 variant, compared to compared with 13 normal tissues (Wang et al., 2010). the parental MDA-MB-231 breast cancer cell line. 16 miRNAs (3.5%) were found to have >3-fold expression To be noted difference between the two cell types. This study showed that miRNA-211 inhibits TGF-β-induced IL-11 Note production by binding to its 3' UTR in bone metastatic This study was partially supported by grants from breast cancer cells (Pollari et al., 2012). Netherlands Organization for Scientific Research, Melanoma VENI grant (Elisa Giovannetti), CCA Foundation 2012 (Elisa Giovannetti, Amir Avan, Godefridus J Peters), Note Iranian grant from Faculty of Medicine, Mashhad Several studies showed that miR-211 is downregulated University of Medical Sciences, Mashhad, Iran (Amir in melanoma and has been found to act as a tumour Avan), Italian Minister of Research, AIRC/Marie Curie suppressor. In particular, Xu and collaborators International Fellowship (Elisa Giovannetti), PRIN- performed miRNA microarray expression in 52 2009 (Elisa Giovannetti), and Istituto Toscano Tumori formalin-fixed and paraffin-embedded specimens from (Elisa Giovannetti). different stages of melanomagenesis and 15 cell lines. They showed that expression of miR-211 was down- References regulated in melanoma cells and melanoblasts compared to melanocytes, and upregulation of miR-211 Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement could lead to suppression of tumor invasion in of miRNA in cell growth and apoptosis. Nucleic Acids Res. melanoma (Levy et al., 2010; Mazar et al., 2010; Xu et 2005;33(4):1290-7 al,. 2012). Chang KW, Liu CJ, Chu TH, Cheng HW, Hung PS, Hu WY, Lin Cervical cancer SC. Association between high miR-211 microRNA expression and the poor prognosis of oral carcinoma. J Dent Res. 2008 Note Nov;87(11):1063-8 In cervical cancer, miR-211 has been shown to be Chen J, Yang T, Yu H, Sun K, Shi Y, Song W, Bai Y, Wang X, upregulated, while inhibition of this miRNA decreased Lou K, Song Y, Zhang Y, Hui R. A functional variant in the 3'- the growth of Hela cells (Cheng et al., 2005). UTR of angiopoietin-1 might reduce stroke risk by interfering with the binding efficiency of microRNA 211. Hum Mol Genet. Stroke risk 2010 Jun 15;19(12):2524-33 Note Levy C, Khaled M, Iliopoulos D, Janas MM, Schubert S, Pinner Brain vascular leaking and inflammation has been S, Chen PH, Li S, Fletcher AL, Yokoyama S, Scott KL, Garraway LA, Song JS, Granter SR, Turley SJ, Fisher DE, reported as two important pathological processes of Novina CD. Intronic miR-211 assumes the tumor suppressive

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 755 MIR211 (microRNA 211) Avan A, et al.

function of its host gene in melanoma. Mol Cell. 2010 Dec Giovannetti E, van der Velde A, Funel N, Vasile E, Perrone V, 10;40(5):841-9 Leon LG, De Lio N, Avan A, Caponi S, Pollina LE, Gallá V, Sudo H, Falcone A, Campani D, Boggi U, Peters GJ. High- Mazar J, DeYoung K, Khaitan D, Meister E, Almodovar A, throughput microRNA (miRNAs) arrays unravel the prognostic Goydos J, Ray A, Perera RJ. The regulation of miRNA-211 role of MiR-211 in pancreatic cancer. PLoS One. expression and its role in melanoma cell invasiveness. PLoS 2012;7(11):e49145 One. 2010 Nov 1;5(11):e13779 Pollari S, Leivonen SK, Perälä M, Fey V, Käkönen SM, Wang FE, Zhang C, Maminishkis A, Dong L, Zhi C, Li R, Zhao Kallioniemi O. Identification of microRNAs inhibiting TGF-β- J, Majerciak V, Gaur AB, Chen S, Miller SS. MicroRNA- induced IL-11 production in bone metastatic breast cancer 204/211 alters epithelial physiology. FASEB J. 2010 cells. PLoS One. 2012;7(5):e37361 May;24(5):1552-71 Xu Y, Brenn T, Brown ER, Doherty V, Melton DW. Differential Asuthkar S, Velpula KK, Chetty C, Gorantla B, Rao JS. expression of microRNAs during melanoma progression: miR- Epigenetic regulation of miRNA-211 by MMP-9 governs glioma 200c, miR-205 and miR-211 are downregulated in melanoma cell apoptosis, chemosensitivity and radiosensitivity. and act as tumour suppressors. Br J Cancer. 2012 Jan Oncotarget. 2012 Nov;3(11):1439-54 31;106(3):553-61 Cai C, Ashktorab H, Pang X, Zhao Y, Sha W, Liu Y, Gu X. MicroRNA-211 expression promotes colorectal cancer cell This article should be referenced as such: growth in vitro and in vivo by targeting tumor suppressor Avan A, Maftouh M, Peters GJ, Giovannetti E. MIR211 CHD5. PLoS One. 2012;7(1):e29750 (microRNA 211). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11):753-756.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 756 Atlas of Genetics and Cytogenetics

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Gene Section Short Communication

SRD5A2 (steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4- dehydrogenase alpha 2)) Nelson LS Tang, Chen Di Liao Department of Chemical Pathology, The Chinese University of Hong Kong, China (NLST, CDL)

Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/SRD5A2ID42385ch2p23.html DOI: 10.4267/2042/51816 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Mutations HGNC (Hugo): SRD5A2 Note Location: 2p23.1 There were over 29 mutations of SRD5A2 gene documented in literature, including 12 single amino DNA/RNA acid missense substitutions (Makridakis et al., 2000; Vilchis et al., 2008; Nie et al., 2011). Description It has been suggested that exon 4 may be a mutation Genomic DNA of SRD5A2 gene spans about 58.6 kbp hotspot region on the SRD5A2 gene (Vilchis et al., on chromosome 2p23. 2008). Some of the more studied polymorphisms of SRD5A2 Transcription included V89L, A49T, and the (TA)n dinucleotide Five exons with a long 3' UTR. repeat. Protein Implicated in Description Prostate cancer SRD5A2 is a microsomal protein of 254 amino acids in Note length. Various genetic studies from multiple ethnic Expression populations have shown genetic variations in the SRD5A2 gene are associated with prostate cancer. Androgen sensitive tissues, such as prostate. Polymorphisms V89L, A29T, and the (TA)n repeat are Localisation some of well-known SRD5A2 variation that have been liked to prostate cancer risk. Microsome. However, these associations are not always consistent. Function For example, the V89L (rs523349) variant is a SRD5A2 protein is an enzyme that converts missense single nucleotide polymorphism resulting in a testosterone to 5-alpha dihydrotestosterone (DHT) and valine to leucine substitution at condon 89 that reduced progesterone or corticosterone into 5-alpha-3- SRD5A2 enzyme activity. oxosteroids. More than couple dozen of studies performed genetic It is active at acidic pH, and is inhibited by finasteride. association studies between V89L polymorphism and prostate cancer risk since 1997. Homology Although the association has been found significant 50% homology with human SRD5A1 isoenzyme and repeatedly, the results were inconsistent and conflicting 46% homology with rat 5-alpha-reductase.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 757 SRD5A2 (steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4- Tang NLS, Liao CD dehydrogenase alpha 2))

(Nam et al., 2001; Salam et al., 2005, Hsing et al., Allen NE, Forrest MS, Key TJ. The association between 2001). polymorphisms in the CYP17 and 5alpha-reductase (SRD5A2) genes and serum androgen concentrations in men. Cancer Recently, a meta-analysis review (Wang et al., 2010) Epidemiol Biomarkers Prev. 2001 Mar;10(3):185-9 was conducted on 25 genetic studies of SRD5A2 V89L Hsing AW, Chen C, Chokkalingam AP, Gao YT, Dightman DA, polymorphism and prostate cancer, which included Nguyen HT, Deng J, Cheng J, Sesterhenn IA, Mostofi FK, additional subgroup analysis in Asian, African, Stanczyk FZ, Reichardt JK. Polymorphic markers in the European and age ≤ 65 group. In overall analysis, no SRD5A2 gene and prostate cancer risk: a population-based significant association was found between V89L and case-control study. Cancer Epidemiol Biomarkers Prev. 2001 prostate cancer risk. Subgroup analysis revealed a Oct;10(10):1077-82 slight but significant increased risk in European men Nam RK, Toi A, Vesprini D, Ho M, Chu W, Harvie S, Sweet J, with at least one L-allele (LL+LV vs VV, OR=1.11; Trachtenberg J, Jewett MA, Narod SA. V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate 95%CI=1.03-1.19; P<0.01), and in men younger than cancer presence and progression. Urology. 2001 65 with LL genotype when compared to those with VV Jan;57(1):199-204 genotype (OR=1.70; 95%CI=1.14-2.68; P=0.02). The Zeigler-Johnson CM, Walker AH, Mancke B, Spangler E, interethnic discrepancy of the effect of V89L may have Jalloh M, McBride S, Deitz A, Malkowicz SB, Ofori-Adjei D, arisen from a variable influence of the risk allele due to Gueye SM, Rebbeck TR. Ethnic differences in the frequency of the significantly varied allelic distribution of V89L prostate cancer susceptibility alleles at SRD5A2 and CYP3A4. between the ethnic groups (Zeigler-Johnson et al., Hum Hered. 2002;54(1):13-21 2002). Salam MT, Ursin G, Skinner EC, Dessissa T, Reichardt JK. It was concluded that the V89L polymorphism plays a Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic low-penetrant role in the risk of prostate cancer among hyperplasia and prostate cancer. Urol Oncol. 2005 Jul- European and men younger than 65 years of age. Aug;23(4):246-53 Oncogenesis Vilchis F, Valdez E, Ramos L, García R, Gómez R, Chávez B. Androgen levels have been suggested to play an Novel compound heterozygous mutations in the SRD5A2 gene important role in the etiology of prostate cancer. The from 46,XY infants with ambiguous external genitalia. J Hum Genet. 2008;53(5):401-6 same SRD5A2 genetic variations linked to prostate cancer has also been repeatedly shown to be associated Jiang J, Tang NL, Ohlsson C, Eriksson AL, Vandenput L, Liao with various circulating androgen level in the blood, C, Wang X, Chan FW, Kwok A, Orwoll E, Kwok TC, Woo J, Leung PC. Association of SRD5A2 variants and serum including testosterone, dihydrotestosterone and various androstane-3alpha,17beta-diol glucuronide concentration in forms of their metabolites (Makridakis et al., 2000; Chinese elderly men. Clin Chem. 2010 Nov;56(11):1742-9 Allen et al., 2001; Hsing et al., 2001). Wang C, Tao W, Chen Q, Hu H, Wen XY, Han R. SRD5A2 Therefore, it is possible that these risk-predisposing V89L polymorphism and prostate cancer risk: a meta-analysis. polymorphisms may cause changes in the SRD5A2 Prostate. 2010 Feb 1;70(2):170-8 enzyme functional activity that results in the variation Nie M, Zhou Q, Mao J, Lu S, Wu X. Five novel mutations of of circulating androgens, and ultimately leads to the SRD5A2 found in eight Chinese patients with 46,XY disorders development of prostate cancer. of sex development. Mol Hum Reprod. 2011 Jan;17(1):57-62 References This article should be referenced as such: Tang NLS, Liao CD. SRD5A2 (steroid-5-alpha-reductase, Hsing AW, Tsao L, Devesa SS. International trends and alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4- patterns of prostate cancer incidence and mortality. Int J dehydrogenase alpha 2)). Atlas Genet Cytogenet Oncol Cancer. 2000 Jan 1;85(1):60-7 Haematol. 2013; 17(11):757-758. Makridakis NM, di Salle E, Reichardt JK. Biochemical and pharmacogenetic dissection of human steroid 5 alpha- reductase type II. Pharmacogenetics. 2000 Jul;10(5):407-13

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 758 Atlas of Genetics and Cytogenetics

in Oncology and Haematology

OPEN ACCESS JOURNAL INIST -CNRS

Gene Section Review

SSX2 (synovial sarcoma, X breakpoint 2) Josiane Eid, Christina Garcia, Andrea Frump Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA (JE, CG, AF)

Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/SSX2ID42406chXp11.html DOI: 10.4267/2042/51817 This article is an update of : Eid J, Garcia C, Frump A. SSX2 (Synovial Sarcoma, X breakpoint 2). Atlas Genet Cytogenet Oncol Haematol 2009;13(3):218-221.

Identity several human cancers. Other names: CT5.2, HD21, HOM-MEL-40, Description MGC119055, MGC15364, MGC3884, SSX, SSX2A, So far, two SSX2 protein isoforms (a and b) are known SSX2B to exist. HGNC (Hugo): SSX2 Their mRNAs correspond to SV1 (1466 bases) and SV3 (1322 bases) splice variants, respectively. Location: Xp11.22 The start codon for both isoforms is located in exon 2. SSX2 isoform a is 233 amino acids (26.5 kD) and DNA/RNA SSX2 isoform b 188 amino acids (21.6 kD). Of both Note isoforms, SSX2 isoform b is the most commonly seen SSX2 is a member of a family of at least nine genes and so far the best studied. (SSX1, SSX2, SSX3, SSX4, SSX5, SSX6, SSX7, SSX8 and SSX9) and ten pseudogenes ( ψSSX1-10), all Expression arranged in two clusters on the X chromosome, except SSX2 is a nuclear protein normally expressed at high ψSSX10 (Gure et al., 2002). levels in the developing and normal adult testis (Apale and B spermatogonia) (Chen et al., 2011; Lim et al., Description 2011), and less abundantly in the thyroid gland (Crew The SSX2 gene locus encompasses 9 exons and 10304 et al., 1995). bp (Xp11; 52725946-52736249). Its structural analysis (Lim et al., 1998) revealed two Transcription functional domains; an N-terminal region (amino acids 20-83) homologous to a Kruppel-associated box The SSX2 gene is transcribed on the minus strand. 7 (KRAB) and a C-terminal 33 amino acids domain SSX2 mRNA splice variants (SV1-SV7) have been (amino acids 155-188) with a potent transcription detected in liver, testis, skin melanoma, endometrium, repressor activity (SSXRD). choriocarcinoma, placenta, spleen of Hodgkins KRAB boxes are usually present in zinc finger proteins lymphoma. and are implicated in transcription repression. SSX2 lacks DNA binding motifs and is thought to function in Protein gene regulation through interaction with other Note transcription regulators. SSX2 is gaining importance as a developmental factor It contains a high density of charged amino acids involved in the pathogenesis of synovial sarcoma, and (about 40%) and several consensus motifs for tyrosine as an immunotherapeutic target for phosphorylation and N-glycosylation.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 759 SSX2 (synovial sarcoma, X breakpoint 2) Eid J, et al.

SSX2 locus and mRNA splice variants. Note: Exons are drawn to scale.

SSX2 protein isoforms. mRNAs and protein composition of SSX2 isoforms a and b. Open boxes are non-coding exons.

Localisation DNA methylation, repressive histone modifications and inaccessibility of promoter regions to transcription SSX2 is usually localized in the nucleus (dos Santos et machineries. al., 2000). Other SSX2-interacting partners include the LIM However, cytoplasmic SSX2 was detected in homeobox protein LHX4 (de Bruijn et al., 2008), a pluripotent mesenchymal stem cells before Ras-like GTPase Interactor, RAB3IP (de Bruijn et al., differentiation (Cronwright et al., 2005). 2002) thought to be involved in vesicular transport, and Function SSX2IP, a putative cell cycle/circadian rhythm regulator. SSX2IP expression SSX2 is thought to function in germ line cell on the surface of myeloid leukemia cells (AML) marks development (Chen et al., 2011) as a repressive gene it as an appropriate target for AML immunotherapy regulator. (Breslin et al., 2007). Its control of gene expression is believed to be Recent evidence demonstrated a role for SSX2IP in epigenetic in nature and to involve chromatin promoting hepatocellular tumor metastasis and modification and remodeling. resistance to chemotherapy (Li et al., 2013). This is likely mediated by SSX2 association with the Active studies are beginning to yield insights into Polycomb gene-silencing complex at the SSXRD SSX2 biological functions. domain (Soulez et al., 1999; Barco et al., 2009; Przybyl Recent evidence demonstrated a regulatory role for et al., 2012), and with histones (Kato et al., 2002). SSX2 in nuclear receptor signaling and cancer cell Polycomb silencing involves chromatin compaction, invasion (Chen et al., 2012).

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A similar SSX2 effect on stem cell migration was They represent the last 78 amino acids of SSX2 reported previously (Cronwright et al., 2005). isoform b. Homology This region lacks the KRAB repressive domain but retains the SSXRD region (Crew et al., 1995; de Leeuw Human SSX2 is a member of a nine-gene family et al., 1995; Wei et al., 2003). (SSX1, SSX2, SSX3, SSX4, SSX5, SSX6, SSX7, SS presents in two distinct morphologies, monophasic, SSX8 and SSX9) located on the X chromosome. The populated by spindle tumor cells, and biphasic with an SSX proteins are highly homologous at the nucleotide additional glandular epithelial component. (about 90%) and the protein level (80%-90%). Several studies have demonstrated a strong correlation They are encoded by six exons and their expression is between the translocation subtype, tumor morphology normally confined to testis (Gure et al., 1997; Gure et and the clinical course of the disease. While the al., 2002). majority of SS18-SSX2 containing tumors were found Recently, a mouse SSX gene family with 13 members to be monophasic, SS18-SSX1 was mostly detected in and conserved KRAB and SSXRD domains has been the biphasic tumors and was associated with a shorter identified (Chen et al., 2003). metastasis-free period and a worse prognosis (Kawai et al., 1998; Antonescu et al., 2000; Ladanyi et al., 2002; Implicated in Fernebro et al., 2006). However, the notion of the Synovial sarcoma SS18-SSX subtype as a prognostic parameter influencing disease progression is still controversial Note due to contradictory data from later studies (Guillou et Synovial sarcoma (SS) is an aggressive soft tissue al., 2004; Ladanyi, 2005). tumor that afflicts young adults between 15 and 40 The molecular function of SS18-SSX is key to cancer years of age. development (dos Santos et al., 2001; de Bruijn et al., Though its cell of origin is still unknown, it is thought 2007; Przybyl et al., 2012). to be a mesenchymal stem cell (Haldar et al., 2007; Fusion of SSX1/2 to SS18 results in the disruption of Naka et al., 2010). SS18 and its associated chromatin- Synovial sarcomas most frequently arise in the para- remodeling/coactivator complexes (SWI/SNF, p300) articular areas, but are also known to appear in other normal function in gene expression (de Bruijn et al., tissues such as the lung, heart, kidney, stomach, 2006). SSX affinity for developmental genes controlled intestine, the abdomen, head and neck, and the nervous by Polycomb leads to the deregulation of such genes by system (Ferrari et al., 2008). SS18-SSX1/2 (Barco et al., 2009; Su et al., 2012). Synovial sarcoma is characterized by a unique Deregulation of expression programs by SS18-SSX1/2 chromosomal translocation event, t(X;18)(p11.2;q11.2) results in a series of biological events implicated in that involves a break in the SS18 gene on chromosome synovial sarcoma pathogenesis. These events likely 18 and another in a SSX gene on the X chromosome. include reprogramming of stem cell differentiation When fusion occurs at the breakpoints, it generates a (Garcia et al., 2012), and untimely activation of hybrid gene, SS18-SSX, which encodes a potent oncogenic pathways such as IGF2 (Sun et al., 2006), oncogene. SS18-SSX is thought to initiate Wnt (Horvai et al., 2006; Pretto et al., 2006; Bozzi et tumorigenesis and contribute to the development of al., 2008), FGF (Ishibe et al., 2005; Garcia et al., 2012), synovial sarcoma (Ladanyi, 2001; Przybyl et al., 2012). and ephrin (Barco et al., 2007), as well as reactivation The t(X;18) tanslocation is the hallmark of synovial of the anti-apoptotic pathway and the bcl-2 oncogene sarcomas. SS18-SSX is present in over 95% of SS (Mancuso et al., 2000, Jones et al., 2013).SS18-SSX2 cases. variants are rare. Its presence in human tumors is therefore of One was described by Fligman et al (1995). It contains considerable diagnostic value and is usually detected an additional 126 bp segment proximal to SSX2 Exon using FISH, RT-PCR, qPCR or real time PCR (Amary 6, where the break occurred in Exon 5 while et al., 2007; Ten Heuvel et al., 2008). maintaining the frame. Of the nine members of the SSX family, the SSX1 and Another SS18-SSX2 variant includes 50 additional SSX2 gene loci are the most frequent sites of breakage base pairs of SSX2 Exon 5 (Otsuka et al., 2006). in SS, and occasionally SSX4. Hybrid/Mutated gene The break in SSX occurs at the beginning of exon 6. SS18-SSX2. According to cDNA sequence data, the SSX2 component contained in the SS18-SSX2 oncogene consists of exons 6 and 8.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 761 SSX2 (synovial sarcoma, X breakpoint 2) Eid J, et al.

SS18-SSX fusion protein generated by the t(X;18)(p11.2;q11.2) chromosomal translocation. (X) represents cross-over. Arrowheads indicate breakpoints on SS18 and SSX.

Cancer / testis antigen reactivated in colorectal carcinoma (Tureci et al., 1998; Scanlan et al., several cancers (CT antigen-SSX2, 2002), hepatocellular carcinoma (Chen et al., 2001; Bricard et al., 2005; Wu et al., 2006), prostate cancer HOM-MEL40, CT5.2) (Dubovsky and McNeel, 2007; Smith and McNeel, Note 2011), glioma (Tureci et al., 1996, Tureci et al., 1998), SSX2 is a major prototype of CT antigens (e.g. MAGE, stomach cancer (Mashino et al., 2001), thyroid cancer GAGE, NY-Eso-1), a group of proteins whose (Tureci et al., 1996), lymphoma (Tureci et al., 1998; expression is restricted to testis and human cancers. A Colleoni et al., 2002), leukemia (Niemeyer et al., large subset of CT antigen genes (over 30), including 2003), neuroblastoma (Chi et al., 2002), osteosarcoma the SSX family, are located on the X chromosome, and (Naka et al., 2002), ovarian cancer (Tureci et al., 1998; are, for reasons unknown, aberrantly reactivated in Valmori et al., 2006), and kidney cancer (Du et al., several major cancers. The complete absence of CT 2005). antigen expression in normal tissues renders them ideal Prognosis targets for cancer immunotherapy (Gure et al., 1997; In several cancers, SSX2 and other CT antigens are Simpson et al., 2005; Smith and McNeel, 2010; Lim et considered diagnostic and prognostic markers of al., 2012). advanced malignancy. In multiple myeloma, non-small Disease cell lung cancer, prostate cancer, and colorectal cancer, Immunogenic response to reactivated SSX2 was first their coordinate expression is correlated with markedly discovered in the sera of patients with malignant reduced survival (Dubovsky and McNeel, 2007; Gure melanoma (Tureci et al., 1996). Since then aberrant et al., 2005; Taylor et al., 2005) and metastasis (Choi expression of SSX2 has been detected in a large array and Chang, 2012). of human cancers: skin melanoma (Tureci et al., 1998), Immunotherapy: breast cancer (Tureci et al., 1998; Mashino et al., The high immunogenicity of CT antigens and their 2001), endometrial cancer (Tureci et al., 1998), lung tissue-restricted expression make them optimal targets cancer (Gure et al., 2005), bladder cancer (Tureci et al., for tumor immunotherapy and vaccine development. 1998), head-neck cancer (Tureci et al., 1998; SSX2 is a major tumor antigen. Due to SSX2 wide Atanackovic et al., 2006), synovial sarcoma (Tureci et expression in cancer, a single anti-SSX2 therapy will al., 1998), multiple myeloma (Taylor et al., 2005), potentially benefit multiple diseases. Immunodominant

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SSX2-derived peptides that elicit adequate T-cell dos Santos NR, de Bruijn DR, Kater-Baats E, Otte AP, van responses have been identified, and initial reports have Kessel AG. Delineation of the protein domains responsible for SYT, SSX, and SYT-SSX nuclear localization. Exp Cell Res. described their successful use in vivo (Wagner et al., 2000 Apr 10;256(1):192-202 2003; Ayyoub et al., 2004a; Ayyoub et al., 2004b; Mancuso T, Mezzelani A, Riva C, Fabbri A et al.. Analysis of Neumann et al., 2004; Ayyoub et al., 2005; Kyyamova SYT-SSX fusion transcripts and bcl-2 expression and et al., 2006; Huang et al., 2007; Neumann et al., 2011; phosphorylation status in synovial sarcoma. Lab Invest. 2000 Smith and McNeel, 2011). Since the majority of tumors Jun;80(6):805-13 express more than one CT antigen, attempts at Chen CH, Chen GJ, Lee HS, Huang GT, Yang PM, Tsai LJ, generating polyvalent T cells directed against multiple Chen DS, Sheu JC. Expressions of cancer-testis antigens in epitopes for simultaneous antigen recognition are human hepatocellular carcinomas. Cancer Lett. 2001 Mar ongoing (Gerdemann et al., 2011; Smith et al., 2011). 26;164(2):189-95 Notably, CT antigen-specific cytotoxic T lymphocytes dos Santos NR, de Bruijn DR, van Kessel AG. Molecular were able to recognize and destroy chemoresistant mechanisms underlying human synovial sarcoma lymphoma cells expressing the cognate antigens development. Genes Chromosomes Cancer. 2001 Jan;30(1):1- 14 (Shafer et al., 2010). Finally, CT antigen directed immunotherapy could potentially become a valuable Ladanyi M. Fusions of the SYT and SSX genes in synovial addition to chemotherapy for effective treatment of sarcoma. Oncogene. 2001 Sep 10;20(40):5755-62 cancer. Mashino K, Sadanaga N, Tanaka F et al.. Expression of multiple cancer-testis antigen genes in gastrointestinal and References breast carcinomas. 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Cancer Res. 2006 Oct 1;66(19):9474-82 Ayyoub M, Hesdorffer CS, Montes M, Merlo A et al.. An immunodominant SSX-2-derived epitope recognized by CD4+ Fernebro J, Francis P, Edén P, Borg A, Panagopoulos I, T cells in association with HLA-DR. J Clin Invest. 2004b Mertens F, Vallon-Christersson J, Akerman M, Rydholm A, Apr;113(8):1225-33 Bauer HC, Mandahl N, Nilbert M. Gene expression profiles relate to SS18/SSX fusion type in synovial sarcoma. Int J Guillou L, Benhattar J, Bonichon F, Gallagher G et al.. Cancer. 2006 Mar 1;118(5):1165-72 Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a Horvai AE, Kramer MJ, O'Donnell R. Beta-catenin nuclear multicenter, retrospective analysis. J Clin Oncol. 2004 Oct expression correlates with cyclin D1 expression in primary and 15;22(20):4040-50 metastatic synovial sarcoma: a tissue microarray study. Arch Pathol Lab Med. 2006 Jun;130(6):792-8 Neumann F, Wagner C, Stevanovic S, Kubuschok B, Schormann C, Mischo A, Ertan K, Schmidt W, Pfreundschuh Kyyamova RG, Gryshkova VS, Zhyvoloup AM. Expression of M. Identification of an HLA-DR-restricted peptide epitope with a SSX2 tumor antigen in baculovirus expression system and its promiscuous binding pattern derived from the cancer testis application for screening of blood serum of melanoma patients. antigen HOM-MEL-40/SSX2. Int J Cancer. 2004 Nov Exp Oncol. 2006 Jun;28(2):110-3 20;112(4):661-8 Otsuka S, Nishijo K, Nakayama T, Aoyama T, Ishibe T, Ayyoub M, Merlo A, Hesdorffer CS, Speiser D, Rimoldi D, Shibata KR, Shima Y, Nakamura T, Otsuka T, Toguchida J. A Cerottini JC, Ritter G, Chen YT, Old LJ, Stevanovic S, Valmori variant of the SYT-SSX2 fusion gene in a case of synovial D. Distinct but overlapping T helper epitopes in the 37-58 sarcoma. Cancer Genet Cytogenet. 2006 May;167(1):82-8 region of SSX-2. Clin Immunol. 2005 Jan;114(1):70-8 Pretto D, Barco R, Rivera J, Neel N, Gustavson MD, Eid JE. Bricard G, Bouzourene H, Martinet O, Rimoldi D, Halkic N, The synovial sarcoma translocation protein SYT-SSX2 recruits Gillet M, Chaubert P, Macdonald HR, Romero P, Cerottini JC, beta-catenin to the nucleus and associates with it in an active Speiser DE. Naturally acquired MAGE-A10- and SSX-2- complex. Oncogene. 2006 Jun 22;25(26):3661-9 specific CD8+ T cell responses in patients with hepatocellular carcinoma. J Immunol. 2005 Feb 1;174(3):1709-16 Sun Y, Gao D, Liu Y, Huang J, Lessnick S, Tanaka S. IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein Cronwright G, Le Blanc K, Götherström C, Darcy P, Ehnman SYT-SSX1. Oncogene. 2006 Feb 16;25(7):1042-52 M, Brodin B. Cancer/testis antigen expression in human mesenchymal stem cells: down-regulation of SSX impairs cell Valmori D, Qian F, Ayyoub M, Renner C, Merlo A, Gnjatic S, migration and matrix metalloproteinase 2 expression. Cancer Stockert E, Driscoll D, Lele S, Old LJ, Odunsi K. Expression of Res. 2005 Mar 15;65(6):2207-15 synovial sarcoma X (SSX) antigens in epithelial ovarian cancer and identification of SSX-4 epitopes recognized by CD4+ T Du P, Yu LZ, Ma M, Geng L, Wang XS, Xin DQ, Na YQ. cells. Clin Cancer Res. 2006 Jan 15;12(2):398-404 [Expression of SSX2 gene in human urologic neoplasms]. Zhonghua Wai Ke Za Zhi. 2005 Mar 15;43(6):379-81 Wu LQ, Lu Y, Wang XF, Lv ZH, Zhang B, Yang JY. Expression of cancer-testis antigen (CTA) in tumor tissues and peripheral Gure AO, Chua R, Williamson B, Gonen M, Ferrera CA, blood of Chinese patients with hepatocellular carcinoma. Life Gnjatic S, Ritter G, Simpson AJ, Chen YT, Old LJ, Altorki NK. Sci. 2006 Jul 17;79(8):744-8 Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer. Clin Amary MF, Berisha F, Bernardi Fdel C, Herbert A, James M, Cancer Res. 2005 Nov 15;11(22):8055-62 Reis-Filho JS, Fisher C, Nicholson AG, Tirabosco R, Diss TC, Flanagan AM. Detection of SS18-SSX fusion transcripts in Ishibe T, Nakayama T, Okamoto T, Aoyama T, Nishijo K, formalin-fixed paraffin-embedded neoplasms: analysis of Shibata KR, Shima Y, Nagayama S, Katagiri T, Nakamura Y, conventional RT-PCR, qRT-PCR and dual color FISH as Nakamura T, Toguchida J. Disruption of fibroblast growth diagnostic tools for synovial sarcoma. Mod Pathol. 2007 factor signal pathway inhibits the growth of synovial sarcomas: Apr;20(4):482-96 potential application of signal inhibitors to molecular target therapy. Clin Cancer Res. 2005 Apr 1;11(7):2702-12 Barco R, Hunt LB, Frump AL, Garcia CB et al.. The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton Ladanyi M. Correlates of SYT-SSX fusion type in synovial through activation of the ephrin pathway. Mol Biol Cell. 2007 sarcoma: getting more complex but also more interesting? J Oct;18(10):4003-12 Clin Oncol. 2005 May 20;23(15):3638-9; author reply 3639-40 Breslin A, Denniss FA, Guinn BA. SSX2IP: an emerging role in Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. cancer. Biochem Biophys Res Commun. 2007 Nov Cancer/testis antigens, gametogenesis and cancer. Nat 23;363(3):462-5 Rev Cancer. 2005 Aug;5(8):615-25 de Bruijn DR, Nap JP, van Kessel AG. The (epi)genetics of human synovial sarcoma. Genes Chromosomes Cancer. 2007 Taylor BJ, Reiman T, Pittman JA, Keats JJ, de Bruijn DR, Mant Feb;46(2):107-17 MJ, Belch AR, Pilarski LM. SSX cancer testis antigens are expressed in most multiple myeloma patients: co-expression of Dubovsky JA, McNeel DG. Inducible expression of a prostate SSX1, 2, 4, and 5 correlates with adverse prognosis and high cancer-testis antigen, SSX-2, following treatment with a DNA frequencies of SSX-positive PCs. J Immunother. 2005 Nov- methylation inhibitor. 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Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 764 SSX2 (synovial sarcoma, X breakpoint 2) Eid J, et al.

Haldar M, Hancock JD, Coffin CM, Lessnick SL, Capecchi MR. Neumann F, Kubuschok B, Ertan K, Schormann C, Stevanovic A conditional mouse model of synovial sarcoma: insights into a S, Preuss KD, Schmidt W, Pfreundschuh M. A peptide epitope myogenic origin. Cancer Cell. 2007 Apr;11(4):375-88 derived from the cancer testis antigen HOM-MEL-40/SSX2 capable of inducing CD4 ⁺ and CD8 ⁺ T-cell as well as B-cell Huang CJ, Chen RH, Vannelli T, Lee F, Ritter E, Ritter G, Old responses. Cancer Immunol Immunother. 2011 LJ, Batt CA. Expression and purification of the cancer antigen Sep;60(9):1333-46 SSX2: a potential cancer vaccine. Protein Expr Purif. 2007 Dec;56(2):212-9 Smith HA, Cronk RJ, Lang JM, McNeel DG. Expression and immunotherapeutic targeting of the SSX family of cancer-testis Bozzi F, Ferrari A, Negri T, Conca E, Luca da R, Losa M, antigens in prostate cancer. Cancer Res. 2011 Nov Casieri P, Orsenigo M, Lampis A, Meazza C, Casanova M, 1;71(21):6785-95 Pierotti MA, Tamborini E, Pilotti S. Molecular characterization of synovial sarcoma in children and adolescents: evidence of Smith HA, McNeel DG. Vaccines targeting the cancer-testis akt activation. Transl Oncol. 2008 Jul;1(2):95-101 antigen SSX-2 elicit HLA-A2 epitope-specific cytolytic T cells. J Immunother. 2011 Oct;34(8):569-80 de Bruijn DR, van Dijk AH, Willemse MP, van Kessel AG. The C terminus of the synovial sarcoma-associated SSX proteins Chen L, Zhou WB, Zhao Y, Liu XA, Ding Q, Zha XM, Wang S. interacts with the LIM homeobox protein LHX4. Oncogene. Cancer/testis antigen SSX2 enhances invasiveness in MCF-7 2008 Jan 24;27(5):653-62 cells by repressing ER α signaling. Int J Oncol. 2012 Jun;40(6):1986-94 Ferrari A, Bisogno G, Alaggio R, Cecchetto G, Collini P, Rosolen A, Meazza C, Indolfi P, Garaventa A, De Sio L, Choi J, Chang H. The expression of MAGE and SSX, and D'Angelo P, Tamaro P, Casanova M, Carli M. Synovial correlation of COX2, VEGF, and survivin in colorectal cancer. sarcoma of children and adolescents: the prognostic role of Anticancer Res. 2012 Feb;32(2):559-64 axial sites. Eur J Cancer. 2008 Jun;44(9):1202-9 Garcia CB, Shaffer CM, Alfaro MP, Smith AL, Sun J, Zhao Z, Ten Heuvel SE, Hoekstra HJ, Suurmeijer AJ. Diagnostic Young PP, VanSaun MN, Eid JE. Reprogramming of accuracy of FISH and RT-PCR in 50 routinely processed mesenchymal stem cells by the synovial sarcoma-associated synovial sarcomas. Appl Immunohistochem Mol Morphol. 2008 oncogene SYT-SSX2. Oncogene. 2012 May 3;31(18):2323-34 May;16(3):246-50 Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A, Lin S, Barco R, Garcia CB, Eid JE. The synovial sarcoma-associated Poulin N, Yi L, Rossi FM, Kast J, Capecchi MR, Underhill TM, SYT-SSX2 oncogene antagonizes the polycomb complex Nielsen TO. Deconstruction of the SS18-SSX fusion protein Bmi1. PLoS One. 2009;4(4):e5060 oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell. 2012 Mar 20;21(3):333-47 Naka N, Takenaka S, Araki N, Miwa T, Hashimoto N, Yoshioka K, Joyama S, Hamada K, Tsukamoto Y, Tomita Y, Ueda T, Lim SH, Zhang Y, Zhang J. Cancer-testis antigens: the current Yoshikawa H, Itoh K. Synovial sarcoma is a stem cell status on antigen regulation and potential clinical use. Am J malignancy. Stem Cells. 2010 Jul;28(7):1119-31 Blood Res. 2012;2(1):29-35 Shafer JA, Cruz CR, Leen AM, Ku S, Lu A, Rousseau A, Przybyl J, Jurkowska M, Rutkowski P, Debiec-Rychter M, Heslop HE, Rooney CM, Bollard CM, Foster AE. Antigen- Siedlecki JA. Downstream and intermediate interactions of specific cytotoxic T lymphocytes can target chemoresistant synovial sarcoma-associated fusion oncoproteins and their side-population tumor cells in Hodgkin lymphoma. Leuk implication for targeted therapy. Sarcoma. 2012;2012:249219 Lymphoma. 2010 May;51(5):870-80 Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A, Lin S, Smith HA, McNeel DG. The SSX family of cancer-testis Poulin N, Yi L, Rossi FM, Kast J, Capecchi MR, Underhill TM, antigens as target proteins for tumor therapy. Clin Dev Nielsen TO. Deconstruction of the SS18-SSX fusion Immunol. 2010;2010:150591 oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell. 2012 Mar 20;21(3):333-47 Chen YT, Chiu R, Lee P, Beneck D, Jin B, Old LJ. Chromosome X-encoded cancer/testis antigens show Jones KB, Su L, Jin H, Lenz C, Randall RL, Underhill TM, distinctive expression patterns in developing gonads and in Nielsen TO, Sharma S, Capecchi MR. SS18-SSX2 and the testicular seminoma. Hum Reprod. 2011 Dec;26(12):3232-43 mitochondrial apoptosis pathway in mouse and human synovial sarcomas. Oncogene. 2013 May 2;32(18):2365-71, Gerdemann U, Katari U, Christin AS, Cruz CR, Tripic T, 2375.e1-5 Rousseau A, Gottschalk SM, Savoldo B, Vera JF, Heslop HE, Brenner MK, Bollard CM, Rooney CM, Leen AM. Cytotoxic T Li P, Lin Y, Zhang Y, Zhu Z, Huo K. SSX2IP promotes lymphocytes simultaneously targeting multiple tumor- metastasis and chemotherapeutic resistance of hepatocellular associated antigens to treat EBV negative lymphoma. Mol carcinoma. J Transl Med. 2013 Mar 1;11:52 Ther. 2011 Dec;19(12):2258-68 This article should be referenced as such: Lim J, Goriely A, Turner GD, Ewen KA, Jacobsen GK, Graem N, Wilkie AO, Rajpert-De Meyts E. OCT2, SSX and SAGE1 Eid J, Garcia C, Frump A. SSX2 (synovial sarcoma, X reveal the phenotypic heterogeneity of spermatocytic breakpoint 2). Atlas Genet Cytogenet Oncol Haematol. 2013; seminoma reflecting distinct subpopulations of spermatogonia. 17(11):759-765. J Pathol. 2011 Aug;224(4):473-83

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Leukaemia Section Short Communication t(6;9)(p23;q34) DEK/NUP214 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: April 2013 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0609.html DOI: 10.4267/2042/51818 This article is an update of : Huret JL. t(6;9)(p23;q34). Atlas Genet Cytogenet Oncol Haematol 1998;2(1):29-31.

Identity

t(6;9)(p23;q34) G-banding (left)- Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at the Waisman Center (top and middle top), Jean-Luc Lai (middle below), and Roland Berger (below); and R-banding - Courtesy Lucienne Michaux (top 2); and Courtesy Christine Pérot (bottom 2).

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 766 t(6;9)(p23;q34) DEK/NUP214 Huret JL

The translocation t(6;9)(p23;q34) results in the formation of a chimeric fusion gene: DEK (6q23) and CAN (9q34). CAN is a putative oncogene which may be activated by fusion of its 3' end to other genes than DEK. One such recently reported gene is called SET and leads to expression of a SET/CAN fusion RNA. The t(6;9)(p21-22;q34) may be seen in either AML M2 or less frequently in M4 or MDS and acute myelofibrosis often in association with excessz basophils. The t(6;9) is reported mostly in young adults. The prognosis of patients carrying the t(6;9) is unfavorable - Courtesy Georges Flandrin.

leukemia-initiating cells, while leukemia-maintaining Clinics and pathology cells represent a larger and phenotypically Disease heterogeneous cell population (Oancea et al., 2010). Acute myeloid leukemias (AML) and myelodysplastic Epidemiology syndromes (MDS) The t(6;9) is found in about 1% of AMLs (0.9% in the Phenotype/cell stem origin series of 69 cases, with a repartition of 1.4% in children Altogether, 191 cases are available: 110 cases extracted AMLs, and 0.7% in adult cases (Slovak et al., 2006)); from the Mitelman database (Cases quick searcher + from this study, median age was 23 years (range 2-66 Molecular biology associations searcher), cases from years), with 30 children out of 69 cases (43%), a Garçon et al., 2005, and cases from the largest study to younger age than in AML in general. From 199 cases date (69 cases) (Slovak et al., 2006). herein reviewed, the sex ratio is balanced: 1M/1F (100 The WHO/FAB classification was: M1-AML: 13% male patients and 99 female patients). (25/191 cases), M2-AML: 34% (64/191), M1/M2- Cytology AML: 1% (2 cases), M4-AML: 24% (45/191), M5- AML: 2% (4 cases), M6-AML: 2% (3 cases), AML not TdT +, HLA-DR, CD13, CD33, CD38, CD45 and otherwise specified (26 cases), refractory anemia with CD117; frequent expression of CD9, CD15, CD34 excess of blasts (RAEB): 7% (13/191), chronic Auer rods are frequently observed. myelogenous leukemia (CML): 2% (3 cases), other Blood data: a marked basophilia is frequent (found in myelodysplastic and/or myeloproliferative syndrome: 44% of the patients in Slovak et al., 2006). 2% (3 cases), acute basophilic leukemia: 1 case, Granulocytic, megakaryocytic, or multilineage unknown: 2 cases. Acute myeloid leukemia is often dysplasia was found in two third of adult cases in the preceded by an episode of myelodysplastic syndrome. same report. The t(6;9) may be secondary to toxic exposure; in some Treatment instances. In the t(6;9), long-term (Sca1+/c-Kit+/lin- /Flk2-) Allogeneic stem cell transplantation might be hematopoietic stem cells (LT-HSC) appear to be the associated with better outcome (Slovak et al., 2006).

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 767 t(6;9)(p23;q34) DEK/NUP214 Huret JL

Overall survival in patients with t(6;9)(p23;q34) (adapted from Slovak et al., 2006): 31 children cases, 32 adult cases, compared with 174 young adult AML in the unfavorable risk cytogenetics subgroup.

Prognosis cases, 5%), +13 (in 3 of 126 cases, 2%), +21. A - 7/del(7q) was found once, a t(9;22)(q24;q11) once. Overall, 65% of patients, 71% of pediatric cases and 58% of adults, achieved complete remission (CR) Variants (Slovak et al., 2006). A three way complex t(6;9;Var) has been found in 3 Median survival is around 1 year (12,5 months in instances. children, 14,4 months in adults, 13,5 months altogether). Genes involved and proteins The 5 year overall survival was 28% in children and 9% in adults (see figure) (Slovak et al., 2006). Patients DEK who achieved prolonged molecular remission had Location better outcome than patients with persistent 6p23 DEK/NUP214 positivity (Garçon et al., 2005). Protein 375 amino-acids; DEK contains acidic domains Genetics (Asp/Glu-rich), a SAF/SAP box, a nuclear localisation Note signal; and other DNA binding domains. Highly conserved nuclear factor; chromatin remodeling FLT3 internal tandem duplications was found in 69% protein, essential for heterochromatin integrity; DEK of children cases and 73% of adult cases in one study localizes preferentially at sites proximal to the (Slovak et al., 2006), and in 88% of adults cases in promoters of expressed genes; acts as a repressor of another study (Oyarzo et al., 2004). A third study transcription by interfering with histone acetyl- grossly confirm this high incidence (Garçon et al., transferases and as an activator of transcription by 2005). stimulating the binding of TFAP2A (the activator protein AP2-alpha) to its target DNA sequences; DEK Cytogenetics introduces super-coils into circular DNA (in Oancea et Cytogenetics morphological al., 2010). DEK is a regulator of stem and progenitor cells and is The t(6;9) may be over loocked. upregulated in a number of neoplasms (breast cancer, Additional anomalies chronic lymphocytic leukemia, small cell lung carcinoma, Merkel cell carcinoma, melanoma, The t(6;9) is the sole anomaly in 85% of 195 cases with glioblastoma, retinoblastoma, cervical, and bladder available data, and in 83% of cases in the largest study cancers) (review in Riveiro-Falkenbach and Soengas, (Slovak et al., 2006); recurrent, although rare, 2010); CEBPA and DEK coordinately activate myeloid additional anomalies are the following: +8 (in 6 of 126 gene expression (Koleva et al., 2012); DEK is an estrogen receptor alpha (ESR1) target gene (Privette

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 768 t(6;9)(p23;q34) DEK/NUP214 Huret JL

Vinnedge et al., 2012). DEK expression modulates von Lindern M, Fornerod M, Soekarman N, van Baal S, Jaegle ATM and DNA-dependent protein kinase signaling, M, Hagemeijer A, Bootsma D, Grosveld G. and contributes to DNA repair (Kavanaugh et al., Translocation t(6;9) in acute non-lymphocytic leukaemia results 2011). in the formation of a DEK-CAN fusion gene. Baillieres Clin Haematol. 1992 Oct;5(4):857-79 NUP214 Lillington DM, MacCallum PK, Lister TA, Gibbons B. Location Translocation t(6;9)(p23;q34) in acute myeloid leukemia 9q34 without myelodysplasia or basophilia: two cases and a review of the literature. Leukemia. 1993 Apr;7(4):527-31 Note Fornerod M, Boer J, van Baal S, Morreau H, Grosveld G. The previous name of NUP214 was CAN. Interaction of cellular proteins with the leukemia specific fusion Protein proteins DEK-CAN and SET-CAN and their normal counterpart, the nucleoporin CAN. Oncogene. 1996 Oct 2090 amino acids; contains dimerization domains (2 17;13(8):1801-8 leucine zippers) and FG repeats; forms homodimers; the C-terminus is essential; the N-terminus is involved Oyarzo MP, Lin P, Glassman A, Bueso-Ramos CE, Luthra R, Medeiros LJ. Acute myeloid leukemia with t(6;9)(p23;q34) is in mRNA export (Köser et al., 2005). Nuclear associated with dysplasia and a high frequency of flt3 gene membrane localisation (cytoplasmic face of mutations. Am J Clin Pathol. 2004 Sep;122(3):348-58 nucleopore); component of the nuclear pore complex; Garçon L, Libura M, Delabesse E, Valensi F, Asnafi V, Berger involved in nucleo-cytoplasmic transport. C, Schmitt C, Leblanc T, Buzyn A, Macintyre E. DEK-CAN molecular monitoring of myeloid malignancies could aid Result of the chromosomal therapeutic stratification. Leukemia. 2005 Aug;19(8):1338-44 Koser J, Maco B, Aebi U, Fahrenkrog B.. The nuclear pore anomaly complex becomes alive: new insights into its dynamics and involvement in different cellular processes. Atlas Genet Hybrid gene Cytogenet Oncol Haematol. March 2005. URL: http://AtlasGeneticsOncology.org/Deep/NuclearPoreComplID2 Description 0048.html 5' DEK - 3' NUP214 on der(6); head to tail DEK/NUP214 fusion gene (SET/NUP214 exceptional); Slovak ML, Gundacker H, Bloomfield CD et al.. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the breakpoint clusters in a single intron of 8 kb (ICB9: need for a prospective, multicenter initiative for rare 'poor 'intron containing breakpoint 9') in NUP214, and in a prognosis' myeloid malignancies. Leukemia. 2006 single intron (of 12 kb) as well (ICB6) in DEK. Jul;20(7):1295-7. Epub 2006 Apr 20. Transcript Oancea C, Ruster B, Henschler R, Puccetti E, Ruthardt M.. The t(6;9) associated DEK/CAN fusion protein targets a 5.5 kb RNA; no NUP214-DEK reciprocal transcript on population of long-term repopulating hematopoietic stem cells chromosome 9. for leukemogenic transformation. Leukemia. 2010 Detection Nov;24(11):1910-9. doi: 10.1038/leu.2010.180. Epub 2010 Sep 9. RNA-PCR. Riveiro-Falkenbach E, Soengas MS.. Control of tumorigenesis Fusion protein and chemoresistance by the DEK oncogene. Clin Cancer Res. Description 2010 Jun 1;16(11):2932-8. doi: 10.1158/1078-0432.CCR-09- 2330. Epub 2010 May 25. (REVIEW) 165 kDa; N-term with almost the entire DEK protein fused to the C-terminal two-thirds of the NUP214 Kavanaugh GM, Wise-Draper TM, Morreale RJ et al.. The human DEK oncogene regulates DNA damage response protein. signaling and repair. Nucleic Acids Res. 2011 Sep Expression / Localisation 1;39(17):7465-76. doi: 10.1093/nar/gkr454. Epub 2011 Jun 7. Nuclear localisation. Koleva RI, Ficarro SB, Radomska HS et al.. C/EBPa and DEK coordinately regulate myeloid differentiation. Blood. 2012 May 24;119(21):4878-88. doi: 10.1182/blood-2011-10-383083. References Epub 2012 Apr 3. Pearson MG, Vardiman JW, Le Beau MM, Rowley JD, Privette Vinnedge LM, Ho SM, Wikenheiser-Brokamp KA, Schwartz S, Kerman SL, Cohen MM, Fleischman EW, Wells SI.. The DEK oncogene is a target of steroid hormone Prigogina EL. Increased numbers of marrow basophils may be receptor signaling in breast cancer. PLoS One. associated with a t(6;9) in ANLL. Am J Hematol. 1985 2012;7(10):e46985. doi: 10.1371/journal.pone.0046985. Epub Apr;18(4):393-403 2012 Oct 10. von Lindern M, Poustka A, Lerach H, Grosveld G. The (6;9) Mitelman F, Johansson B and Mertens F (Eds.). Mitelman chromosome translocation, associated with a specific subtype Database of Chromosome Aberrations and Gene Fusions in of acute nonlymphocytic leukemia, leads to aberrant Cancer (2013). http://cgap.nci.nih.gov/Chromosomes/Mitelman transcription of a target gene on 9q34. Mol Cell Biol. 1990 Aug;10(8):4016-26 This article should be referenced as such: Soekarman D, von Lindern M, van der Plas DC et al.. Dek-can Huret JL. t(6;9)(p23;q34) DEK/NUP214. Atlas Genet Cytogenet rearrangement in translocation (6;9)(p23;q34). Leukemia. 1992 Oncol Haematol. 2013; 17(11):766-769. Jun;6(6):489-94

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Leukaemia Section Short Communication t(6;7)(p25.3;q32.3) DUSP22/FRA7H Sarah H Johnson, George Vasmatzis, Andrew L Feldman Center for Individualized Medicine - Biomarker Discovery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA (SHJ, GV), Department of Laboratory Medicine and Pathology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA (ALF)

Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0607p25q32ID1579.html DOI: 10.4267/2042/51819 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

lesions and may develop locoregional lymph node Clinics and pathology involvement. Disease Pathology ALK-negative anaplastic large cell lymphoma; primary Pathologic findings are similar to those seen in cutaneous anaplastic large cell lymphoma systemic or primary cutaneous ALK-negative ALCL. Phenotype/cell stem origin Detection of t(6;7)(p25.3;q32.3) in ALK-positive ALCL has not been reported. Mature (peripheral) T cell (most cases); occasional cases are of uncertain lineage (so-called "null cell" Treatment type). Unknown. Etiology Evolution No etiologic factors are known. Unknown. Epidemiology Prognosis All reported cases have occurred in adults. Estimated Unknown. frequency of t(6;7)(p25.3;q32.3) in ALK-negative ALCL (systemic or cutaneous) is 10% (13 of 125 Cytogenetics ALK-negative ALCLs tested) (Feldman et al., 2011). Additional cases with rearrangements of 6p25.3 not Cytogenetics morphological involving 7q32.3 also have been reported. Karyotypic findings have not been reported. Clinics Additional anomalies Presentation has not been shown to differ significantly Unknown. from other ALCLs; i.e. systemic ALK-negative ALCLs typically present with lymphadenopathy and/or Variants extranodal tissue involvement, whereas primary Rearrangements of 6p25.3 with other partner loci have cutaneous ALCLs typically present with localized skin been reported.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 770 t(6;7)(p25.3;q32.3) DUSP22/FRA7H Johnson SH, et al.

Primary cutaneous ALCL with t(6;7)(p25.3;q32.3). H&E stains at low (A) and high (B) magnification show a tumor-forming cellular infiltrate in the dermis of the skin. The tumor cells are medium-sized to large atypical lymphoid cells with a sheet-like growth pattern. By immunohistochemical stains, they are negative for CD20 (C), weakly positive for CD3 (D), strongly positive for CD30 (E), and negative for ALK (F).

Dual-fusion FISH demonstrating t(6;7)(p25.3;q32.3) in ALCL. Two tumor cells at left show fusions of the DUSP22-IRF4 locus on 6p25.3 (red) to 7q32.3 (green) (solid arrows). The folded or reniform configuration typical of ALCL nuclei ("hallmark" cells) can be seen. The open arrow at upper right points to a normal cell with round nuclear contours and lacking fusion signals.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 771 t(6;7)(p25.3;q32.3) DUSP22/FRA7H Johnson SH, et al.

Genes involved and proteins DNA/RNA The 7q32.3 breakpoint lies in the non-coding transcript DUSP22 region FLJ43663, immediately telomeric to the fragile site, FRA7H, and the microRNAs, MIR29A and Location MIR29B1. 6p25.3 DNA/RNA Result of the chromosomal In the single reported sequenced case, the translocation disrupted the DUSP22 gene within intron 1. FISH anomaly studies using probes covering different regions of the Hybrid gene DUSP22-IRF4 locus on 6p25.3 showed that in other cases the breakpoint was centromeric to DUSP22 and Note closer to IRF4 (Feldman et al., 2011). Regardless of None known. breakpoint location, gene expression studies showed up Fusion protein to a 50-fold reduction in expression of DUSP22 in the translocated cases compared to untranslocated cases. Note IRF4 expression was similar between translocated and None known. untranslocated cases. References Protein DUSP22 encodes a dual-specificity phosphatase that Feldman AL, Dogan A, Smith DI, Law ME, Ansell SM, Johnson inhibits T-cell antigen-receptor signaling in T cells by SH, Porcher JC, Ozsan N, Wieben ED, Eckloff BW, Vasmatzis G. Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in inactivating the MAP kinase, ERK2. Its function in ALK-negative anaplastic large cell lymphomas by massively ALCL has not been confirmed. parallel genomic sequencing. Blood. 2011 Jan 20;117(3):915-9

FRA7H This article should be referenced as such: Location Johnson SH, Vasmatzis G, Feldman AL. t(6;7)(p25.3;q32.3) 7q32.3 DUSP22/FRA7H. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11):770-772.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 772 Atlas of Genetics and Cytogenetics

in Oncology and Haematology

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Solid Tumour Section Review

Fallopian tube tumors: an overview Roland Gregor Stein, Joachim Diessner, Arnd Hönig, Jörg Wischhusen, Johannes Dietl Wurzburg University Hospital, Department of Obstetrics and Gynecology, Josef-Schneider-Str. 4, 97080 Wurzburg, Germany (RGS, JD, AH, JW, JD)

Published in Atlas Database: March 2013 Online updated version : http://AtlasGeneticsOncology.org/Tumors/FallopTubTumID5279.html DOI: 10.4267/2042/51820 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Inevitably, the considerable overlap between ovarian Identity and fallopian tube carcinomas warrants some coverage Introduction of ovarian cancer in this context. Nevertheless, as This article shall give an overview of different tumors ovarian carcinomas constitute a well-accepted clinical occurring in the fallopian tube. entity (irrespective of their potential origin from the Though being a very rare location of primary or fallopian tube) they shall largely be dealt with in a exclusive tumor manifestation, the fallopian tube is separate place. now receiving increased attention in gynecological oncology since considerable evidence suggests that it Classification represents the site-of-origin of many (if not most) serous pelvic carcinomas (Folkins et al., 2009; Dietl Note and Wischhusen, 2011; Dietl et al., 2011; Seidman et Solid fallopian tube tumors can be subcategorized al., 2011; Vang et al., 2013). based on origin and behavior. Disease definition The WHO classification distinguishes several groups of A tumor is classified as primary fallopian tube tumor solid tumors of the fallopian tube (Alvarado-Cabrero et when it is either restricted to this anatomical structure, al., 2003) shown in Figure 1. or when the fallopian tube is most affected whereas co- Classification locations such as ovary and uterus show lesser Staging involvement or a different histology (Alvarado-Cabrero Malignant tumors of the fallopian tube are classified et al., 2003; Folkins et al., 2009). according to the "Union International contre le cancer" As recent data indicate that the fallopian tube is the (UICC) and the "Fédération internationale de site-of-origin of serous pelvic carcinomas (Folkins et Gynécologie et d'Obstétrique" (FIGO, Table 1 and 2). al., 2009; Dietl and Wischhusen, 2011; Dietl et al., The TNM classification is based on clinical and 2011; Seidman et al., 2011; Vang et al., 2013), pathological findings whereas the FIGO classification histological assessment of the respective involvement requires a surgical staging (UICC, 2009; AJCC, 2010). of ovaries and fallopian tubes may not be sufficient to According to the TNM classification, the carcinomas of distinguish between advanced stages of fallopian tube the fallopian tube approximate different stages (Table 2). and ovarian carcinomas (Kosary and Trimble, 2002).

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Figure 1: WHO Classification of solid tumors of the fallopian tube (Alvarado-Cabrero et al., 2003).

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Table 1: TNM and FIGO Classification of carcinomas of the fallopian tube (UICC, 2009). Table 2: Staging of fallopian tube carcinomas (UICC, 2009).

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of symptoms - intermittent profuse serosanginous Clinics and pathology vaginal Etiology discharge, colicky pain relieved by discharge, The etiology of primary fallopian tube tumors is abdominal or pelvic mass - is reported in only 15% of unknown. Multiparity seems to be protective (Riska et all patients (Ajithkumar et al., 2005). 5% of the patients al., 2003), pregnancies and oral contraceptives decrease show a hydrops tubae profluens. Fallopian tube the risk (Inal et al., 2004). Neither age, nor weight, carcinomas are diagnosed at earlier stages than education level, pelvic inflammatory disease, infertility, epithelial ovarian cancers (Peters et al., 1988; Rose et previous hysterectomy or endometriosis show al., 1990; Gadducci et al., 2001; Pectasides et al., significant correlations especially with fallopian tube 2006). 10-36% show positive PAP smear tests with carcinomas (Henderson et al., 1977; Demopoulos et al., intermittent detection of abnormal, suspicious or poorly 2001; Inal et al., 2004). Demographic distribution is differentiated cells or glands (Ajithkumar et al., 2005). similar to ovarian cancer, and the highest incidence was In 80% of the advanced stages, peritoneal metastases found in white, non-Hispanic women and women aged occur (Levite et al., 2001). Also haematogenous or 60-79. However, recent evidence suggests tubal cancer transluminal metastases were found (Yoonessi, 1979). to be much more frequent (Stewart et al., 2007; Piek et Bilateral tubal involvement has been described in 10- al., 2008). 27% of fallopian tube carcinomas (Schiller and Silverberg, 1971; Hirai et al., 1989; Rose et al., 1990; Epidemiology Alvarado-Cabrero et al., 1999; Rosen et al., 1999; Epidemiological data on malignant fallopian tube Gadducci et al., 2001). tumors are adequate, even though only 0.3-1.1% of all The higher rate of lymph node metastases in gynecological malignancies are typically classified as comparison to ovarian cancer should be considered, as primary fallopian tube carcinomas (Baekelandt et al., staging of fallopian tube carcinomas is surgical. 2000), mostly adenocarcinomas (Schneider et al., Compared to epithelial ovarian cancer, fallopian tube 2000). In the U.S., the incidence is about 3.6 per carcinomas show a higher rate of retroperitoneal and million women per year (Rosenblatt et al., 1989). distant metastases (Yoonessi, 1979; McMurray et al., Stage-adjusted survival rates are generally better than 1986; Maxson et al., 1987; Asmussen et al., 1988; for epithelial ovarian carcinoma (Kosary and Trimble, Peters et al., 1988; Gadducci et al., 2001). Para-aortic 2002). Underestimation of the real incidence might be lymph node metastases were detected in 33% of due to fallopian tube carcinomas being mistaken for patients (Tamimi and Figge, 1981). Another study ovarian cancers (Woolas et al., 1994) which show a revealed 42-59% lymph node metastases in routine significantly higher prevalence. Still, Riska and lymphonodectomy with equal involvement of para- colleagues reported an increasing incidence of fallopian aortic and pelvic lymph nodes (Ajithkumar et al., tube carcinomas from 1.2 per million per year for 1953- 2005). If routine lymphonodectomy is not performed, a 1957 to 5.4 per million per year from 1993-1997 (Riska surgical understaging may occur. Overall, 20-25% of et al., 2003). patients with fallopian tube carcinomas showed FIGO Clinics stage I, 20% stage II, 45-50% stage III and 5-10% stage IV (Ajithkumar et al., 2005). Clinical presentation Ectopic β-HCG-production was reported in two cases Patients with benign tumors of the fallopian tube are of serous or undifferentiated fallopian tube carcinomas often asymptomatic or report local pain. The tumors are (Carapeto et al., 1978; Alvarado-Cabrero et al., 1999). incidentally found during operations for other These tumors contained syncytiotrophoblast-like cells. indications (Etoh et al., 2012). Benign tumors can abet Case reports about renin-producing or alpha fetoprotein tubal torsions (Alvarado-Cabrero et al., 2003). (AFP)-producing tumors have been published (Aoyama Especially papillomas can obstruct the fallopian tube al., 1996; Zabernigg et al., 1997). (Gisser, 1986). Obstruction of the fallopian tube can Fallopian tube carcinomas show frequent expression of cause infertility (Heller et al., 1991; Heatley, 2001). CA-125 (Puls et al., 1993). Hence, >80% of the Primary fallopian tube carcinomas most frequently patients show elevated CA-125 serum levels occur between the fourth and sixth decade of life with a (McMurray et al., 1986; Ajithkumar et al., 2005) that mean patient age of 55 years (Boutselis and Thompson, correlate significantly with disease-free and overall 1971; Sedlis, 1978). Stewart et al. found an incidence survival (Rosen et al., 1999; Ajithkumar et al., 2005). rate of 0.41 per 100000 women with highest incidence Adenomyomas can also cause elevated CA-125 levels rates in women aged 65-69 in a study including 3051 and small volumes of serous ascites. With some cases of primary fallopian tube carcinomas (Stewart et limitations, CA-125 may thus be considered as suitable al., 2007). Symptoms are very diffuse, the Latzko triad tumor marker for use in cancers of the fallopian tube (Baekelandt et al., 2000).

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 776 Fallopian tube tumors: an overview Stein RG, et al.

Figure 2: Histology of an invasive serous-papillary adenocarcinoma of the fallopian tube. a: Tumor formation in the tubal wall. b shows 200 fold magnification with gland formation (*). c: Metastasis in adipous tissue. d: Immunohistochemistry for Ki67 with nuclear positivity. e and f: Immunohistochemistry for p53 also with nuclear positivity.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 777 Fallopian tube tumors: an overview Stein RG, et al.

Figure 3: a: In this H&E staining, the STIC cells show polymorphic nuclei and a multilayer epithelium (arrowheads) compared with normal tubal epithelium (arrows). b: Distinct transition from normal tubal epithelium to p53 positive STIC (p53 immunohistochemistry). c: Invasive fallopian tube carcinoma (arrowheads) next to STIC formation (arrows, H&E).

The average lead time of increasing CA-125 levels Cabrero et al., 2003). In fallopian tubes resected post versus clinical or radiological diagnosis of recurrence is partum, few metaplastic papillary tumors were detected three months with a range from 0.5 to 7 months (Saffos et al., 1980; Keeney and Thrasher, 1988; (Ajithkumar et al., 2005). Bartnik et al., 1989). These tumors consist of papillae Fallopian tube carcinomas can cause paraneoplastic lined by epithelium displaying patterns of a serous symptoms. For example, a paraneoplastic cerebellar borderline tumor. The cells can be positive for degeneration (PCD) with Anti-Yo antibodies is intracellular mucin (Alvarado-Cabrero et al., 2003). associated with fallopian tube carcinomas (Levite et al., Adenomyomas consist of bundle-like growing 2001; Tanaka et al., 2005; Selby et al., 2011). leiomyoma cells and sometimes endometrial tissue remnants. Pathology Endometrioid polyps occur in the interstitial part of the Benign tumors tube attached to the intratubal epithelium and Benign tumors are often solid and clearly delimited. sometimes cause infertility (Heller et al., 1991; They arise at the intraluminal or serosal surface of the Heatley, 2001). fallopian tube. Cystadenofibromas can show vimentin-cytokeratin- Papillomas show fibrovascular stacks with epithelial coexpression. Further, diffuse apical epithelial lining. They can obstruct the fallopian tube (Gisser, membrane antigen (EMA) immunoreactivity occurs. 1986). Gürbüz et al. suggest that tumors are derived from Adenofibromas and cystadenofibromas occur between embryonic remnants of the Müllerian duct (Gürbüz and the third and eighth decade. They remain asymptomatic Ozkara, 2003). and are diagnosed incidentally during other operations Borderline tumors of the fallopian tube occur very (Zheng et al., 1996). Macroscopically, these tumors rarely and can show serous, mucinous or endometrioid grow to 0.5-3cm and can be intraluminal or at the differentiations. Histological features resemble those in serosa surface as well as at the fimbriae. They show a borderline tumors of the ovary (Alvarado-Cabrero et stromal and a papillary structured fraction (Alvarado- al., 1997). Mucinous tumors of the fallopian tube can

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 778 Fallopian tube tumors: an overview Stein RG, et al.

be associated with pseudomyxoma peritonei (McCarthy development and already detectable in the STIC (Kuhn and Aga, 1988), other mucinous lesions or Peutz- et al., 2010). Jeghers-Syndrome (Seidman, 1994). There are also As the post-reproductive fallopian tube lacks reports about adenofibroma with borderline physiological functions and also causes complications malignancy. The prognosis seems to be favorable such as hydrosalpinx, Dietl et al. suggested combined (Zheng et al., 1996; Alvarado-Cabrero et al., 1997). hysterosalpingectomy instead of simple hystercectomy Precursor lesions: Intraepithelial carcinoma or salpingectomy as a recommendable method for Non-invasive carcinomas of the fallopian tube were sterilization in clinical routine (Dietl and Wischhusen, formerly known as "carcinoma in situ". This term 2011; Dietl et al., 2011). should be abandoned as it implies restricted local tumor Invasive carcinoma formation. Intraepithelial carcinoma cells can, however, All tumor subtypes in the ovaries are also known in the form implants on the ovarian surface and the fallopian tube, with serous carcinomas being most peritoneum. Recent publications highlight the fallopian frequent. In a series of 105 fallopian tube carcinomas tube as likely site-of-origin of primary pelvic serous Alvarado-Cabrero et al. found the following carcinomas detected in the fallopian tube, the ovary or distribution of different histologies: About 50% were the peritoneum (Folkins et al., 2009; Dietl and serous, 25% endometrioid, 20% transitional cell or Wischhusen, 2011; Dietl et al., 2011; Seidman et al., undifferentiated carcinomas and 5% were of other 2011; Vang et al., 2013). Serous tubal intraepithelial subtypes (Alvarado-Cabrero et al., 1999). carcinomas (STIC) as well as endometrioid Serous adenocarcinomas are generally invasive with intraepithelial carcinomas (EIC) are thus considered as 50% G3 tumors (Alvarado-Cabrero et al., 1999). precursor lesions (Ambros et al., 1995; Carlson et al., Sometimes immune cell invasion disguises the tumor 2008). This hypothesis is supported by findings from as salpingitis (Cheung et al., 1994). Colgan et al. who found a high frequency of pre- Mucinous adenocarcinomas, a very rare entity, are cancerous lesions in fallopian tubes from patients with often associated with other mucinous carcinomas of the BRCA gene mutations (Colgan, 2003). Lee and female genital tract or the appendix (Seidman, 1994). colleagues could detect mutant p53-signatures Endometrioid adenocarcinomas are very often non- predominantly in epithelial cells at the fimbriated ends invasive or superficially invasive and show a favorable of fallopian tubes from patients with BRCA1 and 2 prognosis (Navani et al., 1996). A part of those tumors mutations. Moreover, the same signatures were also displays characteristics of the wolffian adnexal tumor found in corresponding ovarian cancer tissues (Lee et (Daya et al., 1992; Navani et al., 1996). al., 2007). Interestingly, Li-Fraumeni-Syndrome - Clear cell adenocarcinomas account for 2-10% of all which is associated with p53 mutations and generally fallopian tube carcinomas (Voet and Lifshitz, 1982; increased risk for serous carcinomas - does not Hellstrom et al., 1994; Alvarado-Cabrero et al., 1999). correlate with a higher incidence of PPSC, especially Transitional cell carcinomas are rare in the genital tract. fallopian tube carcinomas. Thus, it seems that other Still, the frequency between 11 and 43% of all fallopian mutations e.g. those affecting BRCA are required to tube carcinomas makes it an important locus-specific drive PPSC development (Xian et al., 2010). Kim and entity (Uehira et al., 1993; Alvarado-Cabrerog et al., colleagues could prove by histology that serous 1999). epithelial cancers develop in the fallopian tubes of Undifferentiated carcinomas lack any patterns of Dicer-PTEN-double-knockout mice. By histology and squamous cells or glandular cells but instead contain pathological behavior these tumors showed multinuclear giant cells (Alvarado-Cabrero et al., characteristic traits of serous epithelial ovarian cancer, 1999). even though oophorectomy was not protective. Instead, Lacy et al. reported immunohistochemical positivity for tumor development could be prevented by c-erbB-2 (HER-2/neu) overexpression in 26% and p53 salpingectomy (Kim et al., 2012). Furthermore, in positivity in 61% of all cases in a cohort of 43 patients prophylactic salpingo-oophorectomy specimen, occult with fallopian tube carcinoma. There was not carcinomas are more frequent in the fallopian tube than significant correlation with survival (Lacy et al., 1995). the ovary (Vang, 2011). While carrying the potential of Ovarian cancer in comparison also shows c-erbB-2 invasiveness, the STIC cells grow sparing the tubal (HER-2/neu) positivity in about 29% of all cases stroma. Figure 3 focusses on the STIC with its distinct (Lanitis et al., 2012). Others, in contrast, described a cellular alterations such as polymorphic nuclei, correlation between p53 immunohistochemical multilayer epithelium and atypic mitoses. Figure 3d positivity and shorter survival (Zheng et al., 1997; also shows an invasive fallopian tube carcinoma with Rosen et al., 2000). FIGO stages, however, did not an adjoining STIC. correlate with survival in this same cohort of 63 In clinical studies, a frequent coexistence of pelvic patients (Rosen et al., 2000). Zheng et al. investigated serous carcinoma and tubal intraepithelial carcinomas the correlating immunohistochemistry and polymerase was found in unselected (Przybycin et al., 2010) and chain reaction-single-strand conformation BRCA mutated patients (Kindelberger et al., 2007). polymorphism (PCR-SSCP) for p53 in 52 cases of Shortening of telomeres is another early event in PPSC fallopian tube carcinoma and 10 normal fallopian tubes

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and found that p53 alterations already occur at early fallopian tube (Dekel et al., 1986). About 40% of these stages suggesting a role in early tumor progression go along with adnexal tumors (Ober and Maier, 1981). (Zheng et al., 1997). Chung and colleagues found that In the fallopian tube, hydatiform moles can survival neither correlated with immunohistochemical histologically correspond to a complete, partial or p53 positivity nor with cMyc overexpression (which invasive mole (Alvarado-Cabrero et al., 2003). occured in 61%). However, the statistical power of this Placental site nodules as non-neoplastic proliferation of study was limited by the small cohort of 18 patients intermediate trophoblast can occur (Alvarado-Cabrero (Chung et al., 2000). Hence, it did not challenge larger et al., 2003). Intermediate trophoblast tumors can be studies which proposed that p53 might have an either benign or malignant (Kurman et al., 1976). Only important role especially in familial BRCA-associated one case of malignant placental site trophoblastic tumor cases of fallopian tube carcinomas. Figure 2 shows has been reported in the fallopian tube (Su et al., 1999). different pathohistological aspects of a serous Lymphoid and haematopoietic tumors adenocarcinoma of the fallopian tube. Malignant lymphoma and leukemia mostly show an Mixed epithelial-mesenchymal tumors involvement of the ipsilateral ovary (Osborne and The least common site for malignant Müllerian mixed Robboy, 1983). 25% of patients with ovary lymphomas tumor (carcinosarcoma, metaplastic carcinoma) is the had a Burkitt-lymphoma or Burkitt-like lymphoma or a fallopian tube accounting for only 4% of all cases. The diffuse large-cell lymphoma. prognosis of these mostly postmenopausal patients is Metastatic tumors poor (Hanjani et al., 1980). For 89% of secondary tumors in the fallopian tube, the In the literature, only one adenosarcoma has been primary tumor was assigned to be of ovarian origin described in the fallopian tube (Gollard et al., 1995). (Woodruff and Julian, 1969). Considering the ongoing Soft tissue tumors paradigm shift which proposes that serous ovarian Leiomyosarcomas are very rare as only 37 cases have carcinomas likely originate from the fallopian tube, been reported in 100 years (Jacoby et al., 1993). these figures have to be reconsidered. Many of these Mesothelial tumors tumors may have originated from the fimbriated end of Adenomatoid tumors mostly occur in middle-aged or the fallopian tube with a secondary manifestation in the elderly women (Inoue et al., 2001). In most cases, they ovary. remain asymptomatic but can also occlude the lumen. Often, they show gland-like structures with a lining of Treatment flat to cuboidal cells (Stephenson and Mills, 1986). Surgical therapy: For fallopian tube tumors and Germ cell tumors especially for carcinomas, surgical removal is the first Until 2003, 50 cases of mature or immature teratoma line treatment. Whereas benign tumors can usually be were reported (Alvarado-Cabrero et al., resected completely, the approach for fallopian tube 2003). For malignant mixed germ cell tumors of the carcinomas should be the same as for epithelial ovarian fallopian tube, only one single case was published (Li cancer with the aim of complete resection or at least et al., 1999). maximum tumor debulking. Trophoblastic tumors Only about 4% of choriocarcinomas occur in the

Table 3: Postoperative treatment of fallopian tube carcinoma (Pectasides et al., 2006).

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Special focus should be placed on para-aortic and platinum-pretreated patients also highlights the role of pelvic lymphadenectomy in regard to the higher rate of Paclitaxel (Tresukosol et al., 1995; Baekelandt et al., lymph node metastases (Yoonessi, 1979; McMurray et 2000; Ichikawa et al., 2000; Gemignani et al., 2001). al., 1986; Maxson et al., 1987; Asmussen et al., 1988; After review of the literature and according to the U.S. Peters et al., 1988; Gadducci et al., 2001). guidelines, Pectasides and colleagues suggested an Klein and colleagues found a significantly reduced adjuvant standard treatment shown in table 3 median survival of 21 months versus 43 months in (Pectasides et al., 2006). patients who had not undergone lymphadenectomy For the treatment of relapse, platinum-sensitive tumors (Klein et al., 1999). (relapse after more than 6 months) receive a Radiotherapy: Although radiotherapy for fallopian reinduction with platinum with or without Paclitaxel, tube carcinomas could be considered, it is inferior to whereas patients with platinum-refractory (relapse adjuvant platin compounds containing chemotherapy. during therapy) or platinum-resistant tumors (relapse Neither irradiation nor intraperitoneal instillation of <6 months) receive Topotecan or liposomal radioisotopes could prevent relapse (Asmussen et al., Doxorubicin (Pectasides et al., 2006). In epithelial 1988). A second look operation with pathological ovarian cancer, Bookman and colleagues as well as complete remission (pCR) is a predictor for longer Hoskins et al. treated patients with relapse after survival. 50% of patients with surgical complete platinum- and Paclitaxel-based chemotherapy with remission will ultimately relapse. Thus, second-look Topotecan (Bookman et al., 1998; Hoskins et al., operations are not generally beneficial and hence no 1998). Also liposomal Doxorubicin can achieve routine treatment (Takeshima and Hasumi, 2000). response rates of 17-26% in patients who have relapsed Adjuvant chemotherapy: Baekeland et al. found a after platinum- and Paclitaxel based chemotherapy 70% response rate to adjuvant platinum-containing (Muggia et al., 1997; Gordon et al., 2000). Recent data chemotherapy in platinum-naive patients with median from the OCEANS trial revealed that addition of response duration of 12.5 months. They further Bevacizumab to the combination of suggested to refrain from postoperative radiation carboplatinum/gemcitabine increases the response rate therapy due to its low efficacy and high rate of and prolongs progression-free survival in patients with complications (Baekelandt et al., 2000). Kosary et al. platinum-sensitive recurrent ovarian, primary gave the general recommendation to treat women with peritoneal, or fallopian tube cancer. Overall survival, fallopian tube carcinomas like women with epithelial however, remained unchanged (Aghajanian et al., ovarian cancer, i.e. by surgical staging and debulking 2012). followed by adjuvant chemotherapy (Kosary and Likewise, the CALYPSO trial which tested the Trimble, 2002). In addition to platinum-based combination of pegylated liposomal doxorubicin chemotherapy, also paclitaxel is becoming more and (PLD)/carboplatin with paclitaxel/carboplatin in more important in the treatment of advanced fallopian platinum-sensitive ovarian cancer patients found a tube tumors (Takeshima and Hasumi, 2000). Patients prolonged time to progression along with reduced side with early stages as IA and IB might not need adjuvant effects of PLD as compared to paclitaxel. Again, chemotherapy. For all higher stages, adjuvant however, there was no effect on overall survival combined chemotherapy is requested. Two randomized (Wagner et al., 2012). controlled trials (International Collaborative Ovarian Still, an intermediate report from the AURELIA trial Neoplasm 1 (ICON1) and Adjuvant Chemotherapy In suggests that supplementation of chemotherapy with Ovarian Neoplasm (ACTION)) compared platinum Bevacizumab might be highly beneficial for patients based adjuvant chemotherapy and mere observation with platinum-resistant ovarian cancer (Pujade- after early stage ovarian cancer surgery and reported 5 Lauraine et al., 2012). year overall survival rates of 74% without and 82% with adjuvant platinum based chemotherapy (Trimbos Prognosis et al., 2003). Prognostic factors for early stage I carcinomas are This could hint at a survival benefit being associated depth of invasion into the tubal wall and tumor rupture with adjuvant chemotherapy also for early stage during surgery. Even early stages tend to metastasize to fallopian tube carcinomas. Cisplatin based the peritoneum (Baekelandt et al., 2000). chemotherapy yielded response rates between 53 and The surgical stage is an independent prognostic factor 92 % (Deppe et al., 1980; Raju et al., 1981; McMurray (Alvarado-Cabrero et al., 1999; Baekelandt et al., et al., 1986; Maxson et al., 1987; Peters et al., 1988; 2000). Carcinomas of the fimbriae region are afflicted King et al., 1989; Muntz et al., 1989; Barakat et al., by a worse prognosis than carcinomas of the isthmic 1993; Pectasides et al., 1994). Several studies also region (Alvarado-Cabrero et al., 1997). included Paclitaxel in the first line therapy (McMurray There are different results concerning the histological et al., 1986; Maxson et al., 1987; Muntz et al., 1991; grading: Vaughan et al. found a significant correlation Ben-Hur et al., 1999; Gemignani et al., 2001). For between grading and survival (Vaughan et al., 1998), relapse therapy, data from epithelial ovarian cancer in Gadducci et al. could also find this in univariate but not

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 781 Fallopian tube tumors: an overview Stein RG, et al.

in multivariate analysis (Gadducci et al., 2001). that these areas may contain putative tumor suppressor Grading further correlates with lymphogenous genes (Jongsma et al., 2002). metastases (Klein et al., 1999). Lymphocytic Different authors (see above) found that infiltration of the tumor correlates with favorable immunohistochemical or PCR-based positivity for p53 outcome (Rosen et al., 1993). The role of DNA-ploidy alterations correlates with shorter survival (Hellstrom et is thought to be negligible (Klein et al., 2002). al., 1994; Zheng et al., 1997; Rosen et al., 2000). Fallopian tube carcinoma patients show an overall survival of 30-50% which is slightly better than the Cytogenetics reported 25-40% for epithelial ovarian cancer (Momtazee and Kempson, 1968; Baekelandt et al., Note 1993; Barakat et al., 1993; Woolas et al., 1994; In BRCA1-related cases of ovarian and fallopian tube Alvarado-Cabrero et al., 1999; Piura and Rabinovich, carcinoma, loss of heterozygosity (LOH) studies 2000). revealed high LOH frequencies on chromosome 13q11, The general 5-year survival rate is about 65% (Sedlis, 13q14, 13q21, 13q22-23, 13q32 and 13q32-4 that were 1978; Deppe et al., 1980; Inal et al., 2004). Kosary and independent of type of BRCA1 mutation, stage and colleagues found in a cohort of 416 women with grade. fallopian tube carcinoma 5 year-survival rates of 95% The authors suggested the long arm of chromosome 13 for stage I (n=102), 75% for stage II (n=29), 69% for to contain putative tumor suppressor genes (Jongsma et stage III (n= 52) and 45% for stage IV (n=151) (Kosary al., 2002). and Trimble, 2002). Genes involved and proteins Genetics BRCA1 (breast cancer 1, early onset) Note Location Fallopian tube carcinomas can manifest as a 17q21 consequence of the hereditary breast-ovarian cancer DNA / RNA syndrome. They are associated with BRCA1 and 6 different mRNA variants that undergo alternative BRCA2 mutations. In a cohort of 44 cases of fallopian splicing. Splicing influences intracellular function and tube carcinoma, 11% of the patients were positive for location. According to ENTREZ Gene, BRCA1 starts BRCA1 mutation and 5% were positive for BRCA2 at NC_000017.10 (41196312..41277500, complement), mutations. Of the patients who received their diagnosis Spidey (mRNA to genomic sequence alignment tool, before the age of 55 years, 28% (5/18) were BRCA http://www.ncbi.nlm.nih.gov/spidey) finds 24 exons. positive. First degree relatives of fallopian tube cancer The mRNA consists of ~81.2kb. patients show an increased risk for early breast and Protein ovarian cancer (Aziz et al., 2001). The encoded protein functions as intracellular tumor A BRCA1-carrier patient undergoing prophylactic suppressor with E3-ubiquitin ligase- and salpingo-oophorectomy showed a fallopian tube cancer phosphopeptide binding activity. As a transcription (Hartley et al., 2000). A positive family history of factor, it is a DNA damage sensor forming (together fallopian tube carcinoma was predictive for BRCA1 with other proteins) the BRCA1-associated genome mutation in 26 Canadian breast-ovarian cancer families surveillance complex (BASC). Germline mutations (Tonin et al., 1995). Friedman et al. reported fallopian lead to the familiar breast and ovarian cancer syndrome tube carcinomas in 2 of 12 families with BRCA1 with highly increased risk for cancer development. mutations (Friedman et al., 1995). Tonin et al. found Working together with RNA polymerase II, the protein BRCA1 mutations in four Ashkenazi Jewish breast- has an important role in transcription, DNA repair of ovarian cancer families with fallopian tube carcinoma double-stranded breaks, and recombination. (Tonin et al., 1996). Zweemer and colleagues detected There are five different protein isoforms. Isoform 1 is fallopian tube carcinomas in 2 of 23 families with the biggest with 1863 amino acids and 220 kDa. The known BRCA1 mutations (Zweemer et al., 2000). highest expression of BRCA1 is found in the ovaries, Thus, genetic evaluation should become part of the thymus and testes. diagnostics for patients with fallopian tube carcinomas. In risk patients, prophylactic oophorectomy should be BRCA2 (breast cancer 2, early onset) accompanied by salpingectomy (Aziz et al., 2001). Location And whether salpingectomy without oophorectomy is 13q12.3 sufficient treatment will be analyzed in the clinical DNA / RNA trials yet to come. Jongsma and colleagues reported frequent loss of According to Spidey, BRCA2 has 27 exons. The heterozygosity (LOH) on chromosome 13 in BRCA1- mRNA spans about 84.2 kb. associated cases of fallopian tube carcinomas indicating In exon 11, the BRC repeats are encoded.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 782 Fallopian tube tumors: an overview Stein RG, et al.

Protein Note Also BRCA2 is involved in DNA stability, especially Tumor protein p53. the double strand repair. DNA / RNA The several BRC motifs in the protein bind the RAD51 11 exons, 8 transcript variants encoding 7 protein recombinase and thus enable DNA repair. The protein isoforms consists of 3418 amino acids with a weight of 384 kDa. (http://www.ncbi.nlm.nih.gov/gene/7157#reference- STK11 (serine/threonine kinase 11) sequences). Location Protein 19p13.3 p53 is a tumor suppressor protein that is synthesized in Note response to cellular stress. It causes cell cycle arrest, apoptosis, senescence, DNA repair, or changes in Mutation of this tumor suppressor gene causes the metabolism via DNA binding. The binding of p53 leads autosomal dominant Peutz-Jeghers-Syndrome which is to transcriptional activation of several genes. Mutations characterized by intestinal polyposis and pigmented are known from several human tumors and also for naevi as well as increased tumor risk (Jeghers et al., hereditary tumor syndroms like Li-Fraumeni- 1949; Giardiello et al., 1987). The protein is regulated Syndrome. Transcription activation is triggered by a by androgens and estrogen in adipocytes (McInnes et homo-tetrameric p53 complex in which mutant al., 2012). isoforms are dominant over the wild-type protein. DNA / RNA Moreover, functional p53 induces its own degradation The gene consists of 10 exons which encompass 23 kb. (with a half-life of 15-30 min) whereas mutant p53 Protein accumulates and thus enables immunohistochemical The protein regulates cell polarity and functions as a detection. tumor suppressor. It consists of 433 amino acids with a Examining a cohort of 43 patients with fallopian tube weight of 48.6 kDa. carcinoma, Lacy et al. found immunohistochemical positivity for c-erbB-2 (HER-2/neu) overexpression in ERBB2 (v-erb-b2 erythroblastic 26% and p53 positivity in 61% of these tumors, but no leukemia viral oncogene homolog 2, significant correlation with survival (Lacy et al., 1995). neuro/glioblastoma derived oncogene Others, however, described p53 immunohistochemical homolog (avian)) positivity to be associated with shorter survival (Zheng et al., 1997; Rosen et al., 2000) whereas FIGO stages Location were not predictive for the outcome in this cohort of 63 17q12 patients (Rosen et al., 2000). Note Using 52 cases of fallopian tube carcinoma and 10 Other names: HER-2/neu, c-erbB-2. normal fallopian tubes, Zheng et al. investigated the DNA / RNA p53 status based on immunohistochemistry and 31 exons, 2 mRNA variants encoding 2 proteins: polymerase chain reaction-single-strand conformation isoform a and b. polymorphisms (PCR-SSCP) and suggested that p53 alterations play a role in early tumor progression as Protein they are not restricted to late stages (Zheng et al., This protein is a member of the epidermal growth 1997). factor receptor (EGFR) family of receptor tyrosine Chung and colleagues found that survival neither kinases. It forms heterodimers with other EGFRs that correlated with immunohistochemical p53 positivity (unlike ErbB-2) have a ligand binding domain and can nor with cMyc overexpression (which occured in 61%). thus initiate intracellular signaling leading to activation However, the statistical power of this study was limited of pathways such as mTOR or PI3K. Overexpression is by the small cohort of 18 patients (Chung et al., 2000). known for several cancers such as breast and ovarian but also fallopian tube carcinomas. MYC (v-myc myelocytomatosis viral Based on a cohort of 43 patients with fallopian tube oncogene homolog (avian)) carcinoma, Lacy et al. reported immunohistochemical Location positivity for c-erbB-2 (HER-2/neu) overexpression in 8q24 26% and p53 positivity in 61% of all cases. They could not find any correlation with survival (Lacy et al., DNA / RNA 1995). 3 exons, 1 variant, 1 isoform. TP53 (tumor protein p53) Protein The protein plays a role in cell cycle and apoptosis. It Location functions as transcription factor. Overexpression is 17p13.1 known in several cancers especially leukaemias and

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 783 Fallopian tube tumors: an overview Stein RG, et al.

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Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Selby KJ, Warner J, Klempner S, Konstantinopoulos PA, Hecht Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, JL.. Anti-Yo antibody associated with occult fallopian tube Cramer DW, McKeon FD, Crum CP.. A candidate precursor to carcinoma. Int J Gynecol Pathol. 2011 Nov;30(6):536-8. doi: serous carcinoma that originates in the distal fallopian tube. J 10.1097/PGP.0b013e3182237ca6. Pathol. 2007 Jan;211(1):26-35. Vang RWJ.. Diseases of the fallopian tube and paratubal Stewart SL, Wike JM, Foster SL, Michaud F.. The incidence of region. Blaustein's pathology of the female genital tract. New primary fallopian tube cancer in the United States. Gynecol York, Springer. 2011. Oncol. 2007 Dec;107(3):392-7. Epub 2007 Oct 24. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Carlson JW, Miron A, Jarboe EA, Parast MM, Hirsch MS, Lee Husain A, Sovak MA, Yi J, Nycum LR.. OCEANS: a Y, Muto MG, Kindelberger D, Crum CP.. Serous tubal randomized, double-blind, placebo-controlled phase III trial of intraepithelial carcinoma: its potential role in primary peritoneal chemotherapy with or without bevacizumab in patients with serous carcinoma and serous cancer prevention. J Clin Oncol. platinum-sensitive recurrent epithelial ovarian, primary 2008 Sep 1;26(25):4160-5. doi: 10.1200/JCO.2008.16.4814. peritoneal, or fallopian tube cancer. J Clin Oncol. 2012 Jun 10;30(17):2039-45. doi: 10.1200/JCO.2012.42.0505. Epub Piek JM, van Diest PJ, Verheijen RH.. Ovarian carcinogenesis: 2012 Apr 23. an alternative hypothesis. Adv Exp Med Biol. 2008;622:79-87. doi: 10.1007/978-0-387-68969-2_7. (REVIEW) Etoh T, Watanabe Y, Imaoka I, Murakami T, Hoshiai H.. Primary adenomyoma of the fallopian tube mimicking tubal No authors listed.. TNM classification of malignant tumors. malignant tumor. J Obstet Gynaecol Res. 2012 Apr;38(4):721- John Wiley Sons: New York. UICC, 2009. 3. doi: 10.1111/j.1447-0756.2011.01764.x. Epub 2012 Mar 2. Folkins AK, Jarboe EA, Roh MH, Crum CP.. Precursors to Kim J, Coffey DM, Creighton CJ, Yu Z, Hawkins SM, Matzuk pelvic serous carcinoma and their clinical implications. Gynecol MM.. High-grade serous ovarian cancer arises from fallopian Oncol. 2009 Jun;113(3):391-6. doi: tube in a mouse model. Proc Natl Acad Sci U S A. 2012 Mar 10.1016/j.ygyno.2009.01.013. Epub 2009 Feb 23. (REVIEW) 6;109(10):3921-6. doi: 10.1073/pnas.1117135109. Epub 2012 No authors listed.. Cancer staging manual. Springer NY Feb 13. Dordrecht Heidelberg London. AJCC (2010). Lanitis E, Dangaj D, Hagemann IS, Song DG, Best A, Kuhn E, Meeker A, Wang TL, Sehdev AS, Kurman RJ, Shih Sandaltzopoulos R, Coukos G, Powell DJ Jr.. Primary human IeM.. Shortened telomeres in serous tubal intraepithelial ovarian epithelial cancer cells broadly express HER2 at carcinoma: an early event in ovarian high-grade serous immunologically-detectable levels. PLoS One. carcinogenesis. Am J Surg Pathol. 2010 Jun;34(6):829-36. doi: 2012;7(11):e49829. doi: 10.1371/journal.pone.0049829. Epub 10.1097/PAS.0b013e3181dcede7. 2012 Nov 26. Przybycin CG, Kurman RJ, Ronnett BM, Shih IeM, Vang R.. McInnes KJ, Brown KA, Hunger NI, Simpson ER.. Regulation Are all pelvic (nonuterine) serous carcinomas of tubal origin? of LKB1 expression by sex hormones in adipocytes. Int J Obes Am J Surg Pathol. 2010 Oct;34(10):1407-16. doi: (Lond). 2012 Jul;36(7):982-5. doi: 10.1038/ijo.2011.172. Epub 10.1097/PAS.0b013e3181ef7b16. 2011 Aug 30. Xian W, Miron A, Roh M, Semmel DR, Yassin Y et al.. The Li- Pujade-Lauraine E, Weber B, Reuss A et al.. AURELIA: A Fraumeni syndrome (LFS): a model for the initiation of p53 randomized phase III trial evaluating bevacizumab (BEV) plus signatures in the distal Fallopian tube. J Pathol. 2010 chemotherapy (CT) for platinum (PT)-resistant recurrent Jan;220(1):17-23. doi: 10.1002/path.2624. ovarian cancer (OC). ASCO 2012 Annual Meeting. Dietl J, Wischhusen J.. The forgotten fallopian tube. Nat Rev Wagner U, Marth C, Largillier R, Kaern J et al.. Final overall Cancer. 2011 Mar;11(3):227; author reply 227. doi: survival results of phase III GCIG CALYPSO trial of pegylated 10.1038/nrc2946-c1. liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Dietl J, Wischhusen J, Hausler SF.. The post-reproductive Cancer. 2012 Aug 7;107(4):588-91. doi: 10.1038/bjc.2012.307. Epub 2012 Jul 26. Fallopian tube: better removed? Hum Reprod. 2011 Nov;26(11):2918-24. doi: 10.1093/humrep/der274. Epub 2011 Vang R, Shih IeM, Kurman RJ.. Fallopian tube precursors of Aug 16. (REVIEW) ovarian low- and high-grade serous neoplasms. Histopathology. 2013 Jan;62(1):44-58. doi: 10.1111/his.12046. Seidman JD, Zhao P, Yemelyanova A.. "Primary peritoneal" high-grade serous carcinoma is very likely metastatic from This article should be referenced as such: serous tubal intraepithelial carcinoma: assessing the new paradigm of ovarian and pelvic serous carcinogenesis and its Stein RG, Diessner J, Hönig A, Wischhusen J, Dietl J. implications for screening for ovarian cancer. Gynecol Oncol. Fallopian tube tumors: an overview. Atlas Genet Cytogenet 2011 Mar;120(3):470-3. doi: 10.1016/j.ygyno.2010.11.020. Oncol Haematol. 2013; 17(11):773-787. Epub 2010 Dec 14.

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Cancer Prone Disease Section Short Communication

Familial Juvenile Polyposis Syndrome Scott K Sherman, James R Howe University of Iowa Department of Surgery, Iowa City, IA, USA (SKS, JRH)

Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Kprones/FamJuvPolID10047.html DOI: 10.4267/2042/51821 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

juvenile polyps. Current diagnostic criteria include the Identity presence of five or more juvenile polyps in the Other names colorectum, or at least one upper and one lower GI JPS juvenile polyp, or any number of juvenile polyps in a patient with a family history of Juvenile Polyposis. Inheritance Juvenile Polyposis has variable expressivity. Even Autosomal Dominant. within the same family carrying a particular susceptibility mutation, some patients may develop Clinics polyps at a young age, while others may have negative Phenotype and clinics endoscopic screening for many years before manifesting polyposis symptoms. The number of Juvenile Polyposis Syndrome (JPS) is a heritable polyps that occur is also highly variable and ranges syndrome characterized by multiple juvenile polyps, from several to hundreds. which occur mainly in the colorectum, but can also In addition to polyps, approximately 15% of patients occur in the stomach and throughout the may have congenital anomalies, particularly of the gastrointestinal tract. heart or aorta. The incidence of Juvenile Polyposis is around 1 in 100000 and although many Juvenile Polyposis patients Differential Diagnosis are diagnosed in childhood, the word "juvenile" in the Juvenile Polyposis must be distinguished from syndrome's name refers not to the age of the patient, hamartomatous polyps found in Peutz-Jegher's, but rather to the histologic classification of the polyp Cowden's, Gorlin's, and Bannayan-Riley-Ruvalcaba (as opposed to an adenomatous polyp, for example). syndromes. Juvenile Polyposis may be more common in patients of These syndromes are caused by mutations in different northern European ancestry, but the syndrome has been genes (STK11 for Peutz-Jegher's, PTEN for Cowden's recognized throughout the world in patients of many and Bannayan-Riley-Ruvalcaba and PTCH1 for ethnicities. Gorlin's), and have additional features which are not The presenting symptom of Juvenile Polyposis is most seen in JPS. often passage of blood per rectum, with subsequent Due to a genetic defect in the same gene (SMAD4), endoscopic evaluation revealing the presence of some patients with Juvenile Polyposis Syndrome also multiple polyps. show features of Hereditary Hemorrhagic Solitary juvenile polyps can be a normal finding on Telangiectasia, and patients with a large continuous colonoscopy in a young patient, but multiple polyps are deletion of both BMPR1A and PTEN manifest severe unusual and are often indicative of JPS. Juvenile Juvenile Polyposis Syndrome of Infancy, which is Polyposis Syndrome is distinguished by a large number associated with additional severe malformations. of polyps, recurrent polyps, or a family history of

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 788 Familial Juvenile Polyposis Syndrome Sherman SK, Howe JR

Diffuse polyposis is evident in this colectomy specimen of a Juvenile Polyposis Syndrome patient.

Neoplastic risk polyps are found, after which time endoscopy may be performed every three years. Unlike the pre-malignant adenomatous polyps of APC In cases where removal of all polyps is not feasible due or HNPCC syndromes, Juvenile Polyps are considered to diffuse polyposis, or when evidence of dysplasia is benign. Nevertheless, JPS patients do have an increased present, colectomy or gastrectomy should be offered. lifetime risk for colon cancer that is estimated to be as Colectomy or gastrectomy is also high as 50%. indicated when polyps result in intractable bleeding, JPS patients also have an increased risk of gastric uncontrollable protein loss through heavy mucus cancer, which may be highest in patients with SMAD4 production, recurrent intussusception, or severe and mutations. persistent symptoms of pain, nausea, or diarrhea. The finding of an isolated juvenile polyp in a patient without evidence of Juvenile Polyposis Syndrome is not associated with an increased risk of cancer. Genes involved and proteins Treatment Note Due to the increased risk of cancer, close screening of Two genes, SMAD4 and BMPR1A, have been affected patients and their family members is confirmed to cause Juvenile Polyposis Syndrome. warranted. Together, these account for approximately 50% of Once a patient is diagnosed with JPS, he or she should cases. Both are members of the BMP/TGF-Beta undergo genetic testing. signaling pathway. If positive, their family members should be tested also SMAD4 to determine who requires screening. However, because Location only around 50% of patients carry a known mutation, if no known mutation is identified, all family members 18q21.1 must be considered to be at-risk and offered screening. Protein Upper and lower endoscopies should be performed at Note diagnosis and all polyps removed. SMAD4 is a 436 amino-acid signal transduction Endoscopy should then be performed annually, until no

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 789 Familial Juvenile Polyposis Syndrome Sherman SK, Howe JR

peptide containing an N-terminal MH1 domain and a c- gastric polyposis is more common in MADH4 mutation carriers terminal MH2 domain. than in BMPR1A mutation carriers. Hum Genet. 2002 Jul;111(1):108-11 SMAD4 is localized to the cytoplasm, but translocates to the nucleus once bound by activated R-Smad Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA. proteins, such as SMAD2 and SMAD3 (which are A combined syndrome of juvenile polyposis activated by TGF-β receptors) and SMAD1, SMAD5, SMAD8 (activated by BMP receptors). and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004 Mar In the nucleus, SMAD4 interacts with additional 13;363(9412):852-9 proteins to stimulate gene transcription. At least 14 distinct germ line SMAD4 missense, nonsense, Delnatte C, Sanlaville D, Mougenot JF, Vermeesch JR, Houdayer C, Blois MC, Genevieve D, Goulet O, Fryns JP, deletion, and promoter mutations lead to JPS. Jaubert F, Vekemans M, Lyonnet S, Romana S, Eng C, Most mutations are concentrated towards the c- Stoppa-Lyonnet D. Contiguous gene deletion within terminus of the SMAD4 protein. chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and BMPR1A PTEN tumor-suppressor genes. Am J Hum Genet. 2006 Jun;78(6):1066-74 Location 10q22.3 Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius MM, Loff S, Back W, Kaufmann A, Keller KM, Blaas SH, Siebert R, Vogt S, Protein Spranger S, Holinski-Feder E, Sunde L, Propping P, Friedl W. High proportion of large genomic deletions and a genotype Note phenotype update in 80 unrelated families with juvenile BMPR1A is a 532 amino-acid transmembrane polyposis syndrome. J Med Genet. 2007 Nov;44(11):702-9 serine/threonine kinase receptor activated by TGF-β Calva D, Howe JR. Hamartomatous polyposis syndromes. superfamily ligands. As a transmembrane receptor, Surg Clin North Am. 2008 Aug;88(4):779-817, vii BMPR1A is normally localized to the cell surface, but Calva-Cerqueira D, Chinnathambi S, Pechman B, Bair J, some JPS mutations may interfere with this Larsen-Haidle J, Howe JR. The rate of germline mutations and localization. When activated by ligand binding, the large deletions of SMAD4 and BMPR1A in juvenile polyposis. BMPR1A receptor causes SMAD1,5, and 8 Clin Genet. 2009 Jan;75(1):79-85 phosphorylation. The activated R-Smad complex can Calva-Cerqueira D, Dahdaleh FS, Woodfield G, Chinnathambi then bind SMAD4, stimulating its translocation to the S, Nagy PL, Larsen-Haidle J, Weigel RJ, Howe JR. Discovery nucleus. At least 30 germ line missense, nonsense, and of the BMPR1A promoter and germline mutations that cause deletion mutations, as well as mutations of the juvenile polyposis. Hum Mol Genet. 2010 Dec 1;19(23):4654- 62 BMPR1A promoter have been found to cause JPS. Calva D, Dahdaleh FS, Woodfield G, Weigel RJ, Carr JC, Chinnathambi S, Howe JR. Discovery of SMAD4 promoters, References transcription factor binding sites and deletions in juvenile Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, polyposis patients. Nucleic Acids Res. 2011 Jul;39(13):5369- Call KM, Tsou HC, Peacocke M, Eng C, Parsons R. Germline 78 mutations of the PTEN gene in Cowden disease, an inherited Dahdaleh FS, Carr JC, Calva D, Howe JR. Juvenile polyposis breast and thyroid cancer syndrome. Nat Genet. 1997 and other intestinal polyposis syndromes with microdeletions of May;16(1):64-7 chromosome 10q22-23. Clin Genet. 2012 Feb;81(2):110-6 Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal Heldin CH, Moustakas A. Role of Smads in TGF β signaling. carcinoma in familial juvenile polyposis. Ann Surg Oncol. Cell Tissue Res. 2012 Jan;347(1):21-36 1998a Dec;5(8):751-6 Latchford AR, Neale K, Phillips RK, Clark SK. Juvenile Howe JR, Ringold JC, Summers RW, Mitros FA, Nishimura polyposis syndrome: a study of genotype, phenotype, and DY, Stone EM. A gene for familial juvenile polyposis maps to long-term outcome. Dis Colon Rectum. 2012 Oct;55(10):1038- chromosome 18q21.1. Am J Hum Genet. 1998b 43 May;62(5):1129-36 O'Malley M, LaGuardia L, Kalady MF, Parambil J, Heald B, Howe JR, Roth S, Ringold JC, Summers RW, Järvinen HJ, Eng C, Church J, Burke CA. The prevalence of hereditary Sistonen P, Tomlinson IP, Houlston RS, Bevan S, Mitros FA, hemorrhagic telangiectasia in juvenile polyposis syndrome. Dis Stone EM, Aaltonen LA. Mutations in the SMAD4/DPC4 gene Colon Rectum. 2012 Aug;55(8):886-92 in juvenile polyposis. Science. 1998c May 15;280(5366):1086- 8 Howe JR, Dahdaleh FS, Carr JC, Wang D, Sherman SK, Howe JR. BMPR1A mutations in juvenile polyposis affect cellular Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, localization. J Surg Res. 2013 Feb 1; Petersen GM, Velculescu VE, Traverso G, Vogelstein B. Germline mutations of the gene encoding bone morphogenetic This article should be referenced as such: protein receptor 1A in juvenile polyposis. Nat Genet. 2001 Jun;28(2):184-7 Sherman SK, Howe JR. Familial Juvenile Polyposis Syndrome. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11):788-790. Friedl W, Uhlhaas S, Schulmann K, Stolte M, Loff S, Back W, Mangold E, Stern M, Knaebel HP, Sutter C, Weber RG, Pistorius S, Burger B, Propping P. Juvenile polyposis: massive

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Deep Insight Section

Premature Chromosome Condensation (PCC): Tools in chromosome and cytogenetic research Eisuke Gotoh Department of Radiology, Jikei University of School of Medicine, 3-25-8, Nishi-Simbashi, Minato-ku, Tokyo, 116, Japan (EG)

Published in Atlas Database: May 2013 Online updated version : http://AtlasGeneticsOncology.org/Deep/PCCToolID20120.html DOI: 10.4267/2042/51822 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Keywords: chromosome condensation/compaction, be briefly summarized. I do not intend to describe the chromosome structure, premature chromosome details of PCC but to introduce simply the usefulness of condensation (PCC), prematurely condensed PCC technique in this chapter to many artisans in chromosomes (PCCs), fusion mediated PCC, drug- cytogenetic field. induced PCC, Calyculin A, Okadaic acid Historical feature of PCC

Eukaryote chromosomes usually condense during About half century ago, the first report for the PCC mitosis. Chromosome condensation is strictly regulated phenomenon was described (Kato and Sandberg, 1967; by cellular elaborated machinery but the details of the Kato and Sandberg, 1968). They reported that the mechanism still remains to be elucidated. Occasionally, several kind of virus infected cells showed something chromosomes condense at outside of mitosis under strange "shattered" or "pulverized" appearance several circumstances (Gotoh et al., 1995; Gotoh and chromosomes. At that time, shattering of chromosomes Durante, 2006). This phenomenon is known as was thought as that clastgenic activity of infected virus premature chromosome condensation (PCC) or affected the cell nuclei, resulted in severe chopping of premature mitosis (PM); the resulted condensed chromosomes of infected cells. chromosomes are called prematurely condensed Thereafter, detailed analysis of premature chromosome chromosomes (PCCs). About a half century ago, the condensation by fused with synchronized cells in first description of PCC phenomenon was reported by mitotic cells using Sendai virus as fusogen (Johnson several artisans from 1967 to 1969 by observing the and Rao, 1970). They found that the "pulverized chromosomes in virus infected mammalian cell (Kato appearance" of chromosomes is selectively observed in and Sandberg, 1967; Kato and Sandberg, 1968). Then, s-phase nuclei. In addition, either G1 or G2 cells do not PCC was introduced in cells fused with mitotic cells show "pulverized" chromosomes but showed using fusogenic viruses such as Sendai virus or condensed form of univalent or bivalent chromosomes, chemicals such as polyethylene glycol (fusion- respectively. These findings suggested that the mediated PCC). Thereafter, PCC has been recognized "pulverized appearance of chromosome" did not due to and utilized as a useful tool for chromosome analysis in the actual breakage of chromosomes. They concluded, wide area of fields, such as radiation biology or therefore, that the nuclei of cells fused in mitotic cells chromosome science. The usefulness of PCC technique condensed prematurely by unknown material which has been further advanced since the chemical mediated rich accumulated in mitotic cells, and observed technique of PCC (drug-induced PCC) has been chromosome structures are equivalent to that of the introduced (Gotoh et al., 1995), as the drug-induced chromosomes of individual cell cycle stage at the time PCC method is technically much simpler and easier. of cell fusion. Utilized drug-induced PCC has explored much wider They named this phenomenon as premature area in cytogenetic fields. In this chapter, history of chromosome condensation (PCC). They also named the PCC, molecular biological mechanism and application material which increased in mitotic cells and promotes trial for cytogenetic approaches of PCC technique will chromosome condensation as mitosis promoting factor

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 791 Premature Chromosome Condensation (PCC): Tools in chromosome and cytogenetic research Gotoh E

(MPF). At the same time a similar phenomenon to PCC Molecular mechanism of PCC is known to occur at second polar body stage during oocyte maturation. This phenomenon is known as Mechanism of fusion-mediated PCC The precise mechanism of chromosome condensation is Germinal Vesicle Break down (GVBD). still almost unclear. Therefore, the molecular Cytoplasm factor which induces GVBD in oocyte mechanism of induction of PCC is still not completely maturation was identified and named as maturation elucidated either. However, accumulated evidence has promoting factor (MPF) (Masui and Markert, 1971; revealed several molecules that might be playing key Masui, 1974). The MPF of somatic cells and oocyte roles in PCC induction. Maturation/Mitosis Promoting were later identified as identical substances, so it is Factor (MPF) is a key enzyme that induces PCC or often called as mitosis/maturation promoting factor GVBD in somatic cell or oocyte, respectively. MPF is (MPF). MPF is now known as complex of now known as the complex of p34cdc2/cyclinB p34cdc2/cyclinB. p34cdc2/cyclinB is regulated (Dunphy et al., 1988; Gautier et al., 1988; Maller et al., negatively by cdc25 and cdc25 is sensitive to type 1 1989) and is playing a central role in cell cycle and type 2A protein phosphatases such as okadaic acid regulation and cell growth control. Activation of and calyculin A. p34cdc2/cyclinB complex (phosphorylated form) After recognized of PCC phenomenon, PCC has been commences at mitotic stage and accumulated activated utilized in widely in cytogenetic fields. Because PCC p34cdc2/cyclinB complex promotes chromosome has a unique advantage that allows the cell nuclei to be condensation (Moreno et al., 1989). Therefore, analyzed like as condensed chromosomes in G1, S and following cell fusion by either viruses or PEG, the G2 cell cycle. interphase nuclei is exposed to activated MPF which is The fusion-PCC protocol using fusogenic virus has, supplied from the mitotic nuclei; consequently however, several drawbacks. interphase cell nuclei condense prematurely condensed The PCC efficiency is highly depend on virus activity to mitotic-like chromosomes. and with a risk of infection during virus manipulation. Thus, chemical induced fusion-PCC protocol was Further mechanism for chemical-mediated PCC Cdc25 is a cell cycle check point proteins which introduced by means of replacing fusogenic virus by regulates entry of mitosis together with cell fusion substance such as polyethylene glycol p34cdc2/cyclinB (Ducommun et al., 1990; Moreno et (Pantelias and Maillie, 1983). al., 1990). Cdc25 is a tyrosine phosphatase which Thereafter, fusion-PCC method has been widely used activates p34cdc2/cyclinB complex by de- in cytogenetic field including radiation biology or other phosphorylation of tyrosine residue (Gould et al., 1990; fields (Cornforth and Bedford, 1983; Mullinger and Dunphy and Kumagai, 1991; Gautier et al., 1991; Johnson, 1983; Hittelman, 1984; Hittelman et al., 1984; Kumagai and Dunphy, 1991; Strausfeld et al., 1991). Hittelman and Pollard, 1984; Pantelias and Maillie, The activity of cdc25 depends on the 1984). phosphorylation/dephosphorylation of itself. Activity Fusion-PCC using polyethylene glycol is very useful of cdc25 is sensitive to PP1 and PP2A (type 1 and type and utilized in wider cytogenetic fields, however the 2A protein phosphatase) (Izumi et al., 1992; Kumagai method is still problematic. The PCC efficiency and Dunphy, 1992; Kinoshita et al., 1993). Okadaic depends on product lot which requires a preparation of acid or calyculin A is specific inhibitors of PP1 and substantial amount of mitotic arrested inducer cells. PP2A. These inhibitors may influence the activity of Therefore, the PCC utilization has been very limited in cdc25 and p34cdc2/cyclinB, finally promoting the specialized institute. To overcome the drawbacks of premature entry in mitotic stage (Kumagai and fusion-mediated PCC, drug-induced PCC technique Dunphy, 1992; Kinoshita et al., 1993). Activated MPF was introduced using protein phosphatase inhibitors molecule (p34cdc2/cyclinB) may finally promote such as okadaic acid or calyculin A (Gotoh et al., chromosome condensation prematurely. This is, 1995). presumably, a possible mechanism of drug-induced This method is very simple and easier than fusion- PCC induced by okadaic acid or calyculin A. mediated PCC, and even more easier than conventional Recently, number of molecules which involved in the chromosome preparation method using colcemid mitotic events have been identified such as SMC (Gotoh et al., 1995). proteins, including condensin (chromosome Therefore, drug-induced PCC method has been used in condensation), cohesin (chromosome cohesion of many fields of chromosome research and cytogenetic replicated chromosomes) (Swedlow and Hirano, 2003), study (Gotoh and Asakawa, 1996; Asakawa and Gotoh, or aurora kinases in centromere function (Tanno et al., 1997; Johnson et al., 1999; IAEA, 2001; Gotoh, 2007; 2006; Meyer et al., 2010; Tanno et al., 2010). IAEA, 2011).

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 792 Premature Chromosome Condensation (PCC): Tools in chromosome and cytogenetic research Gotoh E

Figure 1. Chemical structure, chemical formula and molecular weight (WM) of Okadaic Acid and Calyculin A. Okadaic acid and Calyculin A, both are extracted from marine sponges Halichondria okadai (Kadota) or Discodermia Calyx, respectively. They are strong inhibitors of proteins serine/threonine phosphatases.

These molecules cooperatively regulate the phosphatase inhibitor (molecular weight: 805.2, condensation/compaction and formation of eukaryote molecular formula: C 44 H68 O13 , IC 50 for PP1: 10 - 60 chromosomes, but the detail mechanism is still nM, IC 50 for PP2A: 0.1 - 1 nM). unknown and will be elucidated in the future. It is also used as an inducer of PCC but the PCC efficiency is usual lower than that of calyculin A, in Protocol of drug induced premature particular for attached growing cells. chromosome condensation Thus, using of calyculin A is much recommended. Materials Stock preparation of okadaic acid is same as calyculin Calyculin A, a toxin extracted from marine sponge A. Figure 1 shows the chemical structure, chemical Discodermia Calyx, is a very strong inhibitor for formula and molecular weight (WM) of okadaic acid protein serine/threonine phosphatase (molecular weight and calyculin A. 1009.18, molecular formula: C 50 H81 N4O15 P, IC 50 for Other kinds of protein phosphatase inhibitors such as PP1: 0.5 - 2 nM and IC 50 for PP2A: 0.1 - 1 nM). 35 methyl okadaic acid, cantharidin, cantharidic acid or Calyculin A is available from many chemical endothal are also used as PCC inducers. Microcystin- companies. Calyculin A dissolves in ethanol, methanol LR is a very strong inhibitor for protein phosphatase or DMSO but does not dissolve in water. Calyculin A too but not able to be used as PCC inducer (since is permeable in cell and cell nuclear. For stock solution, microcystin-LR is not permeable in cells). Calyculin A is dissolved in ethanol or DMSO as 1 mM Method concentration and stored at -20°C. Fifty nM of final Drug-induced premature chromosome condensation concentration is usually used to induce PCC in much technique is very simple and has been described kind of cells. Okadaic acid is also a toxin from marine elsewhere. The procedure steps are almost same or sponge Halichondria Okadai, and is a protein even easier than that of conventional mitotic

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 793 Premature Chromosome Condensation (PCC): Tools in chromosome and cytogenetic research Gotoh E

chromosome preparation using colcemid for mitotic biological point of view but also as useful tools for cell arrest, so the artisans who are mastering the cytogenetic fields. Chromosomes are usually prepared chromosome preparation technique will be soon able to from mitotic cells using colcemid block method. The handle. So I do not intend to describe the details of obtained chromosomes are therefore mitotic protocols but simply summarize it (please see the chromosomes only because colcemid simply inhibits following reviews for the details (Gotoh and Durante, assembly of spindle body at mitotic phase, thus the 2006; Gotoh, 2009). cell's arrest in mitosis with condensed chromosomes. In 1. Cell culture and maintain exponentially growing contrast, PCC forces the chromosomes to be condensed condition is a key point to obtain good PCC index. The 'prematurely' not only in mitosis but also in interphase PCC index depends also on cell types for the nuclei of any cell cycle (G1-, S-, G2-, M-phase) (Gotoh experiment use. Usually 50 nM calyculin A for 30 et al., 1995), hence interphase nuclei is allowed to be minutes of incubation is enough to obtain substantial visualized as condensed chromosome form like as number of PCCs. Note that the optimal condition will mitotic chromosomes. Due to this unique aspect, PCC be different for individual cell types. The researcher has been used for analyze various nuclear events that should fix the best combination of concentration and proceed during interphase, such as chromosome incubation time of calyculin A (in general, PCC index breakage and repair after exposure of ionizing increases as either concentration or incubation time irradiation or mutagens either using fusion-mediated increase, but the shape of chromosome will be more PCC (Hittelman and Rao, 1974; Hittelman and Rao, condense). 1975; Cornforth and Bedford, 1983; Hittelman and 2. Thirty-minutes prior to cell harvest, add 50 nM final Pollard, 1984; Sen and Hittelman, 1984; Maillie et al., concentration of calyculin A (1 mM stock solution in 1986), or chemical-mediated PCC (Gotoh and ethanol or DMSO) to the medium and another Asakawa, 1996; Asakawa and Gotoh, 1997; Gotoh et culturing. al., 1999; Ito et al., 2002; Horstmann et al., 2004; El 3. At harvest time, cells usually rounded and loosely Achkar et al., 2005; Srebniak et al., 2005; Terzoudi et attached or even detached from the culture flask and al., 2005). suspended in the medium due to calyculin A effect. One of most successful application of PCC technique is Gently pipetting the medium and harvest the cells with on radiation biodosimetry, in particular to estimate the a medium into a centrifuge tube. irradiation dose after an exposure accident of large dose 4. Spin down gently (250 g ~ 800 rpm, a couple of irradiation (Gotoh and Asakawa, 1996; IAEA, 2001; minutes), remove supernatant and re-suspend the cell Gotoh and Tanno, 2005; Gotoh et al., 2005; IAEA, pellet with 0.075 M KCl to swollen the cells at 37°C 2011; Gotoh, 2012). Estimation of the body irradiation for 20 minutes. exposure dose by means of cytogenetic approach by 5. Fix the cell with same volume of Carnoy's fixative scoring chromosomal aberrations is widely used as a (methanol: acetic acid 1:3 vol: vol), then spin down standard biodosimetry. Prepare and score chromosomes again the same above condition. The cell pellet is again of peripheral blood lymphocytes, using the colcemid re-suspended with the same fixative. Repeat 3 times block protocol which is a simple and well established spin-down/re-suspend/fixation steps, and finally method (cytogenetic biodosimetry, see reviews by samples are suspended in smaller volume of fixative to Lloyd 1984, International Atomic Energy Agency make adequate concentration for chromosome (IAEA), 1986). However, after human body is preparation (chromosome suspension: if cells are too irradiated with large doses (i.e. greater than 10 Gy rich, spin down again chromosome suspension, and whole body), the remained cells in the peripheral blood suspend again the pellet using more volume of fixative. arrest at G2 or G1 phase and do not enter mitosis or In case of cells are too sparse, do the same steps but even undergo mitotic cell death or apoptosis. As a with less volume of fixative). consequence, it is usually impossible to obtain 6. One drop (usually 10 - 15 µl; using yellow pipet tip chromosome from severely damaged cells for of Pipetman) of chromosome suspension is placed on cytogenetic analysis, which has limited the application the cleaned glass slide, chromosome suspension of the conventional colcemid block method for spontaneously spreading and vaporizing and air-dried. cytogenetic biodosimetry to estimate radiation doses Usually one slide glass will enough to score and above 10 Gy. This dose limitation was first overcame analyze substantial number of chromosome spreads. using drug-induced PCC technique (Gotoh et al., 1995), Chromosome sample is then subject to conventional and showed that the maximum estimable dose was 40 staining protocol such as Giemsa staining or FISH Gy of γ-rays (Gotoh and Asakawa, 1996). Figure 2 study if required. shows the Giemsa stained severely damaged human Application of PCC technique for peripheral blood lymphocyte chromosomes, after 48 hours of exposure to 40 Gy of γ-irradiation in vitro. As various cytogenetic investigations clearly seen, all chromosomes are severely damaged PCC is a very interesting phenomenon not only of a and no intact chromosome remains.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 794 Premature Chromosome Condensation (PCC): Tools in chromosome and cytogenetic research Gotoh E

Figure 2. Chromosomes obtained from 48 hours after 40 Gy of in vitro γ-irradiated peripheral blood lymphocytes. As clearly shown, all of chromosomes are severely destroyed by γ-irradiation, and there is no more remain intact chromosome.

Such chromosomes, extremely destroyed, have not ever revealed that chromosome condensation is not an been obtained from the cells exposed to high dose of independent event proceeding during mitosis, but irradiation. Since then, number of cytogenetic tightly coupled with DNA replication or chromosome biodosimetry approaches for high exposure irradiation repair process (Zink et al., 1998; Manders et al., 1999; dose estimation (more than 10 Gy irradiation Pflumm, 2002; Samaniego et al., 2002). But visualizing equivalent of γ-ray) have been applied and reported approaches for chromosome dynamics coupled with (Gotoh and Tanno, 2005; Lamadrid et al., 2007; Wang DNA replication was somehow limited, because it et al., 2009; Balakrishnan et al., 2010; Gotoh, 2012; should be required to observe chromosomes in S-phase, Romero et al., 2013). IAEA has qualified PCC but chromosomes are usually invisible in S-phase as technique as one of standard protocol for biological they are de-condensed. dosimetry (IAEA, 2001; IAEA, 2011). Visualizing dynamics of chromosome condensation has Newer cytological approaches have been challenged been accomplished using drug-induced PCC technique utilizing with PCC technique. Classically, it was (Gotoh, 2007), which showed that chromosome thought that chromosomes condense during mitotic condensation is very tightly coupled with DNA phase. However, recently accumulated findings replication. Involvement of condensin II in sister

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 795 Premature Chromosome Condensation (PCC): Tools in chromosome and cytogenetic research Gotoh E

chromatid separation during the S-phase has also Hittelman WN. Prematurely condensed chromosomes: a model elucidated by means of drug-induced PCC (Ono et al., system for visualizing effects of DNA damage, repair and inhibition at the level of chromosome structure. Nucleic Acids 2013). Symp Ser. 1984;(13):341-71 Molecules (proteins/enzymes: such as condensin and Hittelman WN, Menegaz SD, McCredie KB, Keating MJ. cohesin) involved in chromosome condensation Premature chromosome condensation studies in human mechanism have been recently clarified (Swedlow and leukemia: 5. Prediction of early relapse. Blood. 1984 Hirano, 2003), lamina, microtubules, histone H1 and Nov;64(5):1067-73 topoisomerase II (Kubiak, 1991; Rattner and Wang, Hittelman WN, Pollard M. Visualization of chromatin events 1992; Ishida et al., 1994; Van Hooser et al., 1998; Vass associated with repair of ultraviolet light-induced damage by et al., 2003), shugoshin and protein phosphatase 2A in premature chromosome condensation. Carcinogenesis. 1984 chromosome cohesion (Kitajima et al., 2006; Tanno et Oct;5(10):1277-85 al., 2010), aurora kinases in centromere function Lloyd DC.. An overview of radiation dosimetry by conventional (Tanno et al., 2006; Meyer et al., 2010; Tanno et al., cytogenetic methods. In Biological Dosimetry (ed Eisert WG, 2010). Mendelsohn ML) Volume 1984.Springer, Berlin, p 3-14. However, precise mechanism is still mostly unclear. Pantelias GE, Maillie HD.. The use of peripheral blood PCC is partly the similar but not completely the same mononuclear cell prematurely condensed chromosomes for phenomenon as normal chromosome condensation biological dosimetry. Radiat Res. 1984 Jul;99(1):140-50. 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Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 798 Atlas of Genetics and Cytogenetics

in Oncology and Haematology

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Case Report Section Paper co-edited with the European LeukemiaNet

Homogeneously Staining Region (HSR) harboring CMYC amplification in a patient with primary plasma cell leukemia Nusrat F Pathan, Margarita Palutke, Anwar N Mohamed Cytogenetic Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI, USA (NFP, MP, ANM)

Published in Atlas Database: June 2013 Online updated version : http://AtlasGeneticsOncology.org/Reports/CRMYCampMohamedID100068.html DOI: 10.4267/2042/51823 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

WBC: 14.4x10 9/L 40% plasma cells with atypical Clinics features, Hb; 11.1g/dl, hematocrit of 33.5%, platelets; 9 Age and sex 74,000x10 . 36 years old female patient. Previous history Cyto-Pathology No preleukemia, no previous malignancy, no history of Classification plasma cell myeloma or other malignancy, no inborn condition of note main items patient had solvent and Immunophenotype formaldehyde exposures. Flow cytometry on peripheral blood showed an Organomegaly abnormal clonal plasma cell population expressing No hepatomegaly, no splenomegaly, no enlarged lymph CD38, CD138, and dim CD45, with lambda chain nodes, no central nervous system involvement. restriction. Rearranged Ig Tcr Blood Not performed. WBC: 14.4 X 10 9/l Pathology HB: 11.1g/dl CT scan, MRI and bone scan revealed T5 soft tissue Platelets: 74,000 X 10 9/l mass, multiple osteolytic lesions in skull, ribs, vertebra Bone marrow: Hypercellular marrow 100% with near- and iliac crest. total replacement by sheets of malignant plasma cells Electron microscopy ranging from small uninuclear to very large Not performed. multinucleated cells with prominent nucleoli, and high Diagnosis mitotic activity (Figure 2A). Plasma cell leukemia (PCL). Note At time of presentation her blood work up revealed Survival hypercalcemia; 14.9 mg/dl, BUN; 19 mg/dl; creatinine; 1.5 mg/dl, total protein; 13 g/dl, albumin; 5.09 g/dL, Date of diagnosis: 05-2008 and LDH; 196 units/L. Serum protein electrophoresis Treatment: Steroid, Zometa, radiation, stem cell and immunofixation demonstrated IgGlambda. transplant. Complete remission: No short remission. Treatment related death: No.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 799 Homogeneously Staining Region (HSR) harboring CMYC amplification in a patient Pathan NF, et al. with primary plasma cell leukemia

Figure 1. G-banded karyotype showing two hsr regions (long arrows), t(14;16)(q32;q23) (short arrows) as well as other abnormalities.

Relapse: Her disease recurred and spread to chromosome 13, deletion of p53 and IGH- extramedullary sites spleen and lymph nodes; expired 5 MAF/t(14;16) in approximately 60% of interphase months after diagnosis. cells. Status: Death Results: Last follow up: 10-2008 Furthermore, hybridization with LSI IGH/CMYC/CEP- 8 probe set showed that the two copies of hsr were Survival: 5 months from initial diagnosis entirely labeled with CMYC (Figure 2B). Karyotype Comments Sample: peripheral blood We report a case of primary PCL admitted to the Culture time: 24 and 48 hours unstimulated cultures hospital due to severe diarrhea and a history of 2 Banding: GTG months of bone pain. Results She was found to havehypercalcemia, and at that time 43,X,-X,del(1)(p13p36.1),- her peripheral blood showed 40% abnormal plasma 2,hsr(5)(q31),del(8)(q22q24.1),del(12)(q14q24.1),- cells. 13,t(14;16)(q32;q23),del(15)(q22),- Cytogenetic analysis revealed a hypodiploid karyotype 16,del(17)(p11.2),hsr(17)(q24),add(20)(q13.3), with complex abnormalities including monosomy 13, +mar[cp14]/46,XX[6] (Figure 1). deletion 17p/p53, t(14;16)/IGH-MAF and two copies of hsr indicating a high risk disease (Figure 1). Metaphase Other Molecular Studies FISH revealed that the hsr were positive for CMYC sequences (Figure 2B). Technics: In leukemia, double minute (dmin) and hsr are signs of Fluorescence in situ hybridization using LSI gene amplification, most often represent the CMYC D13S319/LAMP, TP53 and IGH/MAF DNA probes oncogene or drug resistance genes. (Abbott Molecular) revealed loss of

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11) 800 Homogeneously Staining Region (HSR) harboring CMYC amplification in a patient Pathan NF, et al. with primary plasma cell leukemia

Figure 2. (A) Touch imprint of bone marrow biopsy showing several very large multinucleated as well as small uninuclear myeloma cells. (B) FISH analysis with LSI IGH/MYC/CEP8 tricolor, dual fusion translocation DNA probe set. The IGH is labeled with spectrum green, MYC with spectrum orange, and CEP 8 with spectrum aqua. (B) Hybridization of a metaphase showing 2 hsr regions (arrows), 3 IGH green signals, 1 orange MYC signal, and 2 aqua signals identifying chromosome 8. Notice one chromosome 8 has no MYC signal. sequences in acute myeloid leukemia. Hematopathol Mol Dmins tend to occur in elderly with a myelodysplastic Hematol. 1996;10(4):193-9 syndrome and acute myeloid leukemia, and are García-Sanz R, Orfão A, González M et al.. Primary plasma associated with a rapid and aggressive clinical cell leukemia: clinical, immunophenotypic, DNA ploidy, and outcome. cytogenetic characteristics. Blood. 1999 Feb 1;93(3):1032-7 However, an hsr is extremely rare in leukemia and Shou Y, Martelli ML, Gabrea A, Qi Y et al.. Diverse karyotypic based on our search in the medical literature, the abnormalities of the c-myc locus associated with c-myc present case is the first report of CMYC amplification dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):228-33 in the form of an hsr seen in myeloma. In contrast, development of PCL in this patient at relatively young Avet-Loiseau H, Daviet A et al.. Cytogenetic, interphase, and age is quite uncommon, possibly due to history of multicolor fluorescence in situ hybridization analyses in primary plasma cell leukemia: a study of 40 patients at diagnosis, on exposure to mutagens which initiate a series of DNA behalf of the Intergroupe Francophone du Myélome and the mutations. Groupe Français de Cytogénétique Hématologique. Blood. The presence of an hsr in this case is also associated 2001 Feb 1;97(3):822-5 with a very bizarre plasma cell morphology and dismal Gutiérrez NC, Hernández JM et al.. Differences in genetic clinical course. As seen in our patient, dmin and hsr changes between multiple myeloma and plasma cell leukemia have been described in association with deletion of demonstrated by comparative genomic hybridization. 17p13/p53, suggesting that loss of p53 primes leukemic Leukemia. 2001 May;15(5):840-5 cells by increasing their survival, therefore allowing Chang H, Sloan S, Li D, Patterson B. Genomic aberrations in deregulation of other oncogenes such as CMYC and plasma cell leukemia shown by interphase fluorescence in situ hybridization. Cancer Genet Cytogenet. 2005 Jan RAS. Still the molecular events that allow the plasma 15;156(2):150-3 cells to escape the bone marrow environment are Tiedemann RE, Gonzalez-Paz N, Kyle RA et al.. Genetic unclear. Sequential involvement and cooperation of aberrations and survival in plasma cell leukemia. Leukemia. multiple oncogenes and tumor suppressor genes, as 2008 May;22(5):1044-52 well as other epigenetic events, are required for plasma Chang H, Qi X et al.. Genetic aberrations including cell expansion into the peripheral blood and chromosome 1 abnormalities and clinical features of plasma extramedullary tissues. cell leukemia. Leuk Res. 2009 Feb;33(2):259-62 Jimenez-Zepeda VH et al.. Plasma cell leukemia: a highly References aggressive monoclonal gammopathy with a very poor prognosis. Int J Hematol. 2009 Apr;89(3):259-68 Jonveaux P, Berger R. Chromosome studies in plasma cell leukemia and multiple myeloma in transformation. Genes This article should be referenced as such: Chromosomes Cancer. 1992 Jun;4(4):321-5 Pathan NF, Palutke M, Mohamed AN. Homogeneously Dimopoulos MA, Palumbo A, Delasalle KB, Alexanian R. Staining Region (HSR) harboring CMYC amplification in a Primary plasma cell leukaemia. Br J Haematol. 1994 patient with primary plasma cell leukemia. Atlas Genet Dec;88(4):754-9 Cytogenet Oncol Haematol. 2013; 17(11):799-801. Mohamed AN, Mahalak S, Goldfarb SB, Palutke M. Double minute chromosomes contain amplified c-myc oncogene

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Homogeneously Staining Region (HSR) harboring CMYC amplification in a patient Pathan NF, et al. with primary plasma cell leukemia

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