Number 1 January 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Volume 1 - Number 1 May - September 1997

Volume 20 - Number 1 January 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematologyis a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.

It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf

Editorial correspondance

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

Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf

The Atlas of Genetics and Cytogenetics in Oncology and Haematology 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. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).

Publisher Contact:INIST-CNRS Mailing Address:Catherine Morel, 2,Allée du Parc de Brabois, CS 10130, 54519 Vandoeuvre-lès-Nancy France. Email Address:[email protected] Articles of the ATLAS are free in PDF format, and metadata are available on the web in Dublin Core XML format and freely harvestable.A Digital object identifier (DOI®), recorded at the International Agency CrossRefhttp://www.crossref.org/ is assigned to each article.

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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 in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS Editor-in-Chief Jean-Loup Huret (Poitiers, France)

Board Members Sreeparna Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Banerjee Alessandro Department of Health Sciences, University of Milan, Italy; [email protected] Beghini Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; Antonio Cuneo [email protected] Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Paola Dal Cin [email protected] François IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Desangles Dewoitine C212, 91223 Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, Enric Domingo OX37BN, UK [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Kessel 6500 HB Nijmegen, The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Oskar A. Haas Children's Cancer Research Institute Vienna, Vienna, Austria. [email protected] Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; Anne Hagemeijer [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, Nyla Heerema USA; [email protected] Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; Sakari Knuutila [email protected] Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; Lidia Larizza l.larizza@auxologico Roderick Mc Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Leod Cultures, Braunschweig, Germany; [email protected] Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; Cristina Mecucci [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; miller.konstantin@mh- Konstantin Miller hannover.de Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Stefan Nagel Cultures, Braunschweig, Germany; [email protected] Florence Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; Pedeutour [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Susana Raimondi Memphis, Tennessee 38105-3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; Sabine Strehl [email protected] Nancy Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; Uhrhammer [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Roberta Vanni Italy; [email protected] Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Franck Viguié Universitaire Necker-Enfants Malades, 75015 Paris, France; [email protected]

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’InformationScientifique 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 in Oncology and Haematology

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Volume 20, Number 1, January 2016 Table of contents

Gene Section

CHFR (Checkpoint with fork-head associated and ring finger) 1 Ayse E Erson-Bensan, Hesna Begum Akman, Elizabeth M Petty GSTM1 (Glutathione S-transferase M1) 7 Marija Pljesa-Ercegovac, Marija Matic LDOC1 (leucine zipper, down-regulated in cancer 1) 14 Jenn-Ren Hsiao; Jang-Yang Chang NKX2-3 (NK2 homeobox 3) 18 Zhenwu Lin, John P Hegarty, Joanna Floros, Andre Franke SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) 26 WenYong Chen SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1) 36 Hannu Koistinen, Outi Itkonen, Ulf-Hakan Stenman

Leukaemia Section t(6;11)(q21;q23) KMT2A/FOXO3 45 Jean-Loup Huret Unbalanced whole-arm translocation der(1;13) in hematologic malignancies 48 Adriana Zamecnikova, Soad Al Bahar

Solid Tumour Section

Head and Neck: Primary oral mucosal melanoma 52 Cláudia Malheiros Coutinho-Camillo, Silvia Vanessa Lourenço, Fernando Augusto Soares

Atlas Genet Cytogenet Oncol Haematol. 1998; 2(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

CHFR (Checkpoint with fork-head associated and ring finger) Ayse E Erson-Bensan, Hesna Begum Akman, Elizabeth M Petty Department of Biology, Middle East Technical University, Ankara, Turkey (AEEB, HBA); University of Wisconsin School of Medicine, Public Health, Madison, WI 53705-2221, USA (EMP)

Published in Atlas Database: December 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/CHFRID526.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62503/12-2014-CHFRID526.pdf DOI: 10.4267/2042/62503 This article is an update of : Erson AE, Petty EM. CHFR (Checkpoint with fork-head associated and ring finger). Atlas Genet Cytogenet Oncol Haematol 2004;8(3)

Other names: FLJ10796 Abstract Local order Growing evidence in mice, primary human tumors, Genes flanking CHFR in centromere to telomere and mammalian cell culture models indicate that direction on 12q24.33: CHFR may function as a potent tumor suppressor. Peroxisomal membrane protein 2 gene (PXMP2) --- CHFR functions as part of an early G2/M Hypothetical protein gene (MGC5352) --- Golgi checkpoint, more specifically in antephase. autoantigen, golgin subfamily a3 gene (GOLGA3) - Antephase refers to late G2 when chromosome -- Checkpoint with FHA and RING finger gene condensation starts. This early mitotic checkpoint (CHFR) --- Hypothetical gene (GeneID: 90462) --- causes a delay in chromosome condensation in Zinc finger protein 26 gene (ZNF26) response to mitotic stresses. The human CHFR gene Note was originally identified during a search for novel CHFR functions as part of an early G2/M cell cycle checkpoint proteins that have fork-head checkpoint, more specifically in antephase. associated domains. Initial analysis indicated that the Antephase refers to late G2 when chromosome CHFR-associated G2/M checkpoint was inactivated condensation starts. in a subset of cancers as demonstrated by high This early mitotic checkpoint causes a delay in mitotic indices (a high percentage of cells that have chromosome condensation in response to mitotic condensed chromosomes) in response to exposure to stresses. The human CHFR gene was originally the microtubule poison, nocodazole, due to lack of identified during a search for novel cell cycle CHFR expression or CHFR mutations in various checkpoint proteins that have fork-head associated cancers. Many other studies showed promoter domains. Initial analysis indicated that the CHFR- hypermethylation leading to low/no expression of associated G2/M checkpoint was inactivated in a CHFR. subset of cancers as demonstrated by high mitotic Keywords indices (a high percentage of cells that have CHFR, cell cycle, checkpoint, antephase condensed chromosomes) in response to exposure to the microtubule poison, nocodazole, due to lack of Identity CHFR expression or CHFR mutations in a neuroblastoma, an osteosarcoma and 2 colon cancer HGNC (Hugo): CHFR cell lines (4 of 8 different cancer cell lines) (Scolnick Location: 12q24.33 and Halazonetis, 2000).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 1 CHFR (Checkpoint with fork-head associated and ring finger) Erson-Bensan AE, et al.

Domains of CHFR. The forkhead-associated domain of CHFR is located at the N-terminus. RING-finger domain with the ubiquitination activity is located through 303-346 amino acids. Poly-ADP-ribose binding zinc finger motif overlaps with the cystein-rich region near the C-terminus.

Various further studies demonstrated loss of or low Description CHFR expression in various types of cancer cells CHFR encodes a 652 amino acid protein (according including those from colon, esophageal, gastric, lung to BC012072 nucleotide sequence) with FHA and breast cancers. (forkhead associated), RING (really interesting new Over time, CHFR has been identified as an gene) finger and cysteine rich domains. Cysteine rich inactivated tumor suppressor protein in a diverse region further harbors a PBZ domain. No alternative group of solid tumor malignancies, mostly as isoforms have been described to date. demonstrated by promoter CpG island methylation. Domains: - FHA domains (16-123) are present in cell cycle DNA/RNA checkpoint genes, transcription factors, protein Description kinases and have roles in protein-protein interactions with specificity for phosphorylated targets. The CHFR gene spans approximately 47 kb and has The three dimensional structure of CHFR suggests at least 18 exons (BC012072 vs. NT_024477) as that CHFR may be able to recognize as of yet predicted according to Spidey unidentified phosphorylated targets targets (Stavridi (http://www.ncbi.nlm.nih.gov/spidey/) et al., 2002; Tsai 2002).. http://www.ncbi.nlm.nih.gov/spidey/). While - RING finger domains are found in ubiquitin multiple splice forms have been demonstrated ligases. (Toyota et al, 2003), the genomic structure has not Ubiquitin ligases attach ubiquitin to target proteins been experimentally confirmed. during a cascade of enzymatic reactions. RING Transcription finger domains are present in a variety of proteins CHFR mRNA is 3189 bp (BC012072). (e.g. Anaphase promoting complex, APC, Cbl Transcripts that lack exon 2, exon 5 and exon 6 have family proteins, MDM2) implicated in cancer. been detected in various tissues including bone - Cys: Cystein-rich region (476-641) marrow, small intestine, lung, heart, testis, kidney, - PBZ: poly-ADP-ribose binding zinc finger motif stomach and lympocytes as well as some cancer cell (620-644) is at the C terminus. PBZ domain allows lines by RT-PCR. Northern blot transcript analysis CHFR to bind to poly (ADP-ribose). This domain is suggests that limited if any alternative splicing is generally required for the activity of checkpoint present in most fetal and adult tissues where CHFR response proteins (Ahel et al., 2008) is expressed a prominent 3.2 kb is observed. CHFR Expression mRNA is detected in heart, brain, placenta, lung, CHFR is ubiquitiously expressed in normal fetal and liver, muscle, kidney, pancreas by Northern blot adult human tissues. analysis (Scolnick and Halazonetis, 2000). Protein levels are predicted to fluctuate during the Alternative mRNA transcripts lacking specific exons cell cycle possibly through auto-ubiquitination based (2, 5, and/or 6) have been described for CHFR on overexpression studies in cancer cell lines (Toyota et al. 2003) The isoform that lacks exon 2 (Chaturverdi et al., 2002; Kim et al., 2011). happens to lack the FHA domain and was also found Upon mitotic stresses, CHFR protein levels are to be highly expressed in cancer cells when thought to be stabilized and reaching the highest compared to normal samples . levels at G2/M. Pseudogene Localisation No known pseudogene has been reported Various lines of evidence suggest different cellular localizations for CHFR. Endogenous and low Protein ectopic expression of CHFR showed cytoplasm and

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CHFR (Checkpoint with fork-head associated and ring finger) Erson-Bensan AE, et al.

spindle localization patterns during mitosis. Higher reverses chromosome condensation and induces a expression of ectopic CHFR correlated with a shift mitotic arrest and suggested that the ubiquitin ligase in the localization to the nucleus (Burgess et al., function of CHFR may be different than the current 2008). Later on, nuclear presence of CHFR was in vitro model and that instead of Lys48 explained via a short lysine-rich stretch (KKK) at ubiquitination, CHFR may link ubiquitin to target amino acid residues 257-259 (Kwon et al., 2009). protein or proteins via Ly63 due to its interaction Egeberg et al., 2012 suggested a centrosome/primary with the heteromeric ubiquitin conjugating enzyme cilium axis localization of CHFR. CHFR was also complex, Ubc13-Mms2 (Bothos et al., 2003). shown to localize to the mitotic spindle by an In the canonical ubiquitin/proteasome pathway, interaction with TCTP, a protein involved in Lys48 is a signal for degradation of target proteins microtubule stabilization and a-tubulin (Kim, 2011) whereas Lys63 ubiquitination functions as a non- Function proteolytic tag for protein targets. Lys63 ubiquitination is thought to be involved in DNA Initially, CHFR was described to induce an early repair mechanisms. Indeed, CHFR appears to have G2/M checkpoint in response to mitotic stress important roles in DNA damage response (Scolnick and Halozenetis, 2000). Cell lines (Shtivelman et al., 2003). CHFR and RNF8 (A expressing wild-type CHFR exhibit low mitotic ubiquin ligase) ubiquitinate histones (H2A and H2B) index (percentage of cells with condensed upon ioinizing radiation (Al-Hakim et al., 2010; Wu chromosomes) and delayed entry into metaphase et al., 2011). when centrosome separation is inhibited by mitotic These ubiquitinations seem to be important for the stress. In contrast, cancer cell lines lacking CHFR eventual activation of the key DNA damage function enter metaphase without delay and checkpoint effector, ATM (Derks et al., 2006; Lavin demonstrate higher mitotic indices compared to the and Kozlov, 2007). CHFR expressing cell lines. (Erson and Petty, 2004). Recently, CHFR was reported to interact with In vitro studies suggest that the RING finger domain MAD2, an important component of the spindle in CHFR also facilitates ubiquitin ligase function assembly checkpoint. CHFR knockdown resulted in and that it is essential for checkpoint function of mislocalization of MAD2 and disruption of the CHFR (Chaturved et al., 2002).. In vitro Xenopus MAD2/CDC20 interaction. extract experiments suggested that CHFR The cysteine-rich region of CHFR appears to be the specifically targets PLK1 (polo-like kinase 1) for essential domain for the CHFR/MAD2 interaction degradation when extracts are supplemented with and for promoting interaction between MAD2 and high ubiquitin concentrations (Kang, 2002). Thus, CDC20 to inhibit the anaphase-promoting complex according to this in vitro model, CHFR is able to halt (Privette et al., 2008; Keller and Petty, 2011). cell cycle progression early in mitosis by degrading PLK1, a major player for the activation of mitosis Homology promoting factor. In addition, AURORA A is known M.musculus 5730484M20Rik RIKEN cDNA to phosphorylate and activate PLK1 as well as 5730484M20 gene, R.norvegicus LOC288734 CDC25B eventually driving CYCLIN B/CDK1 similar to RIKEN cDNA 5730484M20, budding activation. Interestingly, CHFR was also found to yeast proteins, Dma1 and Dma2 are 58% identical to bind via its cysteine rich C-region and ubiquitinate each other and are possible homologs of human AURORA A, leading to its degradation (Yu et al., CHFR. Dma1 and Dma2 have roles in spindle 2005). The auto-ubiquitylation ability of CHFR at formation and formation of septin ring during G2 Phase was proposed to be required for the cytokinesis (Fraschini et al., 2004). accumulation of Plk1 and mitotic entry in mammalian cells (Kim et al., 2011). Earlier, Oh et Mutations al., showed deubiquitination of Chfr, by USP7/HAUSP (deubiquitinating enzyme) also to Germinal regulate its own stability and activity (Oh et al,. No germline mutations have been reported yet. 2007). On the contrary, Summers et al. suggested PLK1 and Somatic AURORA A levels not to change when CHFR was A panel of 53 lung carcinomas has been screened expressed in HCT116 cells treated with Nocodazole with matching normal tissue and 3 mutations were (Summers et al., 2005). found, one of which was associated with loss of More recently, other proteins including TOPK and heterozygosity. Mutations found in patient samples PTEN have been shown to play a role in the CHFR were: C587T, G695C (both between the FHA and related mitotic spindle checkpoing (Shinde et al. RING domains) and T1697C (in the C-terminal 2013) cysteine rich region of CHFR). However, no Furthermore, Bothos et al., showed that CHFR was correlation was found with a specific diagnosis or able to activate the p38 stress kinase pathway, which stage of the disease in the patients (Mariatos et al.,

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CHFR (Checkpoint with fork-head associated and ring finger) Erson-Bensan AE, et al.

2003). No clear pathogenic mutations in the CHFR negativity (Privette et al., 2007). In another study, coding sequence have been observed in the analysis 110 primary breast cancers were investigated for of tumors (Privette and Petty, 2008). methylation status, only 0.9% showed Epigenetics hypermethylation of CHFR promoter (Tokunaga et al., 2006). Although hypermethylation of CHFR Hypermethylation of the CHFR promoter has been promoter is common in various cancers, this study the most commonly reported mechanism lowering showed it to be a rare event in primary breast CHFR expression observed in tumors (Privitte and carcinomas. Moreover, an interaction between Petty, 2008). CHFR and PARP-1 was shown to have an important role in cell cycle regulation. CHFR, by its E3 Implicated in ubiquitin ligase function, caused degradation of PARP-1, which lead to cell cycle arrest in prophase. Gastric cancer These findings suggested a novel potential In gastric cancer, methylation of CHFR promoter is therapeutic approach for combinational highly recurrent (Hu et al., 2011; Li et al., 2014; chemotherapy with PARP inhibitors for breast Satoh et al., 2003). Decreased CHFR expression has cancer cells (Kashima et al., 2012). been shown in 20% of gastric cell lines and 39% of primary gastric cancers tested (Satoh et al., 2003). In Leukemia a study with 102 paraffin-embedded gastric cancer Methylation of CHFR promoter was detected in 39% samples, 34% of samples showed methylation. No of leukemia patients. CHFR hypermethylation association was found between methylation of incidence was shown to be unchanged between acute CHFR promoter with gender, age, tumor size, tumor myelocytic leukemia and acute lymphocytic differentiation, and lymph node metastasis. leukemia (Gong et al., 2005). According to Cox proportional hazards model in docetaxel-treated gastric cancer patients, resistance Esophageal cancer to docetaxel was found in CHFR unmethylated When expression level of CHFR was investigated, 4 patients. CHFR methylation may serve as a out of 15 esophageal cancer cell lines (26.7%) and 7 docetaxel-sensitive marker in human gastric cancer out of 43 (16.3%) primary esophageal cancers (Li et al., 2014). showed loss of CHFR expression due to Lung cancer hypermethylation of promoter (Shibata et al., 2002). In another study, CHFR transcript was found to be Loss of detectable CHRF levels has been linked to downregulated in 79% of esophageal aberrant hypermethylation in lung cancer (Mizuno et adenocarcinomas (44 of 56 samples) compared to 41 al., 2002). Apart from hypermethylation, normal samples. Immunohistochemical analysis also inactivation of CHFR gene by missense mutations is correlated with expression analysis, 75% (56 of 75) reported for lung carcinomas (Mariatos et al., 2003). of samples showed either weak or no In a study with 165 lung carcinomas, 10% were immunostaining. Hypermethylation of promoter found to have hypermethylated CHFR promoter. In correlated with low CHFR expression in esophageal addition, cancer patients; 31% of samples (18 of 58) displayed Prognosis significant hypermethylation (Soutto et al., 2010). CHFR hypermethylation was significantly Another recent study used 40 esophageal squamous correlated with poor prognosis of lung carcinomas, cell carcinoma patient samples for RT-qPCR suggesting a therapeutic potential for CHFR targeted analysis of CHFR expression. Aberrant approaches (Koga et al., 2013). hypermethylation of the CHFR promoter was Cytogenetics observed in 13 of 29 primary esophageal cancers. A lung cancer patient sample demonstrates loss of The CHFR expression levels of the methylated heterozygosity for a CA repeat located on a BAC that samples was significantly lower than that of the contains the CHFR gene. Several other cancers unmethylated samples (Suzuki et al., 2014) demonstrate allelic imbalance involving Hepatocellular carcinoma chromosome band 12q24 but specific analysis of Aberrant methylation was detected in 22 of 65 (35%) CHFR in these samples has not been investigated. primary hepatocellular carcinomas (HCC), Breast cancer compared to noncancerous liver cells (Sakai et al., An initial screening resulted with 50% of 24 breast 2005). Also, methylation of CHFR was found to be cancer cell lines to have CHFR expression (Erson significantly correlated with advanced disease stage and Petty, 2004). CHFR protein levels were also low (p=0.037) and an infiltrated growth pattern in 36% of breast cancer patients. Lack of CHFR (p=0.047). In another study with 70 HCC samples, expression in primary cancers was associated with methylation frequency of CHFR was 43% (30 out of increased tumor size and estrogen receptor 70) (Li et al., 2012). 5-aza-2'-deoxycytidine (5-aza-

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CHFR (Checkpoint with fork-head associated and ring finger) Erson-Bensan AE, et al.

dC) treatment of HCC cell lines restored expression in colorectal and non-small cell lung cancer Carcinogenesis of CHFR. 2003 Jan;24(1):47-51 Derks S, Postma C, Moerkerk PT, van den Bosch SM, Prostate cancer Carvalho B, Hermsen MA, Giaretti W, Herman JG, In a genome profiling study, blood and bone-marrow Weijenberg MP, de Bruïne AP, Meijer GA, van Engeland M. samples of prostate cancer patients were investigated Promoter methylation precedes chromosomal alterations in colorectal cancer development Cell Oncol 2006;28(5- using methylation-specific multiplex ligation- 6):247-57 dependent probe amplification (MS-MLPA) (Schwarzenbach et al., 2011). MS-MLPA detected Egeberg DL, Lethan M, Manguso R, Schneider L, Awan A, Jørgensen TS, Byskov AG, Pedersen LB, Christensen ST. genetic and epigenetic aberrations of 37 tumor Primary cilia and aberrant cell signaling in epithelial ovarian suppressor genes including CHFR. cancer Cilia 2012 Aug 10;1(1):15 Head and neck cancer Erson AE, Petty EM. CHFR-associated early G2/M checkpoint defects in breast cancer cells Mol Carcinog 19% of 126 head and neck cancer patients showed 2004 Jan;39(1):26-33 methylation of a group of tumor suppressors. CHFR was one of the most frequently methylated genes in Fraschini R, Bilotta D, Lucchini G, Piatti S. Functional characterization of Dma1 and Dma2, the budding yeast tumor tissue compared to normal (Yalniz et al., homologues of Schizosaccharomyces pombe Dma1 and 2011). human Chfr Mol Biol Cell 2004 Aug;15(8):3796-810 Cervical cancer Fu Z, Regan K, Zhang L, Muders MH, Thibodeau SN, French A, Wu Y, Kaufmann SH, Lingle WL, Chen J, Tindall Out of 14 cervical adenocarcinoma specimens tested DJ. Deficiencies in Chfr and Mlh1 synergistically enhance by methylation-specific PCR, 2 of them (12.3%) tumor susceptibility in mice J Clin Invest 2009 showed aberrant methylation of CHFR (Banno et al., Sep;119(9):2714-24 2007). When six cell lines derived from human Gong H, Liu W, Zhou J, Xu H. Methylation of gene CHFR cervical carcinoma were analyzed, hypermethylaton promoter in acute leukemia cells J Huazhong Univ Sci of CHFR was observed in HeLa and SKG-IIIb cells. Technolog Med Sci 2005;25(3):240-2 In another study, sequential methylation of eight Henken FE, Wilting SM, Overmeer RM, van Rietschoten genes including CHFR was linked to HPV-induced JG, Nygren AO, Errami A, Schouten JP, Meijer CJ, Snijders cervical carcinogenesis (Henken et al., 2007). PJ, Steenbergen RD. Sequential gene promoter methylation during HPV-induced cervical carcinogenesis Br References J Cancer 2007 Nov 19;97(10):1457-64 Hu SL, Huang DB, Sun YB, Wu L, Xu WP, Yin S, Chen J, Ahel I, Ahel D, Matsusaka T, Clark AJ, Pines J, Boulton SJ, Jiang XD, Shen G. Pathobiologic implications of methylation West SC. Poly(ADP-ribose)-binding zinc finger motifs in and expression status of Runx3 and CHFR genes in gastric DNA repair/checkpoint proteins Nature 2008 Jan cancer Med Oncol 2011 Jun;28(2):447-54 3;451(7174):81-5 Kashima L, Idogawa M, Mita H, Shitashige M, Yamada T, Al-Hakim A, Escribano-Diaz C, Landry MC, O'Donnell L, Ogi K, Suzuki H, Toyota M, Ariga H, Sasaki Y, Tokino T. Panier S, Szilard RK, Durocher D. The ubiquitous role of CHFR protein regulates mitotic checkpoint by targeting ubiquitin in the DNA damage response DNA Repair (Amst) PARP-1 protein for ubiquitination and degradation J Biol 2010 Dec 10;9(12):1229-40 Chem 2012 Apr 13;287(16):12975-84 Banno K, Yanokura M, Kawaguchi M, Kuwabara Y, Akiyoshi Keller JA, Petty EM. CHFR binds to and regulates MAD2 in J, Kobayashi Y, Iwata T, Hirasawa A, Fujii T, Susumu N, the spindle checkpoint through its cysteine-rich domain Tsukazaki K, Aoki D. Epigenetic inactivation of the CHFR Biochem Biophys Res Commun 2011 Jun 10;409(3):389- gene in cervical cancer contributes to sensitivity to taxanes 93 Int J Oncol 2007 Oct;31(4):713-20 Kim JS, Park YY, Park SY, Cho H, Kang D, Cho H. The Bothos J, Summers MK, Venere M, Scolnick DM, auto-ubiquitylation of E3 ubiquitin-protein ligase Chfr at G2 Halazonetis TD. The Chfr mitotic checkpoint protein phase is required for accumulation of polo-like kinase 1 and functions with Ubc13-Mms2 to form Lys63-linked mitotic entry in mammalian cells J Biol Chem 2011 Sep polyubiquitin chains Oncogene 2003 Oct 16;22(46):7101-7 2;286(35):30615-23 Burgess A, Labbé JC, Vigneron S, Bonneaud N, Strub JM, Koga T, Takeshita M, Ijichi K, Yano T, Maehara Y, Sueishi Van Dorsselaer A, Lorca T, Castro A. Chfr interacts and K. CHFR aberrant methylation involves a subset of human colocalizes with TCTP to the mitotic spindle Oncogene lung adenocarcinoma associated with poor clinical 2008 Sep 18;27(42):5554-66 outcomes Hum Pathol 2013 Jul;44(7):1382-90 Cleven AH, Derks S, Draht MX, Smits KM, Melotte V, Van Kwon YE, Kim YS, Oh YM, Seol JH. Nuclear localization of Neste L, Tournier B, Jooste V, Chapusot C, Weijenberg MP, Chfr is crucial for its checkpoint function Mol Cells 2009 Mar Herman JG, de Bruïne AP, van Engeland M. CHFR 31;27(3):359-63 promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer Clin Cancer Res Lavin MF, Kozlov S. ATM activation and DNA damage 2014 Jun 15;20(12):3261-71 response Cell Cycle 2007 Apr 15;6(8):931-42 Corn PG, Summers MK, Fogt F, Virmani AK, Gazdar AF, Li Y, Yang Y, Lu Y, Herman JG, Brock MV, Zhao P, Guo M. Halazonetis TD, El-Deiry WS. Frequent hypermethylation of Predictive value of CHFR and MLH1 methylation in human the 5' CpG island of the mitotic stress checkpoint gene Chfr gastric cancer Gastric Cancer 2015 Apr;18(2):280-7

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CHFR (Checkpoint with fork-head associated and ring finger) Erson-Bensan AE, et al.

Li Z, Zhang H, Yang J, Hao T, Li S. Promoter Stavridi ES, Huyen Y, Loreto IR, Scolnick DM, Halazonetis hypermethylation of DNA damage response genes in TD, Pavletich NP, Jeffrey PD. Crystal structure of the FHA hepatocellular carcinoma Cell Biol Int 2012 May domain of the Chfr mitotic checkpoint protein and its 1;36(5):427-32 complex with tungstate Structure 2002 Jul;10(7):891-9 Mariatos G, Bothos J, Zacharatos P, Summers MK, Summers MK, Bothos J, Halazonetis TD. The CHFR mitotic Scolnick DM, Kittas C, Halazonetis TD, Gorgoulis VG. checkpoint protein delays cell cycle progression by Inactivating mutations targeting the chfr mitotic checkpoint excluding Cyclin B1 from the nucleus Oncogene 2005 Apr gene in human lung cancer Cancer Res 2003 Nov 14;24(16):2589-98 1;63(21):7185-9 Suzuki Y, Miyagi Y, Yukawa N, Rino Y, Masuda M. Mizuno K, Osada H, Konishi H, Tatematsu Y, Yatabe Y, Epigenetic silencing of checkpoint with fork-head Mitsudomi T, Fujii Y, Takahashi T. Aberrant associated and ring finger gene expression in esophageal hypermethylation of the CHFR prophase checkpoint gene in cancer Oncol Lett 2014 Jan;7(1):69-73 human lung cancers Oncogene 2002 Apr 4;21(15):2328-33 Takeshita M, Koga T, Takayama K, Yano T, Maehara Y, Privette LM, Petty EM. CHFR: A Novel Mitotic Checkpoint Nakanishi Y, Sueishi K. Alternative efficacy-predicting Protein and Regulator of Tumorigenesis Transl Oncol 2008 markers for paclitaxel instead of CHFR in non-small-cell Jul;1(2):57-64 lung cancer Cancer Biol Ther 2010 Nov 1;10(9):933-41 Sakai M, Hibi K, Kanazumi N, Nomoto S, Inoue S, Takeda Tokunaga E, Oki E, Nishida K, Koga T, Yoshida R, Ikeda K, S, Nakao A. Aberrant methylation of the CHFR gene in Kojima A, Egashira A, Morita M, Kakeji Y, Maehara Y. advanced hepatocellular carcinoma Aberrant hypermethylation of the promoter region of the Hepatogastroenterology 2005 Nov-Dec;52(66):1854-7 CHFR gene is rare in primary breast cancer Breast Cancer Res Treat 2006 May;97(2):199-203 Satoh A, Toyota M, Itoh F, Sasaki Y, Suzuki H, Ogi K, Kikuchi T, Mita H, Yamashita T, Kojima T, Kusano M, Fujita Toyota M, Sasaki Y, Satoh A, Ogi K, Kikuchi T, Suzuki H, M, Hosokawa M, Endo T, Tokino T, Imai K. Epigenetic Mita H, Tanaka N, Itoh F, Issa JP, Jair KW, Schuebel KE, inactivation of CHFR and sensitivity to microtubule inhibitors Imai K, Tokino T. Epigenetic inactivation of CHFR in human in gastric cancer Cancer Res 2003 Dec 15;63(24):8606-13 tumors Proc Natl Acad Sci U S A 2003 Jun 24;100(13):7818-23 Schwarzenbach H, Chun FK, Isbarn H, Huland H, Pantel K. Genomic profiling of cell-free DNA in blood and bone Tsai MD. FHA: a signal transduction domain with diverse marrow of prostate cancer patients J Cancer Res Clin specificity and function Structure 2002 Jul;10(7):887-8 Oncol 2011 May;137(5):811-9 Wang M, Shen L, Deng D. Association between CHFR Scolnick DM, Halazonetis TD. Chfr defines a mitotic stress methylation and chemosensitivity of paclitaxel in advanced checkpoint that delays entry into metaphase Nature 2000 gastric cancer Med Oncol 2014 Apr;31(4):907 Jul 27;406(6794):430-5 Wu J, Chen Y, Lu LY, Wu Y, Paulsen MT, Ljungman M, Shibata Y, Haruki N, Kuwabara Y, Ishiguro H, Shinoda N, Ferguson DO, Yu X. Chfr and RNF8 synergistically regulate Sato A, Kimura M, Koyama H, Toyama T, Nishiwaki T, Kudo ATM activation Nat Struct Mol Biol 2011 Jun 26;18(7):761- J, Terashita Y, Konishi S, Sugiura H, Fujii Y. Chfr 8 expression is downregulated by CpG island hypermethylation in esophageal cancer Carcinogenesis Yalniz Z, Demokan S, Suoglu Y, Ulusan M, Dalay N. 2002 Oct;23(10):1695-9 Simultaneous methylation profiling of tumor suppressor genes in head and neck cancer DNA Cell Biol 2011 Shinde SR, Gangula NR, Kavela S, Pandey V, Maddika S. Jan;30(1):17-24 TOPK and PTEN participate in CHFR mediated mitotic checkpoint Cell Signal 2013 Dec;25(12):2511-7 Yu X, Minter-Dykhouse K, Malureanu L, Zhao WM, Zhang D, Merkle CJ, Ward IM, Saya H, Fang G, van Deursen J, Shtivelman E. Promotion of mitosis by activated protein Chen J. Chfr is required for tumor suppression and Aurora kinase B after DNA damage involves polo-like kinase 1 and A regulation Nat Genet 2005 Apr;37(4):401-6 checkpoint protein CHFR Mol Cancer Res 2003 Nov;1(13):959-69 This article should be referenced as such: Soutto M, Peng D, Razvi M, Ruemmele P, Hartmann A, Erson-Bensan AE, Akman HB, Petty EM. CHFR Roessner A, Schneider-Stock R, El-Rifai W. Epigenetic and (Checkpoint with fork-head associated and ring finger). genetic silencing of CHFR in esophageal adenocarcinomas Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1):1- Cancer 2010 Sep 1;116(17):4033-42 6.

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS

Gene Section Review

GSTM1 (Glutathione S-transferase M1) Marija Pljesa-Ercegovac, Marija Matic Institute of Medical, Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Serbia. [email protected]; [email protected]

Published in Atlas Database: December 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/GSTM1ID40768ch1p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62504/12-2014-GSTM1ID40768ch1p13.pdf DOI: 10.4267/2042/62504 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

are: the left repeated region 5 kb downstream from Abstract the 3?-end of the GSTM2 gene and 5 kb upstream from the beginning of the GSTM1 gene; the right Review on GSTM1, with data on DNA, on the repeated region 5 kb downstream from the 3?-end of protein encoded, and where the gene is implicated. the GSTM1 and 10 kb upstream from the 5?-end of Keywords the GSTM5 gene (Xu et al., 1998). The cDNAs GSTM1; Glutathione S-transferase M1 encoded by GSTM1 and GSTM2 share a remarkable 99% sequence identity (Vorachek et al., 1991). The Identity fact that GSTM1 and GSTM2 are physically linked suggests that the frequent deletion of the GSTM1 Other names: GST1, GSTA, MU; H-B, GTH4, locus is caused by unequal crossing-over (Pearson et GTM1, MU-1, GSTM1-1, GSTM1a-1a, GSTM1b- al., 1993). Furthermore, in HeLa cells, it has been 1b confirmed that GSTM2 overexpression, following HGNC (Hugo): GSTM1 transient knockdown of GSTM1 and the absence of Location: 1p13.3 GSTM1 activity, may be compensated by the overexpression of GSTM2 (Bhattacharjee et al., Location (base pair) 2013). Moreover, existence of linkage Starts at 110,230,418 and ends at 110,236,367 bp disequilibrium between GSTM1 and GSTM3 from pter (according to hg19/Feb_2009). suggests that association between phenotype and GSTM1 genotypes may also reflect polymorphism DNA/RNA in GSTM3 or even other GSTM genes (Wu et al., Note 2012). In humans, five GSTM genes are encoded by a 100- Polymorphisms: The restriction mapping data kb gene cluster on chromosome 1p13.3 arranged as revealed the presence of a GST mu cluster with two 5?-GSTM4-GSTM2-GSTM1-GSTM5-GSTM3-3?, GSTM1 genes in tandem situated between the known to be highly polymorphic (Pearson et al., GSTM2 and GSTM5 genes (McLellan et al., 1997). 1993). The GSTM1 gene contains four different alleles, leading to several M1 class polymorphisms, Description designated as GSTM1-0, GSTM1-A, GSTM1-B and The GSTM1 gene is composed of 8 exons spanning GSTM1-1x2 alleles (Wu et al., 2012; Board PG, a region of 21,244 bases, with transcript length of 1981). GSTM1-0 (GSTM1 null allele) arose from a 1,161 bps and translation length of 218 residues recombination event during evolution between 2 (according to ensembl GRCh37 release 78). The highly homologous regions flanking this locus, GSTM1 gene is approximately 20 kb in length and resulting in deletion of a 20-kb segment (Xu et al., is closely flanked by other mu class gene sequences. 1998). The end points of the polymorphic GSTM1 deletion

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GSTM1 gene. The GSTM1 gene spans a region of 21,244 bases, composed of the eights exons (red) and seven introns (green). Exons 1, 2, 3, 4, 5, 6, 7 and 8 are 90bp, 76bp, 65bp, 82bp, 101bp, 96bp, 111bp and 540bp in length, respectively.

This deletion produces a novel 7.4-kb HindIII that are catalytically identical (Widersten et al., fragment with the loss of 10.3- and 11.4-kb HindIII 1991), while the null allele and gene duplication fragments, hence homozygotes for GSTM1 null confer marked differences in enzyme activity (Hayes allele produce no GSTM1 protein. The prevalence of and Strange, 2000). This difference in enzyme GSTM1 deletion polymorphisms varies across activity is due to the fact that the null phenotype is ethnic groups, from 18% to 66% (median, 50%), characterized by an absence of near-neutral with the exception of Asians, for whom it is 38%- enzymes, whereas individuals with either GSTM1-A 58% (Wu et al., 2012). GSTM1-A and GSTM1-B or GSTM1-B phenotype each express one near- differ by a single base in exon 7 (Seidegard et al., neutral transferase (Vos and Van Bladeren, 1990). 1988). Namely, GSTM1-A and GSTM1-B differ by Regarding the subunit composition, each subunit a C?G substitution at base position 534, resulting in contains a glutathion-binding site (G-site) and a a substitution of Lys?Asn at amino acid 172 second adjacent hydrophobic-binding site for the (Widersten et al., 1991). The substitution further electrophilic substrate (H-site) (Ji et al., 1992), results in formation of monodimers (GSTM1A-1A, located in a deep cavity, composed of three relatively GSTM1B-1B) or heterodimers (GSTM1A-1B), mobile structural elements. Fifteen hydrogen bonds although in vitro studies suggest that their activities or salt-bridge contacts are involved in interaction are similar (Widersten et al., 1991). In Saudi Arabian between glutathione and enzyme (Ji et al., 1992). population, a unique GSTM1 variant dGSTM1-1x2, containing a duplicated GSTM1 gene has been Expression identified (Evans et al., 1996). Quantitative analysis of GSTM1 protein in various Transcription human tissues showed that the richest source of cytosolic GSTM1 is the liver. The other sources The 1161-nucleotide transcript encodes a protein of include testis, lungs, stomach, intestine, spleen, 218 amino acid residues brain, kidneys, heart, breast, colon, pituitary and the Pseudogene lymphocytes (Vos and Van Bladeren, 1990; Eaton and Bammler, 1999). Binding of the transcription At least one other mu class GST gene or pseudogene factor AP1 has been suggested as a common exists and is found on chromosome 3, probably in mechanism for up-regulation of GSTs (Hayes and the region 3p24-3pter (Pearson et al., 1993; Pulford, 1995). McLellan et al., 1997). Localisation Protein Cytosolic. Note Function Glutathione S-transferase M1 describes 2 isoforms produced by alternative splicing (UNIPROT). Human GSTM1 enzyme catalyzes the glutathione- dependent detoxification of electrophiles, showing Description highly promiscuous substrate selectivity for many Amino acids: 218. Calculated molecular mass: structurally unrelated chemicals, including 25.712 Da. Isoelectric point: at pH 6.6 (Mannervik environmental carcinogens (e.g. benzo(a)pyrene diol B, 1985). The active GSTM1 enzyme results from epoxides) and several chemotherapeutic agents the homo- or heterodimeric combination of the (such as BCNU, brostallicin, ethacrinic acid, products of the 2 alleles. Namely, in GSTM1 thiopurines, vincristine and chlorambucil) (Depeille examples of gene duplication, as well as, three et al., 2004; Lo and Ali-Osman, 2007). In addition to alleles have been described (GSTM1 null, GSTM1- enzymatic detoxification, GSTM1 acts as a A and GSTM1-B) (Hayes and Strange, 2000). modulator of mitogen-activated protein kinase GSTM1-A and GSTM1-B alleles encode proteins (MAPK) signal transduction pathway and mediates

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apoptosis via a mechanism involving protein-protein The GSTM1-null genotype is also recognized as a interactions. Namely, GSTM1 forms complexes risk factor for synchronous breast cancers and for with apoptosis signal-regulating kinase 1 (ASK1), breast cancer associated with one extramammary inhibiting ASK1 activation during cellular stress cancer (Chiril? et al., 2014). Recently, GSTM1 (Cho et al., 2001; Townsend and Tew, 2003). This polymorphism has been suggested as a prognostic suggests that GSTM1 might confer drug resistance factor in women with breast cancer (Oliveira et al., by two distinct means: by direct inactivation 2014). (detoxification) of chemotherapeutic drugs and/or by acting as inhibitor of MAPK pathway. Oral and pharyngeal cancers Homology Although an association between the GSTM1-null genotype and head and neck tumors has been The close physical proximity exists between the suggested, the meta-analysis of Varela-Lema et al. GSTM1 and GSTM2 loci, which share 99% (2008) showed that GSTM1-null genotype could not nucleotide sequence identity over 460 nucleotides of be associated with oral and pharyngeal tumors in 3'-untranslated mRNA (Pearson et al., 1993). Caucasians, possibly due to the fact that previous meta- and pooled analysis did not analyze ethnic Mutations specificity. However, polymorphic deletion of the GSTM1 gene Germinal seems to markedly alter the alcohol-tobacco None described so far. interaction, contributing to susceptibility to oral and Somatic pharyngeal cancer (Peters et al., 2006). 21 mutations (COSMIC): 15 substitution-missense, Esophageal cancer 5 substitution-synonimous, 1 unknown type. There are contradictory findings regarding the role of GSTM1 polimorphism in susceptibility to Implicated in esophageal cancer. Namely, it seems that ethnic specificity plays a role, since no significant Lung cancer association between GST genotypes and esophageal It has been suggested that GSTM1-null genotype squamous cell or adenocarcinoma risk in Caucasian may be associated with the risk of lung cancer, was found (Dura et al., 2013), while association however there is a possibility that the magnitude of between GSTM1-null genotype and risk of the association varies significantly by esophageal carcinoma has been confirmed in characteristics, such as ethnic background (Ye et al., Chinese population (Zhong et al., 2013). 2006). Furthermore, observations from a large pooled analysis strongly suggest the existence of Gastric cancer gene-gene interactions in lung carcinogenesis, It has been found that GSTM1-null genotype is leading to an increased risk of lung cancer in case of associated with increased risk of gastric cancer. the double deletion of both GSTM1 and GSTT1, When analyzed according to ethnicities, increased which is even more potentiated when CYP1A1-4 is risk of gastric cancer was only observed in Asians, included (Vineis et al., 2007). In studies conducted while no significant association was found in in populations where tobacco use is likely to be the Caucasians or Latin Americans. GSTM1-null primary cause of lung cancer, the GSTM1-null genotype increases susceptibility to gastric cancer genotype was associated with a significantly both in ever-smokers and non-smokers, while the increased lung cancer risk, as well as, in populations significant association was only observed in exposed to sources of indoor air pollution from Helicobacter pylori positive population (Zhao et al., cooking and heating (Hosgood et al., 2007). 2013; Lao et al., 2014). Breast cancer Liver cancer Only a slightly higher breast cancer risk has been GSTM1-null genotype is associated with suggested among women with GSTM1 deletion, significantly increased risk of hepatocellular more significant in post-menopausal women, as well carcinoma only among East Asians and Indians, as, in populations with a lower frequency of GSTM1 while the association is lacking among Caucasian deficiency (Sull et al., 2004). Further analysis and African populations (Shen et al., 2014). This is showed that increased breast cancer risk was further confirmed by results on association between associated with GSTM1-null genotype in Caucasian GSTM1-null genotype and an increased risk of and Asian women, suggesting GSTM1-null hepatocellular carcinoma in Chinese population (Liu genotype as a low-penetrant risk factor for et al., 2013). developing breast cancer (Qiu et al., 2010).

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Pancreatic cancer (2014) found no association with susceptibility to this type of leukemia. Available data are not sufficient to identify the association between the GSTM1 polymorphism and Melanoma pancreatic cancer risk (Fan et al., 2013). The results reported in the latest meta-analysis Renal cell carcinoma suggested that the GSTM1 polymorphism is not a risk factor for developing melanoma (Nie et al., Recent meta-analysis of 11 case-control studies 2011). On the other hand, the association has been showed that the dual null genotype of shown between GSTM1-null and GSTT1-null GSTM1/GSTT1 is significantly associated with an genotypes and sunburns in childhood. Namely, it has increased risk of renal cell carcinoma (Jia et al., been suggested that carriers of GSTM1-null and 2014). However, deletion polymorphism of GSTM1 GSTT1-null genotypes, with history of sunburns in does not contribute individually to susceptibility to childhood, are in increased risk of melanoma (Fortes renal cell carcinoma (Yang et al., 2013; Salinas- et al., 2011). Sánchez et al., 2012) Bladder cancer Basal cell carcinoma and squamous Recent investigation indicates that the GSTM1-null cell carcinoma genotype in combination with the GSTA1-low Available data suggest that GSTM1 polymorphism activity genotype significantly increases the risk of is not associated with risks of basal and squamous bladder cancer in smokers (Matic et al., 2013). In cell carcinomas (Peng et al., 2013). addition, it seems that GSTM1-null and GSTA1-low Thyroid cancer activity genotypes are associated with enhanced oxidative damage in bladder cancer (Savic- Regarding the role of GSTM1 polymorphism in the Radojevic et al., 2013). Furthermore, latest results of risk of thyroid cancer, the results are still Wang et al. (2014) suggested that GSTM1-null inconclusive. genotype is among seven bladder cancer risk- Several studies found the GSTM1-null genotype to associated variants (rs9642880, rs2294008, be associated with an increased risk of thyroid rs798766, rs1495741, GSTM1-null, rs17674580 and cancer, while some showed protective effect or lack rs10936599) that may be used, collectively, to of association. effectively measure inherited risk for bladder cancer. However, the latest meta-analysis suggested that GSTM1-null genotype does not affect susceptibility Prostatic cancer to thyroid cancer (Li et al., 2012; Gonalves et al., It has been shown that GSTM1 gene polymorphism 2009). contributes to prostatic cancer susceptibility (Cai et Colorectal cancer al., 2014). Furthermore, Chen et al. (2013) identified a possible association between GSTM1-null Regarding the role of GSTM1 polymorphism in genotype and prostate cancer recurrence risk with colorectal cancer, results of comprehensive meta- borderline significance. As suggested by Acevedo et analysis conducted on forty-four studies (11,998 al. (2014), GSTM1-active genotype may also be a colorectal cancer cases, 17,552 controls) showed that good prognosis marker, particularly in patients with GSTM1-null allele carriers exhibit increased high-risk tumors. colorectal cancer risk in Caucasian population, while no significant association was detected for Chinese Ovarian cancer subjects (Economopoulos and Sergentanis, 2010). Available meta-analysis show that GSTM1-null When analyzed with respect to smoking, no genotype is not associated with ovarian cancer risk interactions between GSTM1/smoking and (Yin et al., 2013; Xu et al., 2014). colorectal cancer risk have been reported. One polyp Leukemia study suggests an interaction between GSTM1 genotype and smoking (Cotton et al., 2000). Results of recent meta-analysis suggested that heritable GST status could influence the risk of Glaucoma developing acute myeloid leukemia, based on the In their meta-analysis, Huang et al. (2013) suggested finding that the GSTM1-null genotype was that GSTM1-null genotype is associated with associated with an increased risk of acute myeloid increased primary open-angle glaucoma risk in leukemia in East Asians, with a predilection towards Asian populations, but not in Caucasian and mixed the female gender. Furthermore, the double-null populations. Furthermore, dual null genotype of genotypes (GSTM1-null and GSTT1-null) increased GSTM1/GSTT1 is also associated with increased the risk of acute myeloid leukemia in both risk of primary open-angle glaucoma (Huang et al., Caucasians and East Asians (He et al., 2014). 2013). Regarding chronic myeloid leukemia, Banescu et al.

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Endometriosis Eaton DL, Bammler TK. Concise review of the glutathione S-transferases and their significance to toxicology. Toxicol Available data suggest increased risk for Sci. 1999 Jun;49(2):156-64 development of endometriosis among Caucasians Economopoulos KP, Sergentanis TN. GSTM1, GSTT1, and Asians, carriers of GSTM1-null genotype (Ding GSTP1, GSTA1 and colorectal cancer risk: a et al., 2014). comprehensive meta-analysis. Eur J Cancer. 2010 Jun;46(9):1617-31 References Evans DA, Seidegård J, Narayanan N. The GSTM1 genetic polymorphism in healthy Saudi Arabians and Filipinos, and Acevedo CA, Quiñones LA, Catalán J, Cáceres DD, Fullá Saudi Arabians with coronary atherosclerosis. JA, Roco AM. Impact of CYP1A1, GSTM1, and GSTT1 Pharmacogenetics. 1996 Aug;6(4):365-7 polymorphisms in overall and specific prostate cancer Fan Y, Zhang W, Shi CY, Cai DF. Associations of GSTM1 survival. 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Am J Epidemiol. 2000 Jan 1;151(1):7-32 Association of glutathione S-transferase M1, T1, and P1 polymorphisms with renal cell carcinoma: evidence from 11 Depeille P, Cuq P, Mary S, Passagne I, Evrard A, Cupissol studies Tumour Biol 2014 Apr;35(4):3867-73 D, Vian L. Glutathione S-transferase M1 and multidrug resistance protein 1 act in synergy to protect melanoma Lao X, Peng Q, Lu Y, Li S, Qin X, Chen Z, Chen J. cells from vincristine effects. Mol Pharmacol. 2004 Glutathione S-transferase gene GSTM1, gene-gene Apr;65(4):897-905 interaction, and gastric cancer susceptibility: evidence from an updated meta-analysis Cancer Cell Int 2014 Nov Ding B, Sun W, Han S, Cai Y, Ren M. Polymorphisms of 30;14(1):127 glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and endometriosis risk: a meta-analysis. Eur J Obstet Li J, Long J, Hu Y, Tan A, Guo X, Zhang S. 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population evaluated by an updated systematic meta- glutathione transferase active on trans-stilbene oxide are analysis PLoS One 2013;8(2):e57043 due to a gene deletion Proc Natl Acad Sci U S A 1988 Oct;85(19):7293-7 Lo HW, Ali-Osman F. Genetic polymorphism and function of glutathione S-transferases in tumor drug resistance Curr Shen YH, Chen S, Peng YF, Shi YH, Huang XW, Yang GH, Opin Pharmacol 2007 Aug;7(4):367-74 Ding ZB, Yi Y, Zhou J, Qiu SJ, Fan J, Ren N. Quantitative assessment of the effect of glutathione S-transferase genes Mannervik B. The isoenzymes of glutathione transferase GSTM1 and GSTT1 on hepatocellular carcinoma risk Adv Enzymol Relat Areas Mol Biol 1985;57:357-417 Tumour Biol 2014 May;35(5):4007-15 Matic M, Pekmezovic T, Djukic T, Mimic-Oka J, Dragicevic Sull JW, Ohrr H, Kang DR, Nam CM. Glutathione S- D, Krivic B, Suvakov S, et al.. GSTA1, GSTM1, GSTP1, and transferase M1 status and breast cancer risk: a meta- GSTT1 polymorphisms and susceptibility to smoking- analysis Yonsei Med J 2004 Aug 31;45(4):683-9 related bladder cancer: a case-control study Urol Oncol 2013 Oct;31(7):1184-92 Townsend DM, Tew KD. The role of glutathione-S- transferase in anti-cancer drug resistance Oncogene 2003 McLellan RA, Oscarson M, Alexandrie AK, Seidegård J, Oct 20;22(47):7369-75 Evans DA, Rannug A, Ingelman-Sundberg M. Characterization of a human glutathione S-transferase mu Varela-Lema L, Taioli E, Ruano-Ravina A, Barros-Dios JM, cluster containing a duplicated GSTM1 gene that causes Anantharaman D, Benhamou S, Boccia S, Bhisey RA, ultrarapid enzyme activity Mol Pharmacol 1997 Cadoni G, Capoluongo E, Chen CJ, Foulkes W, Goloni- Dec;52(6):958-65 Bertollo EM, Hatagima A, Hayes RB, Katoh T, Koifman S, Lazarus P, Manni JJ, Mahimkar M, Morita S, Park J, Park Nie F, Chen Z, Cao C, Cen Y. Absence of association KK, Pavarino Bertelli EC, de Souza Fonseca Ribeiro EM, between GSTM1 and GSTT1 polymorphisms and Roy B, Spitz MR, Strange RC, Wei Q, Ragin CC. Meta- melanoma susceptibility: a meta-analysis DNA Cell Biol analysis and pooled analysis of GSTM1 and CYP1A1 2011 Oct;30(10):783-8 polymorphisms and oral and pharyngeal cancers: a HuGE- Oliveira AL, Oliveira Rodrigues FF, Dos Santos RE, GSEC review Genet Med 2008 Jun;10(6):369-84 Rozenowicz RL, Barbosa de Melo M. GSTT1, GSTM1, and Vineis P, Anttila S, Benhamou S, Spinola M, Hirvonen A, GSTP1 polymorphisms as a prognostic factor in women Kiyohara C, Garte SJ, Puntoni R, Rannug A, Strange RC, with breast cancer Genet Mol Res 2014 Jan 22;13(2):2521- Taioli E. Evidence of gene gene interactions in lung 30 carcinogenesis in a large pooled analysis Carcinogenesis Patskovsky Y, Patskovska L, Almo SC, Listowsky I. 2007 Sep;28(9):1902-5 Transition state model and mechanism of nucleophilic Vorachek WR, Pearson WR, Rule GS. Cloning, expression, aromatic substitution reactions catalyzed by human and characterization of a class-mu glutathione transferase glutathione S-transferase M1a-1a Biochemistry 2006 Mar from human muscle, the product of the GST4 locus Proc 28;45(12):3852-62 Natl Acad Sci U S A 1991 May 15;88(10):4443-7 Pearson WR, Vorachek WR, Xu SJ, Berger R, Hart I, Vos RM, Van Bladeren PJ. Glutathione S-transferases in Vannais D, Patterson D. Identification of class-mu relation to their role in the biotransformation of xenobiotics glutathione transferase genes GSTM1-GSTM5 on human Chem Biol Interact 1990;75(3):241-65 chromosome 1p13 Am J Hum Genet 1993 Jul;53(1):220- 33 Wang M, Chu H, Lv Q, Wang L, Yuan L, Fu G, Tong N, Qin C, Yin C, Zhang Z, Xu J. Cumulative effect of genome-wide Peng H, He Q, Zhu J, Peng C. Effect of GSTM1 association study-identified genetic variants for bladder polymorphism on risks of basal cell carcinoma and cancer Int J Cancer 2014 Dec 1;135(11):2653-60 squamous cell carcinoma: a meta-analysis Tumour Biol 2013 Apr;34(2):675-81 Widersten M, Holmströ E, Mannervik B. Cysteine residues are not essential for the catalytic activity of human class Mu Peters ES, McClean MD, Marsit CJ, Luckett B, Kelsey KT. glutathione transferase M1a-1a FEBS Lett 1991 Nov Glutathione S-transferase polymorphisms and the synergy 18;293(1-2):156-9 of alcohol and tobacco in oral, pharyngeal, and laryngeal carcinoma Cancer Epidemiol Biomarkers Prev 2006 Wu W, Peden D, Diaz-Sanchez D. Role of GSTM1 in Nov;15(11):2196-202 resistance to lung inflammation Free Radic Biol Med 2012 Aug 15;53(4):721-9 Qiu LX, Yuan H, Yu KD, Mao C, Chen B, Zhan P, Xue K, Zhang J, Hu XC. Glutathione S-transferase M1 Xu C, Chen S, Gao H, Zhao K, You X, Zhang Y, Zhang X, polymorphism and breast cancer susceptibility: a meta- Li Y. Quantitative assessment of the influence of glutathione analysis involving 46,281 subjects Breast Cancer Res Treat S-transferase M1 null variant on ovarian cancer risk J 2010 Jun;121(3):703-8 Cancer Res Ther 2014 Nov;10 Suppl:C201-5 Salinas-Sánchez AS, Sánchez-Sánchez F, Donate-Moreno Xu S, Wang Y, Roe B, Pearson WR. Characterization of the MJ, Rubio-del-Campo A, Serrano-Oviedo L, Gimenez- human class Mu glutathione S-transferase gene cluster and Bachs JM, Martínez-Sanchiz C, Segura-Martín M, the GSTM1 deletion J Biol Chem 1998 Feb 6;273(6):3517- Escribano J. GSTT1, GSTM1, and CYP1B1 gene 27 polymorphisms and susceptibility to sporadic renal cell cancer Urol Oncol 2012 Nov-Dec;30(6):864-70 Yang X, Long S, Deng J, Deng T, Gong Z, Hao P. Glutathione S-transferase polymorphisms (GSTM1, GSTT1 Savic-Radojevic A, Djukic T, Simic T, Pljesa-Ercegovac M, and GSTP1) and their susceptibility to renal cell carcinoma: Dragicevic D, Pekmezovic T, Cekerevac M, Santric V, Matic an evidence-based meta-analysis PLoS One 2013 May M. GSTM1-null and GSTA1-low activity genotypes are 22;8(5):e63827 associated with enhanced oxidative damage in bladder cancer Redox Rep 2013;18(1):1-7 Ye Z, Song H, Higgins JP, Pharoah P, Danesh J. Five glutathione s-transferase gene variants in 23,452 cases of Seidegård J, Vorachek WR, Pero RW, Pearson WR. lung cancer and 30,397 controls: meta-analysis of 130 Hereditary differences in the expression of the human studies PLoS Med 2006 Apr;3(4):e91

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GSTM1 (Glutathione S-transferase M1) Pljesa-Ercegovac M, Matic M

Yin Y, Feng L, Sun J. Association between glutathione S- contributes to increased risk of esophageal carcinoma in transferase M 1 null genotype and risk of ovarian cancer: a Chinese population Tumour Biol 2013 Aug;34(4):2403-7 meta-analysis Tumour Biol 2013 Dec;34(6):4059-63 This article should be referenced as such: Zhao Y, Deng X, Song G, Qin S, Liu Z. The GSTM1 null genotype increased risk of gastric cancer: a meta-analysis Pljesa-Ercegovac M, Matic M. GSTM1 (Glutathione S- based on 46 studies PLoS One 2013 Nov 7;8(11):e81403 transferase M1). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1):7-13. Zhong S, Zhao W, Lu C, Li B, Yuan Y, Guo D, Chang Z, Jiao B, Yang L. Glutathione S-transferase M1 null genotype

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 13 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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LDOC1 (leucine zipper, down-regulated in cancer 1) Jenn-Ren Hsiao; Jang-Yang Chang Department of Otolaryngology, Head, Neck Collaborative Oncology Group, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; [email protected] (JRH); Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University,, National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; E-mail: [email protected] (JYC).

Published in Atlas Database: December 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/LDOC1ID41137chXq27.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62505/12-2014-LDOC1ID41137chXq27.pdf DOI: 10.4267/2042/62505 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract DNA/RNA LDOC1 (leucine zipper, down-regulated in cancer 1) Description is expressed by a wide variety of normal human The LDOC1 gene includes only one exon. tissues but is downregulated in various kinds of human cancers. Epigenetic silencing by promoter Transcription hypermethylation was shown to be an important cause of LDOC1 down-regulation in oral, cervical A longer wild type 1376-bp transcript (Nagasaki et and ovarian cancers. The normal physiological al., 1999), and a much shorter 165-bp splice variant function of LDOC1 is still not clear. But the ability LDOC1S (Duzakale et al. 2014) are reported. of LDOC1 to induce apoptosis in various kinds of The cDNA sequence of wild type LDOC1 contains a human cancer cells suggests this gene may act as a 104-bp 5' untranslated region (5'-UTR), a 438-bp tumor suppressor. open reading frame (ORF), and a 834-bp 3' untranslated region (3'-UTR) including a consensus Keywords polyadenylation signal (Nagasaki et al., 1999). LDOC1, cancer, methylation Pseudogene Identity Not reported. Other names: BCUR1, Mar7, Mart7 HGNC (Hugo): LDOC1 Protein Location: Xq27 Description Location (base pair) The wild type LDOC1 is a 17 kDa protein containing starts at 141175745 and ends at 141177214 bp, 146 amino acids, with a leucine-zipper like motif at complement the N-terminal and a proline-rich region that Local order: from centromere to telomere: similarity to an Src homolog 3 (SH3)-binding SPANXB1, LDOC1, SPANXC domain (Nagasaki et al., 1999).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 14 LDOC1 (leucine zipper, down-regulated in cancer 1) Hsiao JR, Chang JY

A shorter 165-bp splice variant is predicted to BxPC-3 pancreatic cancer cells (Nagasaki et al., translate into a truncated protein of 44 amino acids 2003) and suppressed TNF-a induced activation of that contains only the leucine-zipper region of wide NF-kB (Lee et al., 2013). LDOC1 may also interact type protein (Duzakale et al. 2014). with CCAAT-enhancer binding protein-a (C/EBPa) Expression (Chih et al., 2004). However, in human intrahepatic biliary epithelial cells, over expression LDOC1 LDOC1 is expressed in a wide variety of normal increased the expression of NF-kB (p65), promoted tissues including heart, brain, lung, skeletal muscles, IL-2 and TNF-a secretion and inhibited apoptosis kidney, pancreas, spleen, thymus, prostate, testis, (Song et al., 2013). LDOC1 has recently been ovary, stomach, small intestine, colon, adrenal reported as a eutherian-specific acquired gene that medulla, thyroid, adrenal cortex, thymus (Nagasaki regulates placental endocrine function (Naruse et al., et al., 1999). Down-regulation of LDOC1 have been 2014). reported in various kinds of human cancer tissues, including oral cancer (Lee et al., 2013), Homology hepatocellular carcinoma (Riordan and Dupuy, HomoloGene:32153 2013), Chronic lymphocytic leukemia (Duzakale et al., 2014), prostate cancer (Camões et al., 2012), as Implicated in well as in a variety of human cancer cell lines, including pancreatic cancer cell line, gastric cancer Chronic lymphocytic leukemia cell lines, some breast cancer cell lines (Nagasaki et Prognosis al., 1999), ovarian cancer cell lines (Buchholtz et al., Expression of LDOC1 mRNA correlated with 2014), cervical cancer cell lines (Buchholtz et al., prognostic cytogenetic markers of chronic 2013) and oral cancer cell lines (Lee et al., 2013). lymphocytic leukemia patients. In primary patients, Epigenetic silencing by promoter hypermethylation LDOC1 mRNA-positive group of patients had was shown to be an important cause of LDOC1 significantly poorer overall survival compared to down-regulation in oral cancer (Lee et al., 2013), LDOC1 mRNA-negative group of patients cervical cancer (Buchholtz et al., 2013), and ovarian (Duzakale et al., 2014). cancer cells (Buchholtz et al., 2014). Lymphoma Localisation Oncogenesis LDOC1 localizes predominantly in the nucleus Forced expression of LDOC1 induced apoptosis in (Nagasaki et al., 1999). It may also be retained in Jurkat lymphoma cell lines (Inoue et al., 2015). cytoplasm through interaction with WAVE3 (Mizutani et al., 2005). Leukemia Function Oncogenesis Most reports demonstrated that the biological Forced expression of LDOC1 induced apoptosis in function of LDOC1 is closely related to modulation K562 leukemia cell lines (Inoue et al., 2015). of apoptosis. Forced expression of LDOC1 induced Ovarian cancer apoptosis in Jurkat lymphoma cells, K562 leukemia Cytogenetics cells (Inoue et al., 2015), Hela cervical cancer cells No gene deletion was detected in the 7 ovarian (Buchholtz et al., 2013) and oral cancer cells (Lee et cancer cell lines. al., 2013). Expression of LDOC1 also enhanced TNF-a or phorbol 12-myristate 13-acetate (PMA)- Oncogenesis induced anti-proliferative effects in pancreatic Three of the 7 ovarian cancer cell lines showed cancer cells (Nagasaki et al., 2003). A hematopoietic complete loss of LDOC1 transcription, which may transcriptional factor (MZF-1) important in due to hypermethylation and inactivation of LDOC1 regulating myeloid cell differentiation and promoter. Treatment of de-methylation agent (5-aza- proliferation may interact with LDOC1 and enhance 2'-deoxycytidine) on ovarian cancer cells induced it apoptosis-inducing function in K562 leukemia transcriptional reactivation of LDOC1 gene cells (Inoue et al., 2015). LDOC1 also induced (Buchholtz et al., 2014). apoptosis and inhibited degradation of p53, resulting Cervical cancer in p53 accumulation in MDCK cells. WAVE3 could Cytogenetics interact with LDOC1 with its C-terminal verprolin homolog domain and act as a negative regulator of No gene deletion was detected in the 6 cervical LDOC1. Forced expression of WAVE3 retained cancer cell lines. LDOC1 in cytoplasm and attenuated the apoptosis- Oncogenesis inducing effect of LDOC1 (Mizutani et al., 2005). LDOC1 was silenced in 4 of the 6 cervical cancer Expression of LDOC1 also significantly inhibited cell lines. An association of promoter the NF-kB reporter activity in LDOC1-negative hypermethylation and gene silencing was noted.

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LDOC1 (leucine zipper, down-regulated in cancer 1) Hsiao JR, Chang JY

Reactivation of LDOC1 gene was noted in Me180 LDOC1 was normally expressed in stomach tissue and SiHa cervical cancer cell lines by demethylation (Nagasaki et al., 1999). agent treatment (5-aza-2'-deoxycytidine). Re- Lung cancer expression of LDOC1induced apoptosis-like cell death in Hela cervical cancer cells (Buchholtz et al., Oncogenesis 2013). LDOC1 was differentially expressed in MASPIN- overexpression lung carcinoma cells (LC5) Oral cancer compared to MASPIN-knockdown LC5 cells (Liu et Oncogenesis al., 2012). Hypermethylation and down-regulation of LDOC1 Esophageal cancer were consistently noted in oral cancer samples and oral cancer cell lines. Reactivation of LDOC1 gene Oncogenesis was noted in oral cancer cells by demethylation LDOC1 was down-regulated in a radio-sensitive agent treatment (5-aza-2'-deoxycytidine). Re- esophageal cancer cell line (TE-11) compared to expression of LDOC1suppressed TNF-a induced other relative radio-resistant esophageal cancer cell activation of NF-?B and suppressed the colony lines (Ogawa et al., 2008). forming and in vivo tumorigenic abilities of oral Cutaneous malignant melanoma cancer cells. Epigenetic silencing of LDOC1 may Oncogenesis contribute to alcohol, betel quid and smoking- associated oral carcinogenesis (Lee et al., 2013). LDOC1 was downregulated in peripheral blood leukocytes from a cutaneous malignant melanoma Prostate cancer patient with multiple in-transient metastases, Oncogenesis compared to 3 normal controls (Salemi et al., 2010). LDOC1 was one of the two transcriptional units Hypertension (LDOC1, HPANXC) mapped in a critical region of LDOC1 gene was consistently influential in a three- HPCX locus linked to prostate cancer susceptibility endophenotype model for Taiwanese hypertensive in Finland (Baffoe-Bonnie et al., 2005). In addition, males (Lynn et al., 2009). compared to non-malignant prostate tissue, LDOC1 was under-expressed (1.8 fold decrease) in prostate Premature ovarian cancer tissues, although no methylation of LDOC1 failure/insufficiency (POF/POI) promoter was noted in prostate tumor samples Array comparative genomic hybridization identified (Camões et al., 2012). a cryptic deletion region of Xq27.2 containing Hepato cellular carcinoma LDOC1 and SPANX genes in a 23-year old woman Oncogenesis with premature ovarian failure/insufficiency (Vitek LDOC1 was downregulated in 60% (29/48) of et al., 2012). hepatic cellular carcinoma samples compared to Down's syndrome adjacent non-tumor liver tissues (Riordan and Gene expression of LDOC1 was increased in Dupuy, 2013). peripheral blood leukocytes from 15 (75%) of 20 Pancreatic cancer patients Down's syndrome, as compared to that of 20 Oncogenesis age-, sex-matched normal controls (Salemi et al., 2012). Down-regulation of LDOC1 was noted in 8 of 9 pancreatic cancer cell lines except CAPAN2 cell line Biliary atresia (Nagasaki et al., 1999). LDOC1 was expressed in Over expression LDOC1 in human intrahepatic normal pancreatic tissue (Nagasaki et al., 2003). biliary epithelial cells increased the expression of Expression of LDOC1 significantly inhibited the NF-kB (p65), promoted IL-2 and TNF-a secretion NF-kB reporter activity but does not affect p53, AP1 and inhibited apoptosis of human intrahepatic biliary and CRE-dependent reporter gene expression in epithelial cells, which may induce intrahepatic LDOC1-negative BxPC-3 pancreatic cancer cell biliary epithelial cell hyperplasia and trigger biliary line. LDOC1 also enhanced TNF-a or phorbol 12- atresia, bile duct stenosis and hepatic fibrosis (Song myristate 13-acetate (PMA)-induced anti- et al., 2013). proliferative effects in pancreatic cancer cells (Nagasaki et al., 2003). References Gastric cancer Baffoe-Bonnie AB, Smith JR, Stephan DA, Schleutker J, Oncogenesis Carpten JD, Kainu T, Gillanders EM, Matikainen M, Teslovich TM, Tammela T, Sood R, Balshem AM, Using northern blot, down-regulation of LDOC1 Scarborough SD, Xu J, Isaacs WB, Trent JM, Kallioniemi was noted in 6 (100%) of 6 gastric cancer cell lines. OP, Bailey-Wilson JE. A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a

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haplotype in the HPCX region. Hum Genet. 2005 functions as a negative regulator of LDOC1. J Biochem. Aug;117(4):307-16 2005 Nov;138(5):639-46 Buchholtz ML, Brüning A, Mylonas I, Jückstock J. Nagasaki K, Schem C, von Kaisenberg C, Biallek M, Rösel Epigenetic silencing of the LDOC1 tumor suppressor gene F, Jonat W, Maass N. Leucine-zipper protein, LDOC1, in ovarian cancer cells. Arch Gynecol Obstet. 2014 inhibits NF-kappaB activation and sensitizes pancreatic Jul;290(1):149-54 cancer cells to apoptosis. Int J Cancer. 2003 Jul 1;105(4):454-8 Camões MJ, Paulo P, Ribeiro FR, Barros-Silva JD, Almeida M, Costa VL, Cerveira N, Skotheim RI, Lothe RA, Henrique Naruse M, Ono R, Irie M, Nakamura K, Furuse T, Hino T, R, Jerónimo C, Teixeira MR. Potential downstream target Oda K, Kashimura M, Yamada I, Wakana S, Yokoyama M, genes of aberrant ETS transcription factors are differentially Ishino F, Kaneko-Ishino T. Sirh7/Ldoc1 knockout mice affected in Ewing's sarcoma and prostate carcinoma. PLoS exhibit placental P4 overproduction and delayed parturition. One. 2012;7(11):e49819 Development. 2014 Dec;141(24):4763-71 Chih DY, Park DJ, Gross M, Idos G, Vuong PT, Hirama T, Ogawa R, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Mori Chumakov AM, Said J, Koeffler HP. Protein partners of Y, Mori R, Tomoda K, Katada T, Harada K, Fujii Y. C/EBPepsilon. Exp Hematol. 2004 Dec;32(12):1173-81 Identification of candidate genes involved in the radiosensitivity of esophageal cancer cells by microarray Duzkale H, Schweighofer CD, Coombes KR, Barron LL, analysis. Dis Esophagus. 2008;21(4):288-97 Ferrajoli A, O'Brien S, Wierda WG, Pfeifer J, Majewski T, Czerniak BA, Jorgensen JL, Medeiros LJ, Freireich EJ, Riordan JD, Dupuy AJ. Domesticated transposable element Keating MJ, Abruzzo LV. LDOC1 mRNA is differentially gene products in human cancer. Mob Genet Elements. expressed in chronic lymphocytic leukemia and predicts 2013 Sep 1;3(5):e26693 overall survival in untreated patients. Blood. 2011 Apr 14;117(15):4076-84 Salemi M, Barone C, Romano C, Ridolfo F, Salluzzo R, Scillato F, Scavuzzo C, Caraci F, Calogero AE, Romano C, Inoue M, Takahashi K, Niide O, Shibata M, Fukuzawa M, Bosco P. Expression of LDOC1 mRNA in leucocytes of Ra C. LDOC1, a novel MZF-1-interacting protein, induces patients with Down's syndrome. J Genet. 2012;91(1):95-8 apoptosis. FEBS Lett. 2005 Jan 31;579(3):604-8 Salemi M, Giuffrida D, Soma PF, Giuffrida MC, Galia A, Lee CH, Wong TS, Chan JY, Lu SC, Lin P, Cheng AJ, Chen Calogero AE. Two proapoptotic genes are downregulated in YJ, Chang JS, Hsiao SH, Leu YW, Li CI, Hsiao JR, Chang a patient with melanoma and repeated in-transit JY. Epigenetic regulation of the X-linked tumour metastases. Am J Dermatopathol. 2012 Jun;34(4):454-5 suppressors BEX1 and LDOC1 in oral squamous cell carcinoma. J Pathol. 2013 Jul;230(3):298-309 Song Z, Dong R, Zhao R, Zheng S. Overexpression of LDOC1 in human biliary epithelial cells inhibits apoptosis Liu Y, Geng Y, Li K, Wang F, Zhou H, Wang W, Hou J, Liu through NF-κB signaling. J Pediatr Gastroenterol Nutr. 2013 W. Comparative proteomic analysis of the function and Dec;57(6):713-7 network mechanisms of MASPIN in human lung cells. Exp Ther Med. 2012 Mar;3(3):470-474 Vitek WS, Pagidas K, Gu G, Pepperell JR, Simpson JL, Tantravahi U, Plante BJ. Xq;autosome translocation in Lynn KS, Li LL, Lin YJ, Wang CH, Sheng SH, Lin JH, Liao POF: Xq27.2 deletion resulting in haploinsufficiency for W, Hsu WL, Pan WH. A neural network model for SPANX. J Assist Reprod Genet. 2012 Jan;29(1):63-6 constructing endophenotypes of common complex diseases: an application to male young-onset hypertension This article should be referenced as such: microarray data. Bioinformatics. 2009 Apr 15;25(8):981-8 Hsiao JR, Chang JY. LDOC1 (leucine zipper, down- Mizutani K, Koike D, Suetsugu S, Takenawa T. WAVE3 regulated in cancer 1). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1):14-17.

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

NKX2-3 (NK2 homeobox 3) Zhenwu Lin, John P Hegarty, Joanna Floros, Andre Franke Pennsylvania State University College of Medicine PA USA (ZL); Division of Colon, Rectal Surgery Department of Surgery Pennsylvania State University College of Medicine PA USA (JPH); Departments of Pediatrics, Obstetrics, Gynecology, CHILD Research Center, Pennsylvania State University College of Medicine PA USA (JF); Institute of Clinical Molecular Biology, Christian- Albrechts-University of Kiel, Kiel, Germany (AF)

Published in Atlas Database: November 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/NKX2-3ID51779ch10q24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62506/11-2014-NKX2-3ID51779ch10q24.pdf DOI: 10.4267/2042/62506 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

in endothelia that regulate leukocyte homing through Abstract local control of cellular adhesion. Studies of disease NKX2-3 gene is a member of the homeobox, NKX association indicated that NKX2-3 is associated with family. IBD (both Crohn's disease and ulcerative colitis), The gene encodes a homeodomain-containing intestinal fibrosis, colon rectal cancer, and dental transcription factor. GO (gene ontology) annotations caries. related to this gene include sequence-specific DNA Keywords binding and gene-specific transcription factor NKX2-3, inflammatory bowel disease (IBD), activity. NKX2-3 is essential for normal Crohn's disease (CD), ulcerative disease (UC), development and functions of the small intestine and homeodomain-containing transcription factor spleen of embryonic and adult mice. Disruption of Nkx2-3 in mice results in postnatal lethality and Identity abnormal development of the small intestine and the spleen. Other names: CSX3, NK2.3, NKX2.3, NKX2C, Villus formation in the small intestine appears NKX4-3 considerably delayed in Nkx2-3(null) fetuses due to HGNC (Hugo): NKX2-3 reduced proliferation of the epithelium, while Location: 10q24.2 massively increased growth of crypt cells follows in surviving adults. DNA/RNA A complex intestinal malabsorption phenotype and striking abnormalities of gut-associated lymphoid Note tissue and spleen suggest deranged leukocyte The human NKX2-3 gene has two transcripts. homing. RT-PCR and immunohistochemistry NKX2-3-001, ENST00000344586, 2097 nt mRNA revealed that NKX2-3 controls regional expression encoding a protein of 364 amino acids; NKX2-3- of leukocyte homing coreceptor mucosal addressin 201, ENST00000622383, 1986 nt mRNA encoding cell adhesion molecule-1 (MAdCAM-1) in a protein of 296 amino acids. specialized endothelial cells of the viscera. This indicates a potential role for NXK2-3 in establishing Description the developmental and positional cues The gene has two exons and one intron.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 18 NKX2-3 (NK2 homeobox 3)

Chromosomal location of human NKX2-3 gene. NKX2-3 gene is located on chr 10q24.2, size 3592 bp, starting at 101292690 bp and ending at 101296281 bp from the pter (the end of short arm) of the chromosome 10. The gene orientation is on the plus strand. The NKX2-3 gene consists of 2 exons 527 bp (101292690-101293248 nt) and 1540 bp (101294742-101298281 nt) respectively, an intron 1496 bp (101293248-101294742 nt). GOT1: glutamic-oxaloacetric transaminase 1 soluble; SLC25A28: solute carrier family 25 (mitochondrial iron transporter) member 28; ENTP7: ectonucleoside triphosphate diphophohydrolase 7.

Transcription Function The transcription takes place in a centromere --> NKX2-3 is a nuclear transcription factor that plays telomere orientation. The length of the processed an important role in the regulation of gene mRNA is about 2094 nucleotides. transcription. Studies from siRNA knockdown Pseudogene followed by cDNA profiling indicate that many Not known. genes are regulated by NKX2-3. This indicates involvement of NKX2-3 in the Protein regulation of transcription, of immune and inflammatory response, cell growth and Note proliferation, cell adhesion, metabolic processes, The NKX2-3 protein is a 364-amino acid (molecular angiogenesis, lymph-angiogenesis, and others (Yu et weight 38405.63g/mol) protein. al., 2011). Description Results from NKX2-3 deficient mice and other studies demonstrate that NKX2-3 is essential for The NKX2-3 protein (364 amino acids) translated intestine and spleen development (Pabst et al., 1999; from the long transcript contains a TN domain Pabst et al., 2000). (residues 10-19), HD domain (residues 148-207), SD NKX2-3 is required for heart formation (Fu et al., domain (residues 222-238) and TAD domain 1998) and salivary gland and tooth morphogenesis (residues 239-364). and plays a role during pharyngeal organogenesis Expression (Biben et al., 2002). Expression is mainly observed in pharynx, small NKX2-3 is essential for B cell maturation and T cell intestine, liver, spleen, heart, lymph node, thyroid, dependent immune response (Shaffer et al., 2013), adrenal gland, breast, skin, ovary, prostate, testis, and regulates leukocyte homing through local and retina. control of cellular adhesion molecules including MADCAM-1 and VCAM in mice (Wang et al., Localisation 2000) and IBD patients (our unpublished data). Nucleus, but also observed outside the nucleus.

Human NKX2-3 mRNA. The gene for NKX2-3 consists of two exons of 527 and 1540 bp, respectively. The intron is 1496 bp. Positions of start (cDNA 179 nt) and stop (cDNA 1534 nt) codons are indicated. These data refer to ENSEMBL transcript.

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NKX2-3 (NK2 homeobox 3)

Human NKX2-3 protein. The NKX2-3 protein is a 364-amino acid (molecular weight 38405.63g/mol) protein including a TN domain (tinman domain; transcription repressor domain), HD domain (homeodomain, 60 aa), SD domain (NK2 specific domain), and TAD domain (transcriptional activation domain).

Nkx2-3 and regulation of the arteriovenous Kellermayer et al. 2011 reported that Nkx2.3- endothelial profile deficient mice develop splenic and gut-associated Individual transcription factors interact in a complex vascular and lymphoid tissue abnormalities with network to regulate the arteriovenous profile. disordered segregation of T- and B- cells. Splenic Aranguren et al. 2013 examined the expression of 64 defects include absence of the marginal sinus known arterial and 12 known venous genes from vasculature and an atrophic red pulp sinus network freshly isolated arterial and venous endothelial cells with an extensive network of lymphocyte-filled from human umbilical cord. The expression of endothelial sacs lined by cells expressing LYVE-1, a approximately 36% of the examined arterial genes marker associated with lymphatic endothelium cells was found to be regulated by NKX2-3 (Aranguren et (Kellermayer et al., 2011). al., 2013). This raises the possibility that endothelial Nkx2-3 and lymphoid tissue development differentiation and maturation may be affected by It remains to be determined whether the formation of altered expression of Nkx2-3. enteric lymphatic capillaries is affected by the absence of Nkx2-3, similar to the observed reduction Homology of Peyer's patches. In contrast to the leukocyte NKX2-3 is a homeodomain protein belonging to the homing in pLNs and Peyer's patches, the spleen NK2 family. lacks high endothelial venules (HEVs) and requires The other NK2 family members are Nkx2-1 (at no L-selectin binding for subsequent leukocyte 14q13), Nkx2-2 (at 20p11), Nkx2-3 (at 10q24.2), extravasation. Evidence indicated that the integrity Nkx2-4 (at 20p11), Nkx2-5, Nkx2-6, Nkx2-8, Nkx2- of the marginal sinus and the proper vascular 9 (at 14q13), and Nkx2-10. segregation of the red pulp was controlled by NKX2- Orthologs of NKX2-3 show a high similarity with 3 (Balogh et al., 2007). the homologues in other species, such as 88.46% (nt) Czömpöly et al. 2011 found that the disruption of and 90.86% (aa) with mouse, 60% (aa) with chicken, Nkx2-3 expression in mice, the spleen develops a 79% (nt) with Xenopus laevis, 76.29% (nt) with peripheral lymph node (pLN)-like mRNA zebrafish, 20% (aa) with fruit fly, and 33% (aa) with expression signature, coupled with the appearance of worm. HEVs. These HEV-like vessels undergo postnatal maturation and progressively replace MAdCAM-1 Mutations by pLN addressin together with the display of CCL21 arrest chemokine, reminiscent of HEV A total of 304 genetic variants are documented, formation in pLNs (Czömpöly et al., 2011). This including 128 upstream and 87 downstream of the transformation of splenic vasculature into pLN-like gene, 5 variants in the 5' prime and 15 in the 3' primer vessels emphasizes the importance of Nkx2-3 in untranslated regions, 26 missense and 17 correct vessel formation for spleen ontogeny in synonymous variants in exons, 23 variants in introns, mammals. and 2 in-frame deletions.

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NKX2-3 (NK2 homeobox 3)

Mutations in human NKX2-3 gene. A. The base number at the beginning and the end of each exon is shown. Genetic variations rs10883365 and rs11190140 in 5'-prime upstream are the most used for genetic association study, and rs888208 in 3'UTR is used for allele specific expression. TMP_ESP_10_101294794-101294796 GAA/- in Exon 2 is an in-frame deletion. Of the 26 missense genetic variants only three, rs201429667 (p.A49T), rs79873574 (p.P145T, and rs15105391 (p.L358W) have been observed in multiple studies. Of the 17 synonymous variants five have been observed in multiple studies with high MAF (minor allele frequency): rs41290504 (MAF: 0.483), rs145887258 (MAF: 0.001), rs184601313 (MAF: 0.001), rs113459553 (MAF: 0.039), and rs78122843 (MAF: 0.006) in amino acid residue 49, 80, 156, 185, and 194 respectively. B.The base number at the beginning and the end of each exon is shown. The somatic mutations are shown from left to right: COSM71840 p.T10I, COSM1345223 p.D35G, COSM913762 p.A43V, COSM426905 p.A49A, COSM124757 p.G52E, COSM1217392 p.L70S, COSM3686464 p.S102R, COSM2057374 p.S102S, COSM1638416 p.E109Q, COSM465162 p.R165H, COSM1345224 pA216T, COSM404952 C817_837del21 in-frame, and COSM1217393 p.R362L.

Somatic Liver metastases A total of 13 somatic mutations have been reported: NKX2-3 is expressed to a low level in liver one is a 21 bp deletion, two are synonymous variants, metastases than in primary tumors and normal and 10 missense variants. enterochromaffin cells (Leja et al., 2009). Histological examination showed all the mutations are observed in carcinoma. Inflammatory bowel disease (IBD) NKX2-3 was first identified as IBD susceptibility Implicated in gene from a GWAS study in 2006 (Wellcome Trust Case Control, 2007) and then it was replicated in Colorectal cancer (CRC) several cohorts in both CD and US (Parkes et al., Loss of heterozygosity on chromosome 10 where 2007; Franke et al., 2008; Barrett et al., 2008). The IL10 is located was observed in sporadic CRC. RT- association is widely studied with genetic variations PCR results indicated that the NKX2-3 gene is down rs10883365 and rs11190140, in different IBD regulated (Wang et al., 2008). populations, including Japanese population (484 CD A high expression of NKX2-3 was found in the CRC and 470 controls (Yamazaki et al., 2009), Dutch- experimental group compared to the control group Belgian (2731IBD: 1656 CD and 1075UC) (Li et al., 2012). (Weersma et al., 2009), Eastern European IBD CRC with synchronous liver patients (810 CD and 428 UC) (Meggyesi et al., 2010), Central Pennsylvania population in US (Yu et metastasis al., 2009), Italian cohort (both CD and UC, adult and NKX2-3 with other 6 genes was incorporated into a pediatric IBD) (Latiano et al., 2011), and Lithuanian- genetic model for estimating chemotherapy Latvian population (444 UC and 1154 controls) sensitivity. (Skieceviciene et al., 2013). A specific association of The result from 30 ACC (advanced colorectal NKX2-3 rs1088365 with smoking CD patients has cancer) patients (13 were assigned to experimental been observed (310 CD and 976 controls) (van der group and 17 to the control group) showed an overall Heide et al., 2010). These studies have been accurate prediction rate of 99.3% (Lu et al., 2013). reviewed (Cho and Brant, 2011; Van Limbergen et al., 2014).

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NKX2-3 (NK2 homeobox 3)

Studies on genetic association of Nkx2-3 gene with IBD.

A recent comprehensive meta-analysis of 17 studies Nkx2-3 is highly expressed in the gut mesenchyme, involving 17329 patients and 18029 controls showed such as myofibroblasts and the smooth muscle cells a significantly increased CD or UC risk in persons of the muscularis mucosae. Myofibroblasts are carrying a G allele at rs10883365 polymorphism known to play key roles in wound healing and (A/G) compared with those with an A allele. (OR = fibrosis. Known Nkx2-3 regulation of genes 1.226, 95%CI: 1.177-1.277 and OR = 1.274, 95%CI: mediating fibrogenesis and wound healing, such as 1.175-1.382 respectively). endothelins, angiotensin converting enzyme, and In the subgroup analysis, a significantly increased angiotensin-II, and nitric oxide, may result in active CD risk was found in both Europeans and Asians. deposition of ECM resulting in the characteristic For rs11190140 polymorphism (C/T) and CD risk, fibrosis of CD (Yu et al., 2011). the risk estimate for the allele contrast was OR = Interestingly, related Nkx2.5 is a known repressor of 1.201 (1.136-1.269) (Lu et al., 2014). myofibroblast α-smooth muscle actin (α-SMA) gene Prognosis transcription in the lung (Hu et al., 2010). Similarly, Results from a study in 572 CD, 328 UC patients, aberrant Nkx2-3 expression in the gut may result in 437 non-IBD, and 137 healthy controls using 29 increased intestinal myofibroblast differentiation biomarkers, 4 genetic markers including NKX2-3, 8 intestinal fibrosis. We note that the Nkx2-3- serological markers, and 17 inflammatory markers, regulated transcription factor KLF-4 (gut-enriched indicated that these markers can differentiate non- Krüppel-like factor) represses α-SMA gene IBD from CD and UC patients (Plevy et al., 2013). expression by interacting with Smad3 (TGF-β signaling) to prevent Smad3 binding, resulting in Intestinal fibrosis reduced myofibroblast differentiation (Hu et al., 2007). Intestinal fibrosis is among the most common complications of IBD, and is usually defined as an Dental caries excessive accumulation of scar tissue in the Dental caries, also known as tooth decay or a cavity, intestinal wall. Severe fibrosis is seen in up to 30% is an infection, bacterial in origin. It causes of patients with CD, a high proportion of them demineralization and destruction of the hard tissues require surgery. of the teeth (enamel, dentin and cementum) as a In addition, endothelial-to-mesenchymal transition result of the production of acid by bacterial (EndoMT) results in the trans-differentiation of fermentation of food debris accumulated on the tooth intestinal mucosal microvascular cells (HIMEC) into surface. In a GWAS study with 518987 genetic mesenchymal cells. variations NKX2-3 was shown to be a suggestive This indicates that the intestinal microvasculature genetic association with dental caries pattern in the may also contribute to IBD-associated fibrosis permanent dentition (Shaffer et al., 2013). (Rieder et al., 2011).

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NKX2-3 (NK2 homeobox 3)

Schematic representation of 10q24 and 12p13 regions implicated in the t(10;12). Genomic representation of t(10;12) ETV6 (exon 3)-GOT1 (exon 12) fusion is in frame. The fusion transcript was identified by RT-PCR with primers located in the exon 6 of ETV6 and the exon 3 of GOT1 followed by sequence analysis. The sterile alpha motif (SAM) domain (exons 2 to 4) responsible for hetero- and homodimerization with other ETV6 protein and possibly other ETS family members, are indicated.

Nkx2-3 allelic expression imbalance in human Breakpoints IBD colonic mucosa A ETV6-GOT1 fusion contains a chimeric transcript Arai et al. 2011 (Arai et al., 2011) examined the containing ETV6 sequence fused to genomic expression of Nkx2-3 mRNA from colonic mucosa sequences located at 22961 bp 3' to GOT1 and 79407 from Japanese patients with IBD. Allelic expression bp 5' to NK2 transcription factor related, locus 3 ratios of NKX2.3 mRNA transcribed from risk (NKX2-3). This may result in the dysregulation of haplotype to the non-risk haplotype in the involved NKX2-3, which lies adjacent to the breakpoint mucosa from 10 IBD patients were significantly (Struski et al., 2008). higher than the allelic ratio of respective genomic DNA (p = 0.00195) (Arai et al., 2011). This observed To be noted allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility miRNAs targeting human Nkx2-3 to UC through increasing expression of NKX2.3 The top miRNAs binding the 3'-UTR of the human mRNA in the colonic mucosa. NKX2-3 transcript were identified using TargetScan v6.2 (Lewis et al., 2005) and Miranda algorithm v4.0 (Betel et al., 2006) with parameters of >8-mer References matches with mirSVR scores <= -1 and PhastCons Arai T, Kakuta Y, Kinouchi Y, Kimura T, Negoro K, Aihara score >= 0.6 BP. Identified miRNAs included H, Endo K, Shiga H, Kanazawa Y, Kuroha M, Moroi R, members of the miR-92a microRNA precursor Nagasawa H, Shimodaira Y, Takahashi S, Shimosegawa T. Increased expression of NKX2.3 mRNA transcribed from family of highly conserved miRNAs (miR-25, miR- the risk haplotype for ulcerative colitis in the involved colonic 92a, miR-92b and miR-363). The miR-92a family mucosa. Hum Immunol. 2011 Jul;72(7):587-91 plays an important role in regulating mammalian Aranguren XL, Agirre X, Beerens M, Coppiello G, Uriz M, organs including heart and lungs, and immune Vandersmissen I, Benkheil M, Panadero J, Aguado N, system, formation of blood vessels, and development Pascual-Montano A, Segura V, Prósper F, Luttun A. of endothelial cells. Inhibition of miR-92a can Unraveling a novel transcription factor code determining the human arterial-specific endothelial cell signature. Blood. enhance angiogenesis and viability of endothelial 2013 Dec 5;122(24):3982-92 cells (Zhang et al., 2014). miRNA92a family and miRNA-32 affect expression of endothelial Kruppel- Balogh P, Balázs M, Czömpöly T, Weih DS, Arnold HH, Weih F. Distinct roles of lymphotoxin-beta signaling and the like factors KLF2 and KLF-4, possibly though homeodomain transcription factor Nkx2.3 in the ontogeny of regulation of Nkx2-3 expression (Loyer et al., 2014). endothelial compartments in spleen. Cell Tissue Res. 2007 Epigenetic modification of genetic variant Jun;328(3):473-86 Rs11190140 is a C/T variation followed by G. The Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, C allele is in a CG dinucleotide. The C is subjected Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada to methylation. The genetic variation and epigenetic MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, modification affect the NFAT transcription factor Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle binding to the DNA, T< nonmethylated C< C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath methylated C (John et al., 2011). S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis

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NKX2-3 (NK2 homeobox 3)

E, Cardon LR, Anderson CA, Drummond H, Nimmo E, predict the effects of FOLFOX4 chemotherapy. Cancer Biol Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ther. 2012 Apr;13(6):443-9 Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes Loyer X, Potteaux S, Vion AC, Guérin CL, Boulkroun S, M, Georges M, Daly MJ. Genome-wide association defines Rautou PE, Ramkhelawon B, Esposito B, Dalloz M, Paul JL, more than 30 distinct susceptibility loci for Crohn's disease. Julia P, Maccario J, Boulanger CM, Mallat Z, Tedgui A. Nat Genet. 2008 Aug;40(8):955-62 Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ Res. 2014 Jan Betel D, Wilson M, Gabow A, Marks DS, Sander C. The 31;114(3):434-43 microRNA.org resource: targets and expression. Nucleic Acids Res. 2008 Jan;36(Database issue):D149-53 Lu X, Pan J, Li S, Shen S, Chi P, Lin H, Huang Y, Xu Z, Huang S. Establishment of a predictive genetic model for Biben C, Wang CC, Harvey RP. NK-2 class homeobox estimating chemotherapy sensitivity of colorectal cancer genes and pharyngeal/oral patterning: Nkx2-3 is required with synchronous liver metastasis. Cancer Biother for salivary gland and tooth morphogenesis. Int J Dev Biol. Radiopharm. 2013 Sep;28(7):552-8 2002;46(4):415-22 Lu X, Tang L, Li K, Zheng J, Zhao P, Tao Y, Li LX. Cho JH, Brant SR. Recent insights into the genetics of Contribution of NKX2-3 polymorphisms to inflammatory inflammatory bowel disease. Gastroenterology. 2011 bowel diseases: a meta-analysis of 35358 subjects. Sci May;140(6):1704-12 Rep. 2014 Jan 29;4:3924 Czömpöly T, Lábadi A, Kellermayer Z, Olasz K, Arnold HH, Meggyesi N, Kiss LS, Koszarska M, Bortlik M, Duricova D, Balogh P. Transcription factor Nkx2-3 controls the vascular Lakatos L, Molnar T, Leniček M, Vítek L, Altorjay I, Papp M, identity and lymphocyte homing in the spleen. J Immunol. 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Targeted disruption of the 1998 Nov;125(22):4439-49 homeobox transcription factor Nkx2-3 in mice results in postnatal lethality and abnormal development of small Hu B, Wu YM, Wu Z, Phan SH. Nkx2.5/Csx represses intestine and spleen. Development. 1999 myofibroblast differentiation. Am J Respir Cell Mol Biol. May;126(10):2215-25 2010 Feb;42(2):218-26 Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson Hu B, Wu Z, Liu T, Ullenbruch MR, Jin H, Phan SH. Gut- CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, enriched Krüppel-like factor interaction with Smad3 inhibits Soars D, Drummond H, Lees CW, Khawaja SA, Bagnall R, myofibroblast differentiation. Am J Respir Cell Mol Biol. Burke DA, Todhunter CE, Ahmad T, Onnie CM, McArdle W, 2007 Jan;36(1):78-84 Strachan D, Bethel G, Bryan C, Lewis CM, Deloukas P, John G, Hegarty JP, Yu W, Berg A, Pastor DM, Kelly AA, Forbes A, Sanderson J, Jewell DP, Satsangi J, Mansfield Wang Y, Poritz LS, Schreiber S, Koltun WA, Lin Z. NKX2-3 JC, Cardon L, Mathew CG. Sequence variants in the variant rs11190140 is associated with IBD and alters autophagy gene IRGM and multiple other replicating loci binding of NFAT. Mol Genet Metab. 2011 Sep-Oct;104(1- contribute to Crohn's disease susceptibility. Nat Genet. 2):174-9 2007 Jul;39(7):830-2 Kellermayer Z, Lábadi A, Czömpöly T, Arnold HH, Balogh Plevy S, Silverberg MS, Lockton S, Stockfisch T, Croner L, P. Absence of Nkx2-3 homeodomain transcription factor Stachelski J, Brown M, Triggs C, Chuang E, Princen F, induces the formation of LYVE-1-positive endothelial cysts Singh S. Combined serological, genetic, and inflammatory without lymphatic commitment in the spleen. J Histochem markers differentiate non-IBD, Crohn's disease, and Cytochem. 2011 Jul;59(7):690-700 ulcerative colitis patients. 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Mod Res. 2013 Jan;92(1):38-44 Pathol. 2009 Feb;22(2):261-72 Skieceviciene J, Kiudelis G, Ellinghaus E, Balschun T, Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, Jonaitis LV, Zvirbliene A, Denapiene G, Leja M, Pranculiene often flanked by adenosines, indicates that thousands of G, Kalibatas V, Saadati H, Ellinghaus D, Andersen V, human genes are microRNA targets. Cell. 2005 Jan Valantinas J, Irnius A, Derovs A, Tamelis A, 14;120(1):15-20 Li S, Lu X, Chi P, Pan J. Identification of Nkx2-3 and Schreiber S, Kupcinskas L, Franke A. Replication study of TGFB1I1 expression levels as potential biomarkers to ulcerative colitis risk loci in a Lithuanian-Latvian case-

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control sample. Inflamm Bowel Dis. 2013 Oct;19(11):2349- association of genetic variants in the upstream region of 55 NKX2-3 with Crohn's disease in Japanese patients. Gut. 2009 Feb;58(2):228-32 Struski S, Mauvieux L, Gervais C, Hélias C, Liu KL, Lessard M. ETV6/GOT1 fusion in a case of t(10;12)(q24;p13)- Yu W, Hegarty JP, Berg A, Chen X, West G, Kelly AA, Wang positive myelodysplastic syndrome. Haematologica. 2008 Y, Poritz LS, Koltun WA, Lin Z. NKX2-3 transcriptional Mar;93(3):467-8 regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells. PLoS One. Van Limbergen J, Radford-Smith G, Satsangi J. Advances 2011;6(5):e20454 in IBD genetics. Nat Rev Gastroenterol Hepatol. 2014 Jun;11(6):372-85 Yu W, Lin Z, Kelly AA, Hegarty JP, Poritz LS, Wang Y, Li T, Schreiber S, Koltun WA. Association of a Nkx2-3 Wang CC, Biben C, Robb L, Nassir F, Barnett L, Davidson polymorphism with Crohn's disease and expression of NO, Koentgen F, Tarlinton D, Harvey RP. Homeodomain Nkx2-3 is up-regulated in B cell lines and intestinal tissues factor Nkx2-3 controls regional expression of leukocyte with Crohn's disease. J Crohns Colitis. 2009 Sep;3(3):189- homing coreceptor MAdCAM-1 in specialized endothelial 95 cells of the viscera. Dev Biol. 2000 Aug 15;224(2):152-67 Zhang L, Zhou M, Qin G, Weintraub NL, Tang Y. MiR-92a Wang X, Zbou C, Qiu G, Fan J, Tang H, Peng Z. Screening regulates viability and angiogenesis of endothelial cells of new tumor suppressor genes in sporadic colorectal under oxidative stress. Biochem Biophys Res Commun. cancer patients. Hepatogastroenterology. 2008 Nov- 2014 Apr 18;446(4):952-8 Dec;55(88):2039-44 van der Heide F, Nolte IM, Kleibeuker JH, Wijmenga C, Weersma RK, Stokkers PC, Cleynen I, Wolfkamp SC, Dijkstra G, Weersma RK. Differences in genetic background Henckaerts L, Schreiber S, Dijkstra G, Franke A, Nolte IM, between active smokers, passive smokers, and non- Rutgeerts P, Wijmenga C, Vermeire S. Confirmation of smokers with Crohn's disease. Am J Gastroenterol. 2010 multiple Crohn's disease susceptibility loci in a large Dutch- May;105(5):1165-72 Belgian cohort. Am J Gastroenterol. 2009 Mar;104(3):630- 8 This article should be referenced as such: . Genome-wide association study of 14,000 cases of seven Lin Z, Hegarty JP, Floros J, Franke A. NKX2-3 (NK2 common diseases and 3,000 shared controls. Nature. 2007 homeobox 3). Atlas Genet Cytogenet Oncol Haematol. Jun 7;447(7145):661-78 2016; 20(1):18-25. Yamazaki K, Takahashi A, Takazoe M, Kubo M, Onouchi Y, Fujino A, Kamatani N, Nakamura Y, Hata A. Positive

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 25 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) WenYong Chen Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA

Published in Atlas Database: December 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/SIRT1ID44006ch10q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62507/12-2014-SIRT1ID44006ch10q21.pdf DOI: 10.4267/2042/62507 This article is an update of : Tseng RC, Wang YC. SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol 2010;14(12)

and a number of NF-kappaB and GATA Abstract transcription factor binding sites in addition to a SIRT1 is a member of the mammalian sirtuin genes small 350-bp CpG island in the 5' flanking genomic that encode for seven protein lysine modifiers with region. deacetylase, ADP-ribosyltransferase and other The gene encodes a 747 amino acids protein with a deacylase activities. SIRT1 plays diverse roles in predictive molecular weight of 81.7 kDa and an regulating cell proliferation, differentiation, stress isoelectric point of 4.55 (Alcaín and Villalba, 2009). response, metabolism, energy homeostasis, aging Transcription and cancer. Besides deacetylating histone substrates, SIRT1 transcription is under the control of at least SIRT1 regulates functions of an array of non-histone two negative feedback loops that keep its induction proteins including transcriptional factors for gene tightly regulated under conditions of oxidative regulation, DNA repair machinery elements for stress. reducing catastrophic genome lesions, epigenetic SIRT1 promoter can be regulated by E2F1 and HIC1 factors for chromatin and gene regulation, nuclear during cellular stress. E2F1 directly binds to the receptors and circadian clock as well as related SIRT1 promoter at a consensus site located at bp factors for metabolism, and other cell signaling position -65 and appears to regulate the basal molecules. SIRT1 is involved in many types of expression level of SIRT1. Such high levels of human cancer. SIRT1 lead to a negative feedback loop where E2F1 activity is inhibited by SIRT1-mediated Identity deacetylation. By contrast, the tumor suppressor Other names: EC 3.5.1, hSIR2, hSIRT1, HIC1 and SIRT1 form a transcriptional repression SIR2alpha, SIR2L1 complex that directly binds SIRT1 promoter and represses SIRT1 transcription thereby inhibiting HGNC (Hugo): SIRT1 SIRT1-mediated p53 deacetylation and inactivation. Location: 10q21.3 Two HIC1 binding sites have been assigned to base pair positions -1116 and -1039 within the SIRT1 DNA/RNA promoter (Chen et al., 2005). In addition, two functional p53 binding sites (-178 bp and -168 bp), Description which normally repress SIRT1 expression, have The SIRT1 gene spans about 34 kb including nine been identified. exons. The SIRT1 promoter contains a CCAAT box

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 26 SIRT1 (sirtuin (silent mating type information regulation 2 Chen WY homolog) 1 (S. cerevisiae))

SIRT1 gene expression is modulated at both transcriptional and posttranscriptional levels.

Furthermore, SIRT1 transcription is upregulated by Two proteins have been identified to regulate the MYC that binds at SIRT1 promoter position -80 and SIRT1 activity both positively and negatively by STAT5 that binds at positions -2235 and -1838 in through complex formation in the context of the response to BCR-ABL oncogenic stress (Yuan et al., cellular stress response. 2012). The first identified direct regulator of SIRT1 was the SIRT1 expression is also regulated at the active regulator of SIRT1 (AROS). posttranscriptional level by HuR. It has been The AROS protein is known to significantly enhance demonstrated that HuR, a ubiquitously expressed the activity of SIRT1 on acetylated p53 both in vitro RNA binding protein, associates with the 3' UTR of and in cell lines thereby promoting the inhibitory the SIRT1 mRNA under physiological conditions effect of SIRT1 on p53-mediated transcriptional and helps to stabilize the transcript. This interaction activity of pro-apoptotic genes (e.g. Bax and results in increased SIRT1 mRNA stability and thus p21Waf-1) under conditions of DNA-damage. A in elevated protein levels. Conversely, the HuR- negative regulator of SIRT1, DBC-1 (deleted in SIRT1 mRNA complex is being disrupted upon breast cancer-1), has recently been identified. DBC1 oxidative stress, which finally leads to decreased binds directly to the catalytic domain of SIRT1, mRNA stability and therefore decreased SIRT preventing substrate binding to SIRT1 and inhibiting protein levels. In addition, several microRNA (miR) SIRT1 activity. species negatively regulate SIRT1 mRNA by Reduction of DBC1 inhibits p53-mediated apoptosis targeting its 3' UTR, including miR-34a and miR- after induction of double-stranded DNA breaks 200a (reviewed in Roth and Chen, 2014). owing to SIRT1-mediated p53 deacetylation. Both Pseudogene factors represent the first endogenous, direct regulators of SIRT1 function. SIRT1 activity is also None identified. regulated by cis-elements of its own peptides. The SIRT1 C-terminal region (aa 631-635) is a Protein disordered domain, and it interacts with SIRT1 Description catalytic core domain by competing with DBC1 and Human SIRT1 encodes 747 amino acids protein with activates SIRT1 activity (Kang et al., 2011). A small a nuclear localization signal (NLS) at the N-terminus rigid region at the N-terminus (aa 190-244) of SIRT1 (aa 41-46) and a sirtuin homology domain at the appears to mediates allosteric activators for the center (aa 261-447); this domain is a conserved SIRT1 catalytic core function (Hubbard et al., 2013). catalytic domain for deacetylation. The catalytic In addition, SIRT1 activity is subjected to regulation activity of SIRT1 is dependent on the cofactor by other posttranslational modifications such as nicotinamide adenine dinucleotide (NAD+). sumoylation, phosphorylation and methylation in response to stress signaling and cell cycle changes Expression (reviewed in Wang and Chen, 2013). Expression appears to be ubiquitous in adult tissues

(although at different levels).

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SIRT1 (sirtuin (silent mating type information regulation 2 Chen WY homolog) 1 (S. cerevisiae))

SIRT1 deacetylase activity is modulated through protein-protein interaction and sumoylation at its three protein domains (Liu T et al., 2009).

As an NAD-dependent enzyme, SIRT1 activity is optic neuritis mainly due to decreased deacetylation regulated by cellular NAD metabolism in which of the tumor suppressor p53 and PGC-1a. NAD salvage pathway enzyme nicotinamide (4) SIRT1 represses p53-dependent apoptosis in phosphoribosyltransferase (NAMPT) is often co- response to DNA damage and oxidative stress and activated with SIRT1 to maintain the deacetylase promotes cell survival under cellular stress induced activity (Wang et al., 2011; Menssen et al., 2012). by etoposide treatment or irradiation. Localisation (5) SIRT1 activates FOXO1 and FOXO4, which promote cell-cycle arrest by inducing p27kip1; SIRT1 is predominately in the nucleus (although SIRT1 also induces cellular resistance to oxidative SIRT1 does have some important cytoplasmic stress by increasing the levels of manganese functions as well). In addition to possessing two superoxide dismutase and GADD45 (growth arrest NLSs, SIRT1 contains two nuclear export signals. and DNA damage-inducible protein 45). Thus, the exposure of nuclear localization signals (6) SIRT1 inhibits the transcriptional activity of NF- versus nuclear export signals may dictate the kappaB by deacetylating NF-kappaB's subunit, cytosolic versus nuclear localization of SIRT1. RelA/p65, at lysine 310. Thus, although SIRT1 is Function capable of protecting cells from p53-induced SIRT1 has been reported to play a key role in a apoptosis, it may augment apoptosis by repressing variety of physiological processes such as NF-kappaB. SIRT1 is reported to bind CTIP2 metabolism, neurogenesis and cell survival due to its (BCL11B B-cell CLL/lymphoma 11B) and ability to deacetylate both histone and numerous accelerate the transcriptional repression by this nonhistone substrates. molecule. CTIP2 represses the transcription of its (1) Lysines 9 and 14 in the amino-terminal tail of target genes and is implicated in hematopoietic cell histone H3 and lysine 16 of histone H4 are development. deacetylated by yeast Sir2 and mammalian SIRT1 (7) SIRT1 deacetylates and activates functions of (Sir2alpha). several DNA repair factors, including KU70, NBS1, (2) Metabolic homeostasis is controlled by SIRT1- APE1, XPA/C and WRN for multiple DNA damage mediated deacetylation and thus activation of the repair pathways to cope with genotoxic stress. peroxisome proliferation activating receptor Stimulated repair may help cells avoid catastrophic (PPAR)-gamma co-activator-1a (PGC-1a), which genomic events and survive the damage. stimulates mitochondrial activity and subsequently (8) SIRT1 is involved in epigenetic regulation of increases glucose metabolism, which in turn genes and chromatin. SIRT1 deacetylates several improves insulin sensitivity. SIRT1 represses PPAR- histone tail lysines: histone H4 lysine 16 (H4K16), gamma, a key regulator of adipogenesis, by docking histone H3 K9 and K14, and histone H1 K26. These with its cofactors NCoR (nuclear receptor co- modifications of histone tails are closely related to repressor) and SMRT (silencing mediator of retinoid gene silencing and heterochromatin formation that and thyroid hormone receptors). The upregulation of may underlie certain biological processes. SIRT1 SIRT1 triggers lipolysis and loss of fat. can deacetylate DNA methyltransferase 1 (DNMT1) (3) The activation of SIRT1 appears to be and can either enhance or hinder its neuroprotective in animal models for Alzheimer's methyltransferase activity, thus indirectly affecting disease and amyotrophic lateral sclerosis as well as global or local DNA methylation patterns.

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SIRT1 is a component of the polycomb repressor Chronic myelogenous leukemia complex (PRC) that is involved in silencing genes SIRT1 plays an important role in drug resistance of during normal development. chronic myelogenous leukemia (CML). SIRT1 directly complexes with EZH2, a H3K27 methyltransferase within PRC II complex, and is an Disease integral part of the PRC's silencing functions. A CML is a lethal malignant disease of hematopoietic SIRT1-containing PRC complex, termed PRC4, is stem cells. It is caused by reciprocal translocation of specifically found in transformed cells and chromosomes 9 and 22, producing BCR-ABL fusion embryonic stem cells. gene. BCR-ABL protein has aberrant tyrosine kinase In addition, SIRT1 interacts and deacetylates the activity and predominantly resides in the cytoplasm SUV39H1 methyltransferase, promoting histone H3 in contrast to predominantly nuclear localization of methylation and fostering heterochromatin ABL protein. CML progresses from chronic phase to formation, and repressing rRNA transcription to accelerated phase and blast crisis with increasing protect cells from energy deprivation-dependent numbers of blast cells in bone marrow and blood. apoptosis (reviewed in Roth and Chen, 2014). SIRT1 is activated by BCR-ABL oncogenic transformation in human CML stem/progenitor cells Homology (Yuan et al., 2012; Li et al., 2012). SIRT1 is the mammalian homologue closest to yeast Prognosis NAD+-dependent deacetylase Sir2 (silent CML in chronic phase can be effectively treated information regulation 2). tyrosine kinase inhibitors such as first-line drug It was originally identified as a lifespan extending imatinib, and second-line drugs nilotinb and gene when over-expressed in budding yeast, dasatinib, which results in the five-year survival rate Caenorhabditis elegans, and Drosophila over 85%. However, the residual disease persists as melanogaster. The SIR2 gene is broadly conserved these drugs do not eradicate CML leukemic stem in organisms ranging from bacteria to humans. The cells, and the disease relapses if the drug is ceased. accession numbers for the amino acid sequences CML in advanced phases has much poorer prognosis used are as follows: yeast Sir2 (CAA25667), mouse and the disease typically relapses quickly on tyrosine Sir2alpha (AAF24983), human Sirt1 (AAD40849). kinase inhibitor treatment since the cells acquire All of the sirtuin proteins contain the ~275 residue BCR-ABL mutations that block the binding of the sirtuin homology domain. In many instances a highly drugs to BCR-ABL. conserved protein domain represents a conserved Cytogenetics functional binding site for a metabolite or Philadelphia chromosome, t(9;22) translocation. biomolecule and such conserved binding site domains are often found within enzymatic catalytic Abnormal protein domains. BCR-ABL fusion protein with aberrant tyrosine kinase activity. Mutations Oncogenesis BCR-ABL transformation activates SIRT1 gene Germinal expression in both tyrosine kinase-dependent and A germ line mutation L107P of SIRT1 was found in independent manners, with the former mediating via a family with type I diabetes. Expression of this STAT5 that binds on the SIRT1 promoter to mutant SIRT1 in insulin-producing cells stimulated stimulate the transcription. The mechanism for the production of nitric oxide, cytokines and kinase-independent SIRT1 activation is unknown. chemokines, and decreased anti-inflammatory SIRT1 knockout significantly blocks BCR-ABL activity of pancreatic beta cells (Biason-Lauber et mediated leukemogenesis in a mouse model study al., 2013). (Yuan et al., 2012). Since blocking BCR-ABL kinase activity only partially reduces SIRT1 Somatic expression and the pathway remains active, SIRT1 A small number of SIRT1 somatic mutations were inhibition sensitizes human CML leukemia stem registered in human cancer databases but the cells to tyrosine kinase inhibitors and helps eradicate mutation rate is typically very low (<0.5%) and their these cells by increasing p53 acetylation and effect on SIRT1 function is unknown. Both gene activating p53 downstream target gene expression amplification and deletion are found in human (Li et al., 2012). In addition, SIRT1 promotes cancers depending on cancer types (reviewed in acquisition of resistant BCR-ABL mutations for Roth and Chen, 2014). disease relapse in association with its ability to deacetylate and activate KU70 for increased error- Implicated in prone DNA damage repair in blast crisis CML cells

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SIRT1 (sirtuin (silent mating type information regulation 2 Chen WY homolog) 1 (S. cerevisiae))

(Wang et al., 2013). Targeting SIRT1 may have low HIC1 expression, confirming deregulation clinical implication to improve CML treatment. HIC1-SIRT1-p53 circular loop in clinical model. Acute myeloid leukemia Expression of DBC1, which blocks the interaction between SIRT1 deacetylase and p53, led to SIRT1 plays an important role in drug resistance of acetylated p53 in lung adenocarcinoma patients. acute myeloid leukemia (AML) with FLT-ITD mutation. Prognosis Lung cancer patients with altered HIC1-SIRT1-p53 Disease circular regulation showed poor prognosis. AML is a group of highly heterogenous myeloid leukemia with distinct oncogenic events including Breast cancer various chromosomal aberrations and mutations. The breast cancer associated protein, BCA3, when AML is generally derived from myeloid progenitor neddylated (modified by NEDD8) interacts with cells. SIRT1 protein expression is more consistently SIRT1 and suppresses NF-kB-dependent increased in AML samples, particularly those transcription, also sensitizes human breast cancer harboring FLT-ITD alteration. The change of SIRT1 cells (such as MCF7) to TNF-a-induced apoptosis. mRNA is less consistent in certain AML In addition, it has been shown recently that SIRT7 subcategories from one to another study (Sasca et al., levels of expression increase significantly in breast 2014; Li et al., 2014). cancer, and that SIRT7 and SIRT3 both are highly Prognosis transcribed in lymph-node positive breast biopsies, a AML with FLT-ITD mutation has poor prognosis. stage in which the tumour size is at least 2 mm and the cancer has already spread to the lymph nodes. Abnormal protein SIRT1 up-regulation is also associated with FLT-ITD has constitutively activated tyrosine kinase decreased miR-200a in breast cancer samples, which activity. targets the 3'UTR of SIRT1 mRNA and promotes Oncogenesis epithelial-mesenchymal transition (EMT)-like Similar to BCR-ABL transformation of transformation in mammary epithelial cells. SIRT1 hematopoietic stem cells, SIRT1 expression change is essential for oncogenic signaling of in AML cells is likely a result of cellular response to estrogen/estrogen receptor α (ERα) in breast cancer. oncogenic stress. However, protein regulation of SIRT1 inactivation suppresses estrogen/ERα- SIRT1 appears more important in the AML setting. induced cell growth and tumor development, and SIRT1 protein is stabilized by USP22, a induces apoptosis. SIRT1 is found to be significantly deubiquitinase that is induced by c-MYC in FLT- up-regulated in the invasive ductal carcinoma, and ITD AML cells (Li et al., 2014). In addition, SIRT1 positively regulates the expression of aromatase, an activity is further regulated by ATM-DBC1 in a enzyme responsible for a key step in the biosynthesis FLT-ITD dependent manner (Sasca et al., 2014). of estrogen in breast cancer. However, in HMLER Inhibition of SIRT1 sensitizes FLT-ITD AML breast cancer cells, SIRT1 was found to suppress stem/progenitor cells to tyrosine kinase inhibitor EMT, and reduced SIRT1 expression increases treatment, and may help improve management of metastasis of these cells in nude mice (reviewed in this category of AML. Yuan et al., 2013). Lymphoma Prostate cancer In large B-cell lymphoma patients, positive SIRT1 is significantly overexpressed in primary expression of SIRT1 protein was seen in 74% of human prostate cancer tissues and cell lines. SIRT1 patients, and significantly associated with shorter inhibition via nicotinamide, sirtinol, short hairpin overall survival. Inhibition of SIRT1/2 by Cambinol RNAs or mutation of the 25 amino acid C-terminal induces apoptosis in Burkitt lymphoma cells SIRT1 activator sequence, results in a significant (reviewed in Yuan et al., 2013). inhibition of prostate cancer cell growth, viability Prognosis and chemoresistance. SIRT1 is highly expressed in Large B-cell lymphoma with SIRT1 upregulation advanced prostate cancer tissues and promotes showed poor prognosis. prostate cancer cell invasion, migration and metastasis through MMP2, EMT inducing Lung cancer transcription factor ZEB1, and cortactin. Distinct status of p53 acetylation/deacetylation and Concomitant with SIRT1 activation, NAMPT is HIC1 alteration mechanism result from different over-expressed in prostate cancer, likely enabling SIRT1-DBC1 (deleted in breast cancer 1) control supply of NAD+ for SIRT1 functions. In the and epigenetic alteration in lung squamous cell transgenic mouse model, SIRT1 expression carcinoma and lung adenocarcinoma. The lung promotes murine prostate carcinogenesis initiated by squamous cell carcinoma patients with low p53 Pten-deficiency (reviewed in Yuan et al., 2013). acetylation and SIRT1 expression mostly showed

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SIRT1 (sirtuin (silent mating type information regulation 2 Chen WY homolog) 1 (S. cerevisiae))

Liver cancer Twist and MBD1 thus suppressing E-cadherin transcription activity. However, one study showed SIRT1 expression is significantly elevated in that SIRT1 inhibits proliferation of pancreatic cancer hepatocellular carcinoma (HCC) tissues, and the cells expressing oncogenic pancreatic expression levels correlate with tumor grades and adenocarcinoma up-regulated factor (PAUF), by predict poor prognosis. SIRT1 expression also suppression of β-catenin and cyclin-D1 (reviewed in positively correlates with c-MYC levels in HCC. Yuan et al., 2013). SIRT1 and c-MYC regulate each other via a positive feedback loop and act synergistically to promote cell Thyroid cancer proliferation of both mouse and human liver tumor SIRT1 is overexpressed in human thyroid cancers cells. SIRT1 promotes tumorigenesis and and it is positively correlated with c-MYC protein chemoresistance in HCC, and inhibition of SIRT1 levels. Transgenic SIRT1 expression promotes suppresses the proliferation of HCC cells in vitro or murine thyroid carcinogenesis initiated by Pten- in vivo via the induction of cellular senescence or deficiency. SIRT1 increases c-MYC transcription apoptosis. Accordingly, expression of miRNA-34a and stabilizes c-MYC protein in thyroid cancers is reduced in HCC, and the reduced expression of from SIRT1 transgenic mice or cultured thyroid miRNA-34a is associated with worse outcome of cancer cells (reviewed in Yuan et al., 2013). HCC patients. Treatment of established HCC xenograft with miR-34a-expressing adenovirus in a Colon cancer mouse model results in complete tumor regression Highly-expressed c-MYC correlates with increased without recurrence (reviewed in Yuan et al., 2013). SIRT1 protein level in colorectal cancer. Gastric cancer In 121 colorectal serrated lesions, the higher expression of c-MYC and SIRT1 protein is strongly SIRT1 protein expression in gastric cardiac associated with higher grades of malignancy. In carcinoma is significantly higher than that in normal another study with a total of 485 colorectal cancer gastric tissues and is associated with lymphatic patients, SIRT1 overexpression was detected in 180 metastasis, TNM [the extent of tumor (T), the extent (37%) tumors. of spread to lymph nodes (N), and the presence of SIRT1 expression is associated with microsatellite distant metastasis (M)] stage, survival rate and mean instability and CpG island methylator phenotype, survival time. In another study, positive expression although not patient prognosis. Reduced expression of SIRT1 was seen in 73% of gastric cancer patients. of miR-34a, a negative regulator of SIRT1 mRNA, SIRT1 expression is also significantly associated is observed in drug-resistant DLD-1 colon cancer with shorter overall survival and relapse-free cells, and introduction of miR-34a induces apoptosis survival. SIRT1 is required for activating by downregulating SIRT1. However, one study transcription factor 4 (ATF4)-induced multidrug showed that in colorectal adenocarcinoma, SIRT1 resistance in gastric cancer cells. ATF4 facilitates overexpression was observed in approximately 25% multidrug resistance in gastric cancer cells through of stage I/II/III tumors but rarely in advanced stage direct binding to SIRT1 promoter and activating IV tumors. Approximately 30% of carcinomas SIRT1 expression. Significantly, inhibition of showed lower SIRT1 expression than normal tissues. SIRT1 by RNAi or a specific inhibitor (EX-527) In another clinical observation, SIRT1 protein sensitizes gastric cancer cells to therapeutic expression is gradually decreased during the normal- treatment (reviewed in Yuan et al., 2013). adenoma-adenocarcinoma-metastasis stage in Pancreatic cancer colorectal cancers, with the positivity 100%, 80.8%, 41.9%, and 35.7%, respectively (reviewed in Yuan SIRT1 overexpression was observed in pancreatic et al., 2013). cancer tissues at both mRNA and protein levels. Increased SIRT1 positivity is associated with Ovarian cancer patients' age (over 60 years old), larger tumor size Expression of SIRT1 protein is significantly (larger than 4 cm), and higher TNM stage. SIRT1 increased in malignant ovarian epithelial tumors knockdown induces apoptosis and senescence, compared to that in benign and borderline epithelial inhibits invasion and enhances chemosensitivity in tumors. High proportion (86%) of serous ovarian pancreatic cancer cells. In pancreatic cancer, SIRT1 cancer expressed SIRT1. Interestingly, increased regulates ADM (acinar-to-ductal metaplasia) and SIRT1 protein in serous ovarian epithelial cancer supports cancer cell viability through deacetylating was associated with increased overall survival (Jang pancreatic transcription factor-1a and β-catenin. et al., 2009). Inhibition of SIRT1 is effective in suppression of ADM and in reducing cell viability in established Brain tumor pancreatic ductal adenocarcinoma. In addition, In glioblastoma, SIRT1 is highly expressed in tumor- SIRT1 promotes EMT ability as well as invasion of derived CD133+ progenitor cells compared to pancreatic cancer cell by forming a complex with CD133-cells and knockdown of SIRT1 expression

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enhances the radio-sensitivity and radiation-induced Contributing to this effect, SIRT1, coordinated by apoptosis in the CD133+ cells. SIRT1 is also PPARα, suppresses genes involved in mitochondrial frequently expressed in human medulloblastomas functions. In a separate study, cardiac hypertrophy is relative to surrounding noncancerous cerebellar reduced in Sirt1 deficient mice in response to tissues and its expression is correlated with the physical exercise and angiotensin II due to impaired formation and prognosis of medulloblastomas. Akt activation as a result of its acetylation SIRT1 and N-MYC form a positive feedback (Sundaresan et al., 2011). regulation loop during the tumorigenesis of neuroblastoma, and preventive treatment with the Breakpoints SIRT1 inhibitor Cambinol significantly reduces tumorigenesis in N-MYC transgenic mice (reviewed No breakpoints are associated with SIRT1. in Yuan et al., 2013). 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Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB.. mouse and human prostate cancer. Cancer Res. 2007 Jul Tumor suppressor HIC1 directly regulates SIRT1 to 15;67(14):6612-8. modulate p53-dependent DNA-damage responses. Cell. 2005 Nov 4;123(3):437-48. Imai S, Armstrong CM, Kaeberlein M, Guarente L.. Transcriptional silencing and longevity protein Sir2 is an Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, NAD-dependent histone deacetylase. Nature. 2000 Feb Miyagishi M, Nakajima T, Fukamizu A.. Silent information 17;403(6771):795-800. regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. Inoue T, Hiratsuka M, Osaki M, Yamada H, Kishimoto I, 2004 Jul 6;101(27):10042-7. Epub 2004 Jun 25. Yamaguchi S, Nakano S, Katoh M, Ito H, Oshimura M.. 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Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D, Stark J, Zschoernig B, Mahlknecht U.. SIRTUIN 1: regulating the Bhatia R, Chen WY.. Activation of stress response gene regulator. Biochem Biophys Res Commun. 2008 Nov SIRT1 by BCR-ABL promotes leukemogenesis. Blood 14;376(2):251-5. Epub 2008 Sep 5. 2012; 119: 1904-1914. van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W.. Medema RH, Burgering BM.. FOXO4 is acetylated upon Negative regulation of the deacetylase SIRT1 by DBC1. peroxide stress and deacetylated by the longevity protein Nature. 2008 Jan 31;451(7178):587-90. hSir2(SIRT1). J Biol Chem. 2004 Jul 9;279(28):28873-9. Epub 2004 May 4. Zhou X, Fan LX, Sweeney WE Jr, Denu JM, Avner ED, Li X.. Sirtuin 1 inhibition delays cyst formation in autosomal- This article should be referenced as such: dominant polycystic kidney disease. J Clin Invest. 2013 Jul Chen WY. SIRT1 (sirtuin (silent mating type information 1;123(7):3084-98. regulation 2 homolog) 1 (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1):26-35.

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS

Gene Section Review

SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1) Hannu Koistinen, Outi Itkonen, Ulf-Hakan Stenman Department of Clinical Chemistry, University of Helsinki (HK,OI, UHS), Laboratory Division HUSLAB, Helsinki University Central Hospital (OI), Helsinki, Finland [email protected]; [email protected]; [email protected]

Published in Atlas Database: December 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/SPINK1ID42375ch5q32.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62508/12-2014-SPINK1ID42375ch5q32.pdf DOI: 10.4267/2042/62503 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract single Kazal type serine protease inhibitor domain. Review on SPINK1, with data on DNA, on the Description protein encoded, and where the gene is implicated. Maps to chromosomal region 5q32: 147,204,131- Keywords: SPINK1 147,211,349 on reverse (minus) strand (7,219 bp). Gene consists of 4 exons (Horii et al., 1987). Region Identity between 3.8 and 4.0 kb upstream from the translation Other names: PSTI, TATI, SPIK initiation codon contains an interleukin-6 responsive HGNC (Hugo): SPINK1 element (IL6RE) and two potential AP-1 binding sites (Ohmachi et al., 1993; Yasuda et al., 1993). Location: 5q32 CAATCAATAAC sequence (-149 to -139) is a Location (base pair): location 147,204,131- potential pancreas-specific regulatory element 147,211,349 reverse (minus) strand (Human genome (Yasuda et al., 1998). assembly GRCh37.p12, Ensembl release 73 - This region in the SPINK1 promoter has been September 2013). subsequently identified as a binding site for hepatic Local order: Several other SPINK genes have been nuclear factor (HNF1) (Boulling et al., 2011). A mapped in the same chromosomal region. From putative binding site for pancreas-specific centromere to telomere (Ensembl genome browser transcription factor 1 (PTF1) has also been identified 73): DPYSL3 (reverse strand) - JAKMIP-2 (reverse) within the SPINK1 promoter (Boulling et al., 2011). - SPINK1 (reverse) - SCGB3A2 (forward) - C5orf46 Transcription (reverse) - SPINK5 (forward) - SPINK14 (forward) - SPINK6 (forward) - SPINK13 (forward) - SPINK7 SPINK1 mRNA (NCBI Reference Sequence: (forward). NM_003122.3) has 454 bp (Yamamoto et al., 1985). Expression, at least in some cell lines, is regulated by DNA/RNA IL-6 (Yasuda et al., 1993). Three differentially spliced mRNA forms have been described (Ensembl, Some other SPINK family members are similar in release 73). Two of these have been classified as size, are encoded for by 4 exons and contain a protein encoding.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 36 SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1) Koistinen H, et al.

Chromosomal location and gene structure of SPINK1 gene (extracted from Ensembl database release 73). Some putative regulatory elements are also shown (Ohmachi et al., 1993; Yasuda et al., 1993; Yasuda et al., 1998; Boulling et al., 2011). After the translation-initiating codon (ATG) exons of the major transcript are shown in black. One splicing variant also contains parts outside of these exons. *, CAATCAATAAC, potential pancreas-specific regulatory element; IL6RE, interleukin-6 responsive element; AP-1, activator protein-1 element; HNF1, hepatic nuclear factor; PTF1, pancreas-specific transcription factor 1.

et al 1967). SPINK1 is mainly expressed in the Protein pancreas, but to a lesser extent also in several other In the literature, SPINK1 is widely referred to as tissues, e.g., in the gastrointestinal tract, including TATI (tumor-associated trypsin inhibitor) and PSTI the liver, duodenum, small intestine, gall bladder, (pancreatic secretory trypsin inhibitor). colon, appendix, stomach, and in the genitourinary tract, e.g., prostate and urothelium (Paju and Description Stenman, 2006; Itkonen and Stenman, 2014). SPINK1(NCBI Reference Sequence: NP_003113.2 ; Expression has been found also in kidney, lung, UniProtKB/Swiss-Prot: ISK1_HUMAN, P00995; breast, brain, spleen and ovary. SPINK1 is often PDB: 1cgj; 1cgi; 1hpt) is a 6242 Da secreted protein, strongly expressed in ETS-rearrangement-negative containing 79 amino acids. Mature SPINK1 contains prostate cancers (Tomlins et al., 2008). A putative 56 amino acids and three disulfide bonds. It has a bipartite pancreas-specific transcription factor 1 Kazal-type serine protease inhibitor domain and (PTF1)-binding sequence has been identified belongs to the SPINK (serine peptidase inhibitor, (Boulling et al., 2011) in the SPINK1 gene. Outside Kazal-type) family. SPINK1 has been reported to the pancreas, SPINK1 has been considered an inhibit several proteases, including human trypsin-1 inflammatory pleiotropic cytokine, which is and -2 (cationic and anionic trypsins), acrosin and regulated by immune and inflammatory responses. granzyme A (Pubols et al., 1974; Huhtala et al., In some cell lines, the expression is regulated by IL- 1984; Turpeinen et al., 1988; Tsuzuki et al., 2003). 6 (Yasuda et al., 1993). In cultured prostate cancer cells, SPINK1 expression has been shown to be Expression regulated by androgens (Paju et al., 2007). In mouse, SPINK1 was first characterized in bovine pancreas the synthesis of Spink3 (mouse orthologue of (Kazal et al. 1948) and pancreatic juice (Greene SPINK1) is dependent upon testicular androgens in 1966), and later from human pancreatic juice (Fritz the sex accessory tissues, but not in the pancreas (Mills et al., 1987).

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SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1) Koistinen H, et al.

Ribbon diagram of recombinant SPINK1 variant (RSCB Protein Data Bank code 1HPT (Hecht et al., 1991)). Protein Workshop program (Moreland et al., 2005) with the surfaces feature (Xu and Zhang, 2009) was used for visualization. Cysteines, forming three disulfide bonds, are shown as balls and sticks. The atoms of asparagine-34 (N34) residue, mutation in which is associated with chronic pancreatitis, and reactive site lysine (K41) are shown as balls without side-chains. Alpha-helix is shown in blue and beta-sheets in yellow.

Very high serum and urine concentrations occur in be ruled out. It has been suggested that SPINK1 patients with pancreatitis (Ogawa, 1988). Serum mediates tumor growth, differentiation, and levels of SPINK1 may also be elevated in several angiogenesis via stimulation of the EGF-receptor or cancers, including prostate cancer, ovarian cancer by suppression of serine-protease- or caspase- and benign cysts, renal-cell carcinoma, bladder dependent apoptosis (Ateeq et al., 2011; Gouyer et carcinoma, and colorectal cancer (Paju and Stenman, al., 2008). There is evidence that SPINK1 plays a 2006; Itkonen and Stenman, 2014). Severe role in tissue differentiation (Ohmuraya et al., 2005) inflammation, tissue destruction and major trauma and repair (Marchbank et al., 1996), reproduction leads to an acute phase reaction causing increased (Huhtala, 1984) and regulation of apoptosis (Lu et circulating SPINK1 concentrations. al., 2011). Over-expression of SPINK1 in cancer Localisation could block cancer cell apoptosis resulting in suppression of the immune response and escape of SPINK1 is highly expressed in the pancreas (Kazal cancer cells from immune surveillance (Lamontagne et al., 1948). It has been localized to the zymogen et al., 2010). granules of pancreatic acinar cells, where it protects the pancreas from premature activation of Homology trypsinogens. SPINK1 is secreted into the pancreatic fluid along with digestive enzymes. Many cancers SPINK1 contains a Kazal-type serine protease secrete SPINK1 causing elevated serum inhibitor domain, found in many other proteins and concentrations (Paju and Stenman, 2006; Itkonen especially in members of SPINK family. Apart from and Stenman, 2014). this domain, SPINKs do not share high sequence similarity. Apart from SPINK5, SPINKs are of Function similar size and most genes contain the same number SPINK1 is a protease inhibitor and has been reported of exons. Some of the family members lack to inhibit human trypsin-1 and -2 (cationic and functional annotatation. A functional SPINK1 anionic trypsins), but not trypsin-3 orthologue, Spink3 (NP_033284.1), has been found (mesotrypsin)(Sahin-Tóth, 2005). SPINK1 also in mouse. The rat has two orthologues, Spink1 inhibits granzyme A (Tsuzuki et al., 2003), plasmin, (NP_690919.1) and Spink3 (NP_036806.1) urokinase, tissue plasminogen activator (Turpeinen (HomoloGene, Release 67). Orhologues have been et al., 1988) and acrosin (Huhtala et al., 1984). found also in common chimpanzee SPINK1 has been reported to exert growth (XP_001160275.1), rhesus macaque stimulation of cultured cells (Niinobu et al., 1990) (XP_001102888.1), grey wolf (XP_850557.1) and and to activate the EGF-receptor (Ozaki 2009; Ateeq cattle (NP_001020519.1). Sequence similarity et al., 2011). However, growth stimulation by between SPINK1 and EGF has been reported (Hunt mechanisms other than via EGF receptor cannot et al., 1974).

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SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1) Koistinen H, et al.

Relative mRNA expression levels of SPINK1 in different tissues. The data is from the IST4 database containing gene expression data in ~10 000 samples (http://ist.medisapiens.com/) (Kilpinen et al., 2008).

Mutations Gaber A 2010). Disease NCBI SNP database HCC is the fifth most frequently diagnosed cancer (http://www.ncbi.nlm.nih.gov/SNP/) reports 631 and the second most common cause of cancer death SPINK1 SNPs (Homo sapiens, December 29., worldwide in men (Jemal et al., 2011). 2014). In females the rate is about half of that of men. Half At least 15 missense mutations have been described of the cases occur in China and liver cancer is less in the mature polypeptide and three in the signal common in Western countries. peptide (Chen and Férec, 2009). Association of HCC is the most common type of liver cancer. It may mutations with familial pancreatitis and other be caused by viral infections, like hepatitis B and C, diseases has been described (see below). or cirrhosis. Most tumors in the liver are not primary liver Implicated in cancers, but metastases of other cancers. Liver cancer Prognosis Up-regulation of SPINK1 in tissue has been shown Plasma SPINK1 concentration is elevated in HCC to distinguish hepatocellular carcinoma (HCC) from patients and it correlates with tumor size (Ohmachi benign liver disease and normal liver (Marshall A et al., 1993). 2013). Elevated serum concentrations of SPINK1 Overexpression of SPINK1 mRNA is a stage- are associated with adverse prognosis of independent prognostic factor and a predictor of hepatocellular cancer (Lyytinen et al., 2013). Serum early tumor recurrence in HCC (Lee et al., 2007) and SPINK1 is also a useful marker for distinguishing in cholangiocarcinoma (Tonouchi et al., 2006). between patients with or without liver metastasis of Serum SPINK1 has been shown to predict adverse colorectal and breast cancer (Taccone W 1991; prognosis in HCC (Lyytinen I 2013).

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Prostate cancer High expression of SPINK1 has been associated with adverse prognosis and liver metastases (Gaber SPINK1 is often overexpressed in ETS- et al., 2010; Gaber at al., 2009) rearrangement-negative prostate cancers (Tomlins et al., 2008). Bladder cancer Disease Urinary SPINK1 is a useful marker for high-grade Prostate cancer is a considerable health care problem bladder cancer (Kelloniemi et al., 2003; Shariat et with 342 000 new cases and about 71 000 deaths al., 2005; Gkialas et al., 2008, Patschan et al., 2012). annually in the EU countries, it is the most frequently Disease diagnosed cancer in men and the third most common Bladder cancer is more common in males than in cause of cancer death (data from GLOBOCAN females and there is great geographic variation in 2008). incidence (Jemal et al., 2011). The highest incidence Prostate cancer can be diagnosed by screening at an rates are found in Europe, North America and early stage, when most patients can be cured by Northern Africa. Smoking, occupational exposures radical prostatectomy or radiotherapy. and chronic infection with Schistosoma hematobium However, about one third of the tumors relapse. are major risk factors. Most bladder cancers Most of these cases can be treated by androgen originate from the epithelial lining of the urinary ablation, but within 3 - 5 years the tumor usually bladder. Transitional cell carcinoma is the most becomes castration-resistant. common type of bladder cancer. Prognosis Prognosis High SPINK1 expression has been associated with Serum SPINK1 has been shown to be an independent adverse prognosis in prostate cancer in some prognostic factor for bladder cancer (Kelloniemi et (Tomlins et al., 2008; Paju et al., 2007), but not all al., 2003) and for prediction of the response to studies (Leinonen et al., 2013; Grupp et al., 2013; chemotherapy (Pectasides et al., 1996). SPINK1 Lippolis et al., 2013). expression is stronger in noninvasive than in The differences may be related to the type of invasive tumors and decreases with advancing tumor treatment, e.g., surgery or androgen ablation stage (Hotakainen et al., 2006; Patschan et al., 2012). (Leinonen et al., 2013). Ovarian cancer Breast cancer The association of SPINK1 (TATI) and cancer was Disease first observed in a patients with ovarian cancer Breast cancer is the most common cancer among (Stenman et al. 1982) women worldwide, accounting for 23% of all cases Disease (Jemal et al., 2011). Although the prognosis has Ovarian cancer is the leading cause of death from improved due to early diagnosis and therapies, breast gynecologic cancer. Most cases are diagnosed at cancer remains a major cause of death among advanced stages and, thus have relatively poor women (14% of the cancer deaths). Most neoplasms prognosis. The vast majority of ovarian cancers are of the breast originate from the ductal epithelium, epithelial. Cancer of the fallopian tubes is similar to while a minority originates from the lobular ovarian cancer. epithelium. A family history of breast cancer is Prognosis associated with a 2-3-fold higher risk of the disease. Increased SPINK1 expression is associated with Prognosis adverse outcome in epithelial ovarian cancer SPINK1 expression is associated with poor (Huhtala et al., 1983; Paju et al., 2004). Elevated prognosis in estrogen receptor-positive breast cancer serum SPINK1 is an independent prognostic factor (Soon et al., 2011). (Venesmaa et al., 1994; Venesmaa et al., 1998; Paju Colorectal cancer et al., 2004). Elevated serum SPINK1 has been observed in some Gastric cancer patients with colorectal cancer. (Solakidi et al., 2004; SPINK1 is detected in the normal gastric mucosa. Pasanen et al., 1995) Disease Disease Gastric cancers account for 8% of all cancer cases Colorectal cancer is the third most commonly and 10% of the deaths (Jamal et al., 2011). Over 70% diagnosed cancer in males and the second in females of new cases and deaths occur in developing (Jemal et al., 2011). It originates from colon or countries and rates are higher in males than in rectum, but, based on genetic studies, these are the females. same tumor. When locally confined, colorectal Helicobacter pylori infection is the main risk factor, cancer is often curable by surgery. but smoking also increases the risk of gastric cancer. Prognosis Prognosis

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SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1) Koistinen H, et al.

The prognosis of gastric cancer is generally poor and Elevated serum and urine concentrations are caused metastases develop frequently. High tissue by pancreatitis, i.e., inflammation of pancreas. Some expression of SPINK1 is a sign of favorable outcome hereditary mutations of the SPINK1 gene, increase and loss of SPINK1 immunoreactivity in tumor the risk of pancreatitis. These cases are characterized tissue is associated with adverse prognosis (Wiksten by recurrent episodes of pancreatitis starting at et al., 2008). Serum SPINK1 is elevated in 50% of young age. These episodes often lead to tissue patients with gastric cancer (Solakidi et al., 2004). damage and loss of pancreatic function, including insulin production. This also increases the risk of Renal cell carcinoma pancreatic cancer. Disease Prognosis Renal cancer comprises five distinct histological The life expectancy of the pancreatitis patients is types. Within each type, there is considerable close to normal. However, patients have an increased variation in clinical course and survival. Presently, risk of developing pancreatic cancer (Weiss, 2014). many tumors are detected at an early stage by sonography performed for various reasons. Tropical calcific pancreatitis Prognosis SPINK1 mutations, especially the N34S mutation Prognosis of metastatatic and advanced disease is has been reported to associate with tropical calcific poor, but surgical treatment of localized disease is pancreatitis (Bhatia et al., 2002). often curative. There are no specific serum markers Disease for RCC. Elevated serum SPINK1 has been shown Tropical calcific pancreatitis (OMIM: 608189) is a to be an independent prognostic factor in renal cell special type of chronic pancreatitis that occurs only carcinoma (Meria et al., 1995; Paju et al., 2001). in tropical countries. Pancreatitis, hereditary (Online Prognosis Mendelian Inheritance in Man Patients usually present at young age with recurrent abdominal pain and nutritional deficiencies. The (OMIM): 167800) disease often leads to beta-cell deficiency and SPINK1 polymorphisms are found more frequently diabetes requiring insulin before the age of 30. in patients with hereditary and idiopatic chronic Prognosis is dismal and many patients succumb to pancreatitis (23%) than in healthy controls (0.4%) complications caused by malnutrition. (Witt et al., 2000; Chen and Férec, 2009). Several mutations of SPINK1 cause loss-of-function by References splicing, frameshift, deletion or initiation codon mutation. Some missense mutations have been Ateeq B, Tomlins SA, Laxman B, Asangani IA, Cao Q, Cao X, Li Y, Wang X, Feng FY, Pienta KJ, Varambally S, suggested to affect polypeptide folding, leading to Chinnaiyan AM. Therapeutic targeting of SPINK1-positive intracellular retention and degradation of the prostate cancer. Sci Transl Med. 2011 Mar 2;3(72):72ra17 mutated polypeptide (Boulling et al., 2012). These Bhatia E, Choudhuri G, Sikora SS, Landt O, Kage A, Becker mutations are suggested to cause pancreatitis M, Witt H. Tropical calcific pancreatitis: strong association because of SPINK1 deficiency. The most common with SPINK1 trypsin inhibitor mutations. Gastroenterology. mutation worldwide is a 101A>G transition within 2002 Oct;123(4):1020-5 exon 3 resulting in the substitution of Asp by Ser at Boulling A, Keiles S, Masson E, Chen JM, Férec C. codon 34 (N34S) (Witt et al., 2000). The frequency Functional analysis of eight missense mutations in the of the N34S mutation in pancreatitis patients is 9-29 SPINK1 gene. Pancreas. 2012 Mar;41(2):329-30 % as compared to 0.5-2.5 % in the general Chen JM, Férec C. Chronic pancreatitis: genetics and population. In functional studies no differences in pathogenesis. Annu Rev Genomics Hum Genet. SPINK1 expression, trypsin inhibitory activity or 2009;10:63-87 binding to trypsin have been found between wild- Fritz H, Hüller I, Wiedemann M, Werle E. [On protease type and N34S-SPINK1. The mutations D50E, inhibitors, V. On the chemistry and physiology of the specific trypsin inhibitors from the ox, dog, pig and human Y54H and R67C result in marked reduction or pancreas]. Hoppe Seylers Z Physiol Chem. 1967 complete loss of SPINK1 secretion, and are Apr;348(4):405-18 classified as disease-causing mutations although Gaber A, Johansson M, Stenman UH, Hotakainen K, trypsin inhibitory activity of the mutated proteins Pontén F, Glimelius B, Bjartell A, Jirström K, Birgisson H. was retained (Király et al., 2007). The P55S High expression of tumour-associated trypsin inhibitor mutation of SPINK1 is found in healthy controls as correlates with liver metastasis and poor prognosis in well as in pancreatitis patients with an incidence of colorectal cancer. Br J Cancer. 2009 May 19;100(10):1540- 8 0.5-1.3 % and 0.9-7 %, respectively (Witt et al., 2000; Pfutzer et al., 2000). The role of this mutation Gaber A, Nodin B, Hotakainen K, Nilsson E, Stenman UH, Bjartell A, Birgisson H, Jirström K. Increased serum levels in pancreatitis remains unclear. of tumour-associated trypsin inhibitor independently predict Disease

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SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1) Koistinen H, et al.

a poor prognosis in colorectal cancer patients. BMC Cancer. intracellular retention and degradation. Gut. 2007 2010 Sep 17;10:498 Oct;56(10):1433-8 Gkialas I, Papadopoulos G, Iordanidou L, Stathouros G, Kiraly O, Boulling A, Witt H, Le Maréchal C, Chen JM, Tzavara C, Gregorakis A, Lykourinas M. Evaluation of urine Rosendahl J, Battaggia C, Wartmann T, Sahin-Toth M, tumor-associated trypsin inhibitor, CYFRA 21-1, and urinary Férec C. Signal peptide variants that impair secretion of bladder cancer antigen for detection of high-grade bladder pancreatic secretory trypsin inhibitor (SPINK1) cause carcinoma. Urology. 2008 Nov;72(5):1159-63 autosomal dominant hereditary pancreatitis Hum Mutat 2007 May;28(5):469-76 Greene LJ, Rigbi M, Fackre DS. Trypsin inhibitor from bovine pancreatic juice. J Biol Chem. 1966 Dec Kume K, Masamune A, Ariga H, Hayashi S, Takikawa T, 10;241(23):5610-8 Miura S, Suzuki N, Kikuta K, Hamada S, Hirota M, Kanno A, Shimosegawa T. Do genetic variants in the SPINK1 Grupp K, Diebel F, Sirma H, Simon R, Breitmeyer K, Steurer gene affect the level of serum PSTI? J Gastroenterol 2012 S, Hube-Magg C, Prien K, Pham T, Weigand P, Michl U, Nov;47(11):1267-74 doi: 10 Heinzer H, Kluth M, Minner S, Tsourlakis MC, Izbicki JR, Sauter G, Schlomm T, Wilczak W. SPINK1 expression is Lamontagne J, Pinkerton M, Block TM, Lu X. Hepatitis B tightly linked to 6q15- and 5q21-deleted ERG-fusion and hepatitis C virus replication upregulates serine protease negative prostate cancers but unrelated to PSA recurrence. inhibitor Kazal, resulting in cellular resistance to serine Prostate. 2013 Nov;73(15):1690-8 protease-dependent apoptosis J Virol 2010 Jan;84(2):907- 17 Hecht HJ, Szardenings M, Collins J, Schomburg D. Three- dimensional structure of the complexes between bovine Lee YC, Pan HW, Peng SY, Lai PL, Kuo WS, Ou YH, Hsu chymotrypsinogen A and two recombinant variants of HC. Overexpression of tumour-associated trypsin inhibitor human pancreatic secretory trypsin inhibitor (Kazal-type). J (TATI) enhances tumour growth and is associated with Mol Biol. 1991 Aug 5;220(3):711-22 portal vein invasion, early recurrence and a stage- independent prognostic factor of hepatocellular carcinoma Horii A, Kobayashi T, Tomita N, Yamamoto T, et al.. Primary Eur J Cancer 2007 Mar;43(4):736-44 structure of human pancreatic secretory trypsin inhibitor (PSTI) gene. Biochem Biophys Res Commun. 1987 Dec Leinonen KA, Saramäki OR, Furusato B, Kimura T, 16;149(2):635-41 Takahashi H, Egawa S, Suzuki H, Keiger K, Ho Hahm S, Isaacs WB, Tolonen TT, Stenman UH, Tammela TL, Nykter Hotakainen K, Bjartell A, Sankila A, Järvinen R, Paju A, M, Bova GS, Visakorpi T. Loss of PTEN is associated with Rintala E, Haglund C, Stenman UH. Differential expression aggressive behavior in ERG-positive prostate cancer of trypsinogen and tumor-associated trypsin inhibitor (TATI) Cancer Epidemiol Biomarkers Prev 2013 Dec;22(12):2333- in bladder cancer. Int J Oncol. 2006 Jan;28(1):95-101 44 Huhtala ML. Demonstration of a new acrosin inhibitor in Lippolis G, Edsjö A, Stenman UH, Bjartell A. A high-density human seminal plasma. Hoppe Seylers Z Physiol Chem. tissue microarray from patients with clinically localized 1984 Jul;365(7):819-25 prostate cancer reveals ERG and TATI exclusivity in tumor Huhtala ML, Kahanpää K, Seppälä M, Halila H, Stenman cells Prostate Cancer Prostatic Dis 2013 Jun;16(2):145-50 UH. Excretion of a tumor-associated trypsin inhibitor (TATI) Lu F, Lamontagne J, Sun A, Pinkerton M, Block T, Lu X. in urine of patients with gynecological malignancy. Int J Role of the inflammatory protein serine protease inhibitor Cancer. 1983 Jun 15;31(6):711-4 Kazal in preventing cytolytic granule granzyme A-mediated Hunt LT, Barker WC, Dayhoff MO. Epidermal growth factor: apoptosis Immunology 2011 Dec;134(4):398-408 internal duplication and probable relationship to pancreatic Lyytinen I, Lempinen M, Nordin A, Mäkisalo H, Stenman secretory trypsin inhibitor. Biochem Biophys Res Commun. UH, Isoniemi H. Prognostic significance of tumor- 1974 Oct 8;60(3):1020-8 associated trypsin inhibitor (TATI) and human chorionic Itkonen O, Stenman UH. TATI as a biomarker. Clin Chim gonadotropin-beta (hCGbeta) in patients with hepatocellular Acta. 2014 Apr 20;431:260-9 carcinoma Scand J Gastroenterol 2013 Sep;48(9):1066- 73 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011 Mar- Marchbank T, Chinery R, Hanby AM, Poulsom R, Elia G, Apr;61(2):69-90 Playford RJ. Distribution and expression of pancreatic secretory trypsin inhibitor and its possible role in epithelial KAZAL LA, SPICER DS, BRAHINSKY RA. Isolation of a restitution Am J Pathol 1996 Mar;148(3):715-22 crystalline trypsin inhibitor-anticoagulant protein from pancreas. J Am Chem Soc. 1948 Sep;70(9):3034-40 Marshall A, Lukk M, Kutter C, Davies S, Alexander G, Odom DT. Global gene expression profiling reveals SPINK1 as a Kelloniemi E, Rintala E, Finne P, Stenman UH. Tumor- potential hepatocellular carcinoma marker PLoS One associated trypsin inhibitor as a prognostic factor during 2013;8(3):e59459 follow-up of bladder cancer. Urology. 2003 Aug;62(2):249- 53 Meria P, Toubert ME, Cussenot O, Bassi S, Janssen T, Desgrandchamps F, Cortesse A, Schlageter MH, Teillac P, Kilpinen S, Autio R, Ojala K, Iljin K, Bucher E, Sara H, Pisto Le Duc A. Tumour-associated trypsin inhibitor and renal cell T, Saarela M, Skotheim RI, Björkman M, Mpindi JP, Haapa- carcinoma Eur Urol 1995;27(3):223-6 Paananen S, Vainio P, Edgren H, Wolf M, Astola J, Mills JS, Needham M, Parker MG. A secretory protease Nees M, Hautaniemi S, Kallioniemi O. Systematic inhibitor requires androgens for its expression in male sex bioinformatic analysis of expression levels of 17,330 human accessory tissues but is expressed constitutively in genes across 9,783 samples from 175 types of healthy and pancreas EMBO J 1987 Dec 1;6(12):3711-7 pathological tissues. Genome Biol. 2008;9(9):R139 Moreland JL, Gramada A, Buzko OV, Zhang Q, Bourne PE. Király O, Wartmann T, Sahin-Tóth M. Missense mutations The Molecular Biology Toolkit (MBT): a modular platform for in pancreatic secretory trypsin inhibitor (SPINK1) cause developing molecular visualization applications BMC Bioinformatics 2005 Feb 6;6:21

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Yasuda T, Ogawa M, Murata A, Ohmachi Y, Yasuda T, Mori This article should be referenced as such: T, Matsubara K. Identification of the IL-6-responsive element in an acute-phase-responsive human pancreatic Koistinen H, Itkonen O, Stenman UH. SPINK1 (Serine secretory trypsin inhibitor-encoding gene Gene 1993 Sep Peptidase Inhibitor, Kazal Type 1). Atlas Genet 15;131(2):275-80 Cytogenet Oncol Haematol. 2016; 20(1):36-44. Yasuda T, Yasuda T, Ohmachi Y, Katsuki M, Yokoyama M, Murata A, Monden M, Matsubara K. Identification of novel

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Leukaemia Section Short Communication t(6;11)(q21;q23) KMT2A/FOXO3 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Published in Atlas Database: January 2015 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0611q21q23ID1128.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62509/01-2015-t0611q21q23ID1128.pdf DOI: 10.4267/2042/62509 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

occured after Hodgkin disease, a pro-B ALL occured Abstract 2.5 years after treatment for a M3-AML with the Review on t(6;11)(q21;q23) KMT2A/FOXO3 in classical t(15;17), and the 2 other ALLs were also acute promyelocytic leukaemia, with data on clinics, therapy-induced leukemia cases. Also, another case, and the genes involved. a M5a occured after radiotherapy for carcinoma of the larynx. There was 6 male and 5 female patients, Clinics and pathology Median age was 40-45 years (range: ? (pediatric case) - 80). The 5 patients with proved Disease KMT2A/FOXO3 hybrid gene were: a boy and a girl, Acute myeloid leukemia (AML), acute a F/15 yrs, M/22 yrs, and a M/40 yrs. lymphoblastic leukemia (ALL), and other Prognosis lyphoproliferative diseases. Scarce data (34months+ survival in one of the ALLs Epidemiology with proved KMT2A/FOXO3 hybrid gene). Eleven cases of t(6;11)(q21;q23) have been described so far: 5 cases of AML (2 M5a-AML, 1 Cytogenetics M2-AML, 2 AML not otherwise specified (NOS)), Cytogenetics morphological 3 cases of pediatric ALL, 1 case of acute undifferentiated leukemia (AUL), 1 case of The t(6;11)(q21;q23) is the sole abnormality in 5 of prolymphocytic leukemia, and 1 case of peripheral 9 cases, and in 2 of 3 cases with proved T-cell lymphoma (Heim et al., 1992; Hillion et al., KMT2A/FOXO3 hybrid gene. 1997; Bernard et al., 1998; Wong et al., 1999; Stark et al., 2004; Andersen et al., 2005; Helbig et al., Genes involved and 2006; Zuna et al., 2009; Meyer et al., 2013; Parkin et proteins al., 2013). However, the formation of a hybrid KMT2A/FOXO3 was ascertained only in 5 of these FOXO3 11 cases, namely in the M2-AML, in the AUL, and Location in the 3 pediatric ALLs (Hillion et al., 1997; Bernard et al., 1998; Zuna et al., 2009; Meyer et al., 2013). 6q21 The involvement of KMT2A was ascertained in Protein another case (an AML-NOS, Stark et al., 2004), 673 amino acids. FOXO3 has both a NLS (nuclear while other cases may have other gene localization signal, amino acids 249-251, 269-271) rearrangements instead. Five of the 5 cases with a and a NES (nuclear export signal, amino acids 386- proved KMT2A/FOXO3 hybrid gene were therapy- 396), possess a forkhead domain (DNA-binding related leukemias: the M2-AML occured 2 years domain, amino acids 148-257) and a transactivation after treatment for Hodgkin disease, the AUL also domain (amino acids 1251-673).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 45 t(6;11)(q21;q23) KMT2A/FOXO3 Huret JL

MLL/FOXO3 Fusion Protein

FOXO3 is a transcription factor which recognizes Wang et al., 2012; Menniti et al., 2014; Tseng et al., and binds to the DNA consensus sequence 2014; reviews in Greer and Brunet, 2008; Calnan [AG]TAAA[TC]A. and Brunet, 2008; Webb and Brunet, 2014). FOXO transcription factors are key targets of the KMT2A insulin PI3K-Akt signalling pathway. AKT-induced phosphorylation at Thr32, Ser253 and Ser315 results Location in the export of FOXO3 from the nucleus to the 11q23.3 cytoplasm. SGK1 (6q23.2) also downregulates Note FOXO3 through phosphorylation at Thr32, Ser253 KMT2A (HGNC official name!) is better known as and Ser315. YWHAB (14-3-3-beta, 20q13.12) and MLL. YWHAZ (14-3-3-zeta, 8q22.3) bind FOXO3, Protein decrease FOXO3 binding to DNA, and promote 3969 amino acids; Transcriptional regulatory factor. FOXO nuclear export. Lys242, Lys245 and Lys259 MLL is known to be associated with more than 30 of FOXO3 are acetylated by CREBBP (16p13.3) to proteins, including the core components of the decrease its DNA affinity IKBKB (8p11.21) induces SWI/SNF chromatin remodeling complex and the the phosphorylation of FOXO3 at Ser644 and transcription complex TFIID. MLL binds promotors induces proteasome dependent degradation of of HOX genes through acetylation and methylation FOXO3. SIRT1 (10q21.3), SIRT2 (19q13.2), and of histones. SIRT3 (11p15.5) contribute to FOXO3 MLL is a major regulator of hematopoesis and deacetylation, and promote FOXO3 poly- embryonic development, through regulation of HOX ubiquitination and degradation. Lysine residues genes expression regulation (HOXA9 in particular). K242, K259, K290 and K569 of FOXO3 are likely the sites for ubiquitination. Result of the chromosomal FOXO transcription factors induce apoptosis, promote cell cycle arrest at the transition G1/S, up- anomaly regulate genes involved in DNA repair, allow detoxification of reactive oxygen species; they are Hybrid gene also implicated in glucose metabolism and Note autophagy; FOXO3 induces expression of target A MLL split was detected in one case (Stark et al., genes involved in stress resistance. FOXO 2004), and a hybrid MLL/FOXO3 in 5 additional transcription factors may regulate lifespan and cases (Hillion et al., 1997; Bernard et al., 1998; Zuna increase longevity, and may act as tumour et al., 2009; Meyer et al., 2013). suppressors (Tsai et al., 2007; Dobson et al., 2011; Description

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 46

t(6;11)(q21;q23) KMT2A/FOXO3 Huret JL

In-frame fusion of MLL exon 1 to 7, 8, or 11 to the Kolenova A, Bueno C, Menendez P, Wehner S, Eckert C, second exon of FOXO3. Talmant P, Tondeur S, Lippert E, Launay E, Henry C, Ballerini P, Lapillone H, Callanan MB, Cayuela JM, Herbaux Fusion protein C, Cazzaniga G, Kakadiya PM, Bohlander S, Ahlmann M, Choi JR, Gameiro P, Lee DS, Krauter J, Cornillet-Lefebvre Description P, Te Kronnie G, Schfer BW, Kubetzko S, Alonso CN, zur MLL N-term fused to FOXO3 from amino acid 208 Stadt U, Sutton R, Venn NC, Izraeli S, Trakhtenbrot L, to 673. Madsen HO, Archer P, Hancock J, Cerveira N, Teixeira MR, Lo Nigro L, Möricke A, Stanulla M, Schrappe M, Sedék L, Szczepan'ski T, Zwaan CM, Coenen EA, van den Heuvel- References Eibrink MM, Strehl S, Dworzak M, Panzer-Grümayer R, Dingermann T, Klingebiel T, Marschalek R.. The MLL Andersen MK, Christiansen DH, Pedersen-Bjergaard J. recombinome of acute leukemias in 2013. Leukemia. 2013 Centromeric breakage and highly rearranged chromosome Nov;27(11):2165-76. doi: 10.1038/leu.2013.135. Epub 2013 derivatives associated with mutations of TP53 are common Apr 30. in therapy-related MDS and AML after therapy with alkylating agents: an M-FISH study. Genes Chromosomes Parkin B, Ouillette P, Li Y, Keller J, Lam C, Roulston D, Li Cancer. 2005 Apr;42(4):358-71 C, Shedden K, Malek SN.. Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia. Bernard OA, Hillion J, Le Coniat M, Berger R. A new case Blood. 2013 Jan 10;121(2):369-77. doi: 10.1182/blood- of translocation t(6;11)(q21;q23) in a therapy-related acute 2012-04-427039. Epub 2012 Nov 21. myeloid leukemia resulting in an MLL-AF6q21 fusion. Genes Chromosomes Cancer. 1998 Jul;22(3):221-4 Stark B, Jeison M, Gabay LG, Mardoukh J, Luria D, Bar-Am I, Avrahami G, Kapeliushnik Y, Sthoeger D, Herzel G, Calnan DR, Brunet A. The FoxO code. Oncogene. 2008 Apr Steinberg DM, Cohen IJ, Goshen Y, Stein J, Zaizov R, 7;27(16):2276-88 Yaniv I.. Classical and molecular cytogenetic abnormalities and outcome of childhood acute myeloid leukaemia: report Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, from a referral centre in Israel. Br J Haematol. 2004 Fridman R, Tzivion G. Bimodal regulation of FoxO3 by AKT Aug;126(3):320-37. and 14-3-3. Biochim Biophys Acta. 2011 Aug;1813(8):1453- 64 Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD.. Crystal structure of the human FOXO3a-DBD/DNA complex Greer EL, Brunet A.. FOXO transcription factors in ageing suggests the effects of post-translational modification. and cancer. Acta Physiol (Oxf). 2008 Jan;192(1):19-28. doi: Nucleic Acids Res. 2007;35(20):6984-94. Epub 2007 Oct 10.1111/j.1748-1716.2007.01780.x. Review. 16. Heim S, Sørensen AG, Christensen BE, Pedersen NT.. Re- Tseng AH, Wu LH, Shieh SS, Wang DL.. SIRT3 interactions emergence in remission of primary clone in acute with FOXO3 acetylation, phosphorylation and myelogenous leukaemias with multiple chromosomal ubiquitinylation mediate endothelial cell responses to aberrations at diagnosis. Br J Haematol. 1992 hypoxia. Biochem J. 2014 Nov 15;464(1):157-68. doi: Oct;82(2):332-6. 10.1042/BJ20140213. Helbig G, Stella-Holowiecka B, Bober G, Majewski M, Wang F, Chan CH, Chen K, Guan X, Lin HK, Tong Q.. Grzegorczyk J, Wozniczka K, Kruzel T, Dziaczkowska J, Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2- Najda J, Wojnar J, Holowiecki J.. The achievement of mediated FOXO3 ubiquitination and degradation. complete molecular remission after autologous stem cell Oncogene. 2012 Mar 22;31(12):1546-57. doi: transplantation for T-cell lymphoma with associated 10.1038/onc.2011.347. Epub 2011 Aug 15. hypereosinophilia, rare aberration t(6;11) and elevated IL-4 and IgE. Haematologica. 2006 Aug;91(8 Suppl):ECR42. No Webb AE, Brunet A.. FOXO transcription factors: key abstract available. regulators of cellular quality control. Trends Biochem Sci. 2014 Apr;39(4):159-69. doi: 10.1016/j.tibs.2014.02.003. Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA.. Epub 2014 Mar 13. Review. AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor Wong KF, Chan JK, Sin VC.. T-cell prolymphocytic subfamily. Blood. 1997 Nov 1;90(9):3714-9. leukemia with a novel translocation (6;11)(q21;q23). Cancer Genet Cytogenet. 1999 Jun;111(2):149-51. Menniti M, Iuliano R, D'Antona L, Talarico C, Amato R, Perrotti N. SGK1 (serum/glucocorticoid regulated kinase 1) Zuna J, Burjanivova T, Mejstrikova E, Zemanova Z, Atlas Genet Cytogenet Oncol Haematol. September 2014 Muzikova K, Meyer C, Horsley SW, Kearney L, Colman S, Ptoszkova H, Marschalek R, Hrusak O, Stary J, Greaves M, Meyer C, Hofmann J, Burmeister T, Gröger D, Park TS, Trka J.. Covert preleukemia driven by MLL gene fusion. Emerenciano M, Pombo de Oliveira M, Renneville A, Genes Chromosomes Cancer. 2009 Jan;48(1):98-107. doi: Villarese P, Macintyre E, Cavé H, Clappier E, Mass-Malo K, 10.1002/gcc.20622. Zuna J, Trka J, De Braekeleer E, De Braekeleer M, Oh SH, Tsaur G, Fechina L, van der Velden VH, van Dongen JJ, This article should be referenced as such: Delabesse E, Binato R, Silva ML, Kustanovich A, Aleinikova O, Harris MH, Lund-Aho T, Juvonen V, Heidenreich O, Huret JL. t(6;11)(q21;q23) KMT2A/FOXO3. Atlas Genet Vormoor J, Choi WW, Jarosova M, Cytogenet Oncol Haematol. 2016; 20(1):45-47.

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Leukaemia Section Short Communication

Unbalanced whole-arm translocation der(1;13) in hematologic malignancies Adriana Zamecnikova, Soad Al Bahar Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait [email protected]

Published in Atlas Database: December 2014 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/der0113q10q10ID1653.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62510/12-2014-der0113q10q10ID1653.pdf DOI: 10.4267/2042/62510 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

(11M/9F). Found in: chronic myeloproliferative Abstract disorders (8 of the 20 available cases): polycythemic Whole-arm chromosome translocations involving myelofibrosis (PPMF) in 1 case, essential the long arm of chromosome 1 are nonrandom trombocytopenia (ET) in 1 case, chronic myeloid aberrations in hematologic malignancies that leukemia (CML) in 1 case; myelodysplastic commonly involve acrocentric chromosomes. syndromes (MDS) in transformation in 3 patients as Among them, unbalanced whole-arm translocations well as in acute myeloid leukaemia (2 patients), between chromosomes 1 and 13 are relatively rare multiple myeloma (4 patients) and in lymphoid cytogenetic aberrations and has been reported in malignancies (8 patients). both lymphoid and myeloid neoplasms. Evolution Keywords Whether karyotypic changes associated with extra chromosome 1; chromosome 13; translocation; copies of 1q are primary events or they are induced hematologic malignancies during disease evolution as a side effect of cytotoxic treatments is unclear. Clinics and pathology May be found as a sole anomaly in chronic Disease myeloproliferative disorders (Andrieux et al, 2003; Tanaka et al, 2006), indicating that der(1;13) might Myeloproliferative disorders, multiple myeloma and be a primary change in myeloid disorders. lymphoid malignancies Occurred as part of complex karyotypes in multiple Phenotype/cell stem origin myeloma and lymphoproliferative malignancies, Reported in diverse hematologic disorders suggesting that 1q abnormalities may be secondary events in these diseases representing clonal Etiology evolution associated with natural disease evolution. Different factors like constitutional fragility of the Prognosis 1q heterochromatin, cytotoxic drugs, ionizing radiation and/or oncogenic viruses are suspected to It is likely that the prognosis depends on the patient be implicated in the origin of 1q rearrangements. diagnosis in myeloid malignancies (chronic disease versus acute leukemia). Epidemiology Prognosis in multiple myeloma and lymphoid Reported at least in 20 cases (Table 1); median age malignancies is uncertain. 52 years (range 20-86), balanced sex ratio

Atlas Genet Cytogenet Oncol Haematol. 48 Unbalanced whole-arm translocation der(1;13) in hematologic Zamecnikova A, Al Bahar S. malignancies

G-banded partial karyogram of bone marrow cells showing the der(1;13)(q10;q10) chromosome. Fluorescence in situ hybridization with Vysis (Abbott Molecular) LSI 1p36 (red)/ 1q25 (green) and LSI Rb (red) probes showing an extra green signal located on 1q25 on the der(1;13)(q10;q10) chromosome (arrow)

Cytogenetics Result of the chromosomal Cytogenetics morphological anomaly Presents as -13, + der(1;13)(q10;q10); less Fusion protein frequently as der(1;13)(p10;q10) or Oncogenesis der(1;13)(q10;p10) Acquired whole-arm chromosome translocations with involvement of the 1q heterochromatin are Genes involved and accompanied by genomic imbalances in hematologic proteins malignancies. The chromosome 1 pericentromeric heterochromatin is a notoriously an unstable Genes involved are unknown; the region 1q21-1q32 chromosomal region that is involved in diverse has been suggested to contain oncogenes that are chromosomal rearrangements leading to gene involved in disease pathogenesis dosage abnormalities.

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Unbalanced whole-arm translocation der(1;13) in hematologic Zamecnikova A, Al Bahar S. malignancies

Abbreviations: Ref., reference; PPMF, postpolycythemic myelofibrosis; f, female; m, male; MDS, myelodysplastic syndrome; FA, Fanconi anemia; CML, chronic myeloid leukemia; AML, acute myeloid leukemia; ET, essential thrombocythemia; MM, multiple myeloma; DLBCL, diffuse large B-cell lymphoma. Chromosome anomalies detected in the lymph node. Reference : 1. Swolin et al., 1983; 2. Fleischman et al., 1989; 3. Horiike et al., 1994; 4. Hashimoto et al., 1995; 5. Sawyer et al., 1995; 6. Sawyer et al., 1998; 7. Lindvall et al., 2001; 8. Andrieux et al., 2003; 9. Gascoyne et al., 2003; 10. Horsman et al., 2003; 11. Lestou et al., 2003; 12. Tanaka et al., 2006; 13. Adeyinka et al., 2007; 14. Mohamed et al., 2007; 15. Johnson et al., 2008; 16. Bajaj et al., 2011; 17. Flach et al., 2011; 18. Quentin et al., 2011; 19. Sawyer et al., 2014

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The acquisition of the long arm of chromosome 1 ras mutation and karyotypic evolution are closely results in trisomy of the whole-arm of chromosome associated with leukemic transformation in myelodysplastic syndrome. Leukemia. 1994 Aug;8(8):1331-6 1 and partial monosomy of the involved chromosome. Duplication of the chromosome Horsman DE, Okamoto I, Ludkovski O, Le N, Harder L, Gesk S, Siebert R, Chhanabhai M, Sehn L, Connors JM, segment of 1q11-1q32 is commonly observed in Gascoyne RD. Follicular lymphoma lacking the these rearrangements, indicating that certain t(14;18)(q32;q21): identification of two disease subtypes. Br chromosome 1 regions, especially 1q21-1q32 might J Haematol. 2003 Feb;120(3):424-33 harbor pathogenetically relevant oncogenes. The Johnson NA, Al-Tourah A, Brown CJ, Connors JM, unbalanced nature of the der(1;13)(q10;q10) Gascoyne RD, Horsman DE. Prognostic significance of indicates that the gain of 1q may play an important secondary cytogenetic alterations in follicular lymphomas. role in neoplastic transformation and/or disease Genes Chromosomes Cancer. 2008 Dec;47(12):1038-48 progression. Although a der(1;13)(q10;q10) Lestou VS, Gascoyne RD, Sehn L, Ludkovski O, translocation has been reported in various neoplastic Chhanabhai M, Klasa RJ, Husson H, Freedman AS, conditions, such as multiple myeloma and Connors JM, Horsman DE. Multicolour fluorescence in situ hybridization analysis of t(14;18)-positive follicular lymphoma, this translocation is also observed in both lymphoma and correlation with gene expression data and chronic and acute myeloid disorders. The clinical outcome. Br J Haematol. 2003 Sep;122(5):745-59 observation of this anomaly was closely associated Lindvall C, Nordenskjöld M, Porwit A, Björkholm M, Blennow with leukemic transformation in myeloid E. Molecular cytogenetic characterization of acute myeloid malignancies suggesting that der(1;13)(q10;q10) leukemia and myelodysplastic syndromes with multiple might be a rare but nonrandom primary change in chromosome rearrangements. Haematologica. 2001 these disorders preceding or accompanying disease Nov;86(11):1158-64 evolution. Mohamed AN, Bentley G, Bonnett ML, Zonder J, Al-Katib A. Chromosome aberrations in a series of 120 multiple myeloma cases with abnormal karyotypes. Am J Hematol. References 2007 Dec;82(12):1080-7 Adeyinka A, Wei S, Sanchez J. Loss of 17p is a major Quentin S, Cuccuini W, Ceccaldi R, Nibourel O, Pondarre consequence of whole-arm chromosome translocations in C, Pagès MP, Vasquez N, Dubois d'Enghien C, Larghero J, hematologic malignancies. Cancer Genet Cytogenet. 2007 Peffault de Latour R, Rocha V, Dalle JH, Schneider P, Mar;173(2):136-43 Michallet M, Michel G, Baruchel A, Sigaux F, Gluckman E, Leblanc T, Stoppa-Lyonnet D, Preudhomme C, Socié G, Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald Soulier J. Myelodysplasia and leukemia of Fanconi anemia M, Bauters F, Laï JL. Karyotypic abnormalities in are associated with a specific pattern of genomic myelofibrosis following polycythemia vera. Cancer Genet abnormalities that includes cryptic RUNX1/AML1 lesions. Cytogenet. 2003 Jan 15;140(2):118-23 Blood. 2011 Apr 14;117(15):e161-70 Bajaj R, Xu F, Xiang B, Wilcox K, Diadamo AJ, Kumar R, Sawyer JR, Lukacs JL, Munshi N, Desikan KR, Singhal S, Pietraszkiewicz A, Halene S, Li P. Evidence-based genomic Mehta J, Siegel D, Shaughnessy J, Barlogie B. Identification diagnosis characterized chromosomal and cryptic of new nonrandom translocations in multiple myeloma with imbalances in 30 elderly patients with myelodysplastic multicolor spectral karyotyping. Blood. 1998 Dec syndrome and acute myeloid leukemia. Mol Cytogenet. 1;92(11):4269-78 2011 Jan 20;4:3 Sawyer JR, Tian E, Heuck CJ, Epstein J, Johann DJ, Flach J, Dicker F, Schnittger S, Schindela S, Kohlmann A, Swanson CM, Lukacs JL, Johnson M, Binz R, Boast A, Haferlach T, Kern W, Haferlach C. An accumulation of Sammartino G, Usmani S, Zangari M, Waheed S, van Rhee cytogenetic and molecular genetic events characterizes the F, Barlogie B. Jumping translocations of 1q12 in multiple progression from MDS to secondary AML: an analysis of 38 myeloma: a novel mechanism for deletion of 17p in paired samples analyzed by cytogenetics, molecular cytogenetically defined high-risk disease. Blood. 2014 Apr mutation analysis and SNP microarray profiling. Leukemia. 17;123(16):2504-12 2011 Apr;25(4):713-8 Sawyer JR, Waldron JA, Jagannath S, Barlogie B. Fleischman EW, Prigogina EL, Ilynskaya GW, Probatova Cytogenetic findings in 200 patients with multiple myeloma. NA, Konstantinova LN, Kruglova GV, Volkova MA, Cancer Genet Cytogenet. 1995 Jul 1;82(1):41-9 Osmanov DS. Chromosomal characteristics of malignant lymphoma. Hum Genet. 1989 Jul;82(4):343-8 Swolin B, Weinfeld A, Waldenström J, Westin J. Cytogenetic studies of bone marrow and extramedullary Gascoyne RD, Lamant L, Martin-Subero JI, Lestou VS, tissues and clinical course during metamorphosis of chronic Harris NL, Müller-Hermelink HK, Seymour JF, Campbell LJ, myelocytic leukemia. Cancer Genet Cytogenet. 1983 Horsman DE, Auvigne I, Espinos E, Siebert R, Delsol G. Jul;9(3):197-209 ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood. Tanaka Y, Nagai Y, Mori M, Fujita H, Togami K, Kurata M, 2003 Oct 1;102(7):2568-73 Matsushita A, Maeda A, Nagai K, Tanaka K, Takahashi T. Multiple granulocytic sarcomas in essential Hashimoto K, Miura I, Chyubachi A, Saito M, Miura AB. thrombocythemia. Int J Hematol. 2006 Dec;84(5):413-6 Correlations of chromosome abnormalities with histologic and immunologic characteristics in 49 patients from Akita, This article should be referenced as such: Japan with non-Hodgkin lymphoma. Cancer Genet Cytogenet. 1995 May;81(1):56-65 Zamecnikova A, Al Bahar S. Unbalanced whole-arm translocation der(1;13) in hematologic malignancies. Horiike S, Misawa S, Nakai H, Kaneko H, Yokota S, Taniwaki M, Yamane Y, Inazawa J, Abe T, Kashima K. N-

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Solid Tumour Section Review

Head and Neck: Primary oral mucosal melanoma Cláudia Malheiros Coutinho-Camillo, Silvia Vanessa Lourenço, Fernando Augusto Soares Department of Anatomic Pathology, AC Camargo Cancer Center, São Paulo - Brazil. [email protected]

Published in Atlas Database: July 2017 Online updated version : http://AtlasGeneticsOncology.org/Tumors/HybridOralMelanomaID6647.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62511/07-2017-HybridOralMelanomaID6647.pdf DOI: 10.4267/2042/62511

This article is an update of : Hybrid Head and Neck: Primary oral mucosal melanoma. Atlas Genet Cytogenet Oncol Haematol 2016;20(1) Pseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) SERPINE1/FOSB. Atlas Genet Cytogenet Oncol Haematol 2015;19(10)

Abstract Classification Primary Oral Mucosal Melanoma (POMM) is an Mucosal melanoma of Head and Neck (MMHN) aggressive and rare disease that involves mostly the have been classified as stage I, disease confined to hard palate and upper gingiva, followed by the primary site; stage II, regional lymph node mandibular gingiva, lip mucosa, and other oral sites. metastasis; and stage III, distant metastasis POMM develops primarily between the 5th and 8th (Ballantyne, 1970). Most patients will present with decades of life and most studies report a similar localized (stage I) disease and this classification distribution between males and females. In contrast offers limited prognostic information. Prasad et al. to cutaneous melanomas, the risk factors and (2004) proposed a classification system based on the pathogenesis are poorly understood. However, level of invasion: level 1, in situ melanoma; level 2, genetic profiling of mucosal melanomas have superficially invasive; and level 3, deeply invasive. identified a number of altered genes, such as KIT, The American Joint Committee on Cancer (AJCC) BRAF and N-RAS, suggesting that molecular published a dedicated staging system for MMHN pathways like the mitogen-activated protein kinase based on the tumor, node, metastasis (TNM) (MAPK) pathway (RAS/MEK/ERK) and the classification similar to the staging system for phosphotidylinositol-3-kinase-PTEN pathway cutaneous melanoma (Edge et al., 2010) (Table 1); (PI3K/AKT/PTEN/mTOR) might be used for however, primary MMHN limited to the mucosa are potential targeted therapy. considered T3 lesions to reflect their aggressive Keywords behavior (Tacastacas et al., 2014; Warszawik- Mucosal Melanoma; Head and Neck Hendzel et al., 2014).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(1) 53 Hybrid Head and Neck: Primary oral mucosal melanoma Coutinho-Camillo CM, et al.

Table 1. Classification for the mucosal melanoma of the head and neck - AJCC Cancer Staging Manual 7th edition (2010) - T3- T4a / N1 / M0

site of the lesion. Clinically, POMM lesions may be Clinics and pathology macular or nodular and they can appear as black, Etiology brown, white, gray, purple, or reddish shades. Satellite lesions are frequently present surrounding The etiopathogenesis of mucosal melanomas is not the initial tumor. Approximately a third of all oral yet established. Sun exposure is not related to its melanomas are asymptomatic (Warszawik-Hendzel genesis. However, ethnicity, family history, et al., 2014; Lourenço et al., 2014). POMM syndromes and preexisting lesions may influence its lesions are usually found during routine dental development (Batsakis et al., 1982; Lopez et al., in examination. Alternatively, symptoms may include press; Warszawik-Hendzel et al., 2014). complaints of ill-fitting dentures, ulceration, and Epidemiology bleeding (Patel et al., 2002; Rapidis et al., 2003; POMM is rare and represents 0.2 to 8.0% of all Gavriel et al., 2010). In Figure 1, an example of oral melanomas diagnosed in Europe and United States mucosal melanoma can be observed. and 0.26% of all oral cavity tumors (McLaughlin et al., 2005; Chidzonga et al., 2007; Sortino-Rachou et al., 2009). Most studies report a similar distribution of mucosal melanomas (MM) between males and females. However, there is a significant discrepancy in the incidence of MMHN between races: among Japanese oral melanoma accounts for 7.5% of all melanomas versus less than 1% in Caucasians. MM develops primarily between the 5th and 8th decades of life and the incidence increases with age (López et al., in press; Warszawik-Hendzel et al., 2014; Lourenço et al., 2014; Mihajlovic et al., 2012; Meleti et al., 2007). Clinics POMM involves mostly the hard palate and upper gingiva, followed by mandibular gingiva, lip Figure 1. Primary oral mucosal melanoma affecting the mucosa, and other oral sites. Image exams are lower gingival and lip mucosa. mandatory to confirm that oral mucosa is the primary

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Hybrid Head and Neck: Primary oral mucosal melanoma Coutinho-Camillo CM, et al.

Pathology Treatment Usually mucosal melanomas can be diagnosed with The mainstay treatment for mucosal melanoma is confidence on H&E stained sections. In case of complete surgical resection. In patients with amelanotic lesions, immunohistochemical stains are recurrent disease and without distant disease, a of significant help. second surgical procedure is considered as the best Useful markers include S-100 protein, HMB-45, and option (Lopez et al., in press). Melan-A (Meleti et al., 2007; Lourenço et al., 2014). Although malignant melanoma has been regarded as Histologically, POMM is characterized by the a radioresistant tumor, radiotherapy has become proliferation of neoplastic melanocytes with variable utilized as adjuvant treatment, considering the tumor phenotypes epithelioid, spindle, and plasmacytoid heterogeneity. tumor cells that are arranged in a sheet-like, Precise indications for radiotherapy have not been organoid, alveolar, solid, or desmoplastic defined and it is generally used only in advanced and architecture. recurrent cases (Krengli et al., 2008; Wagner et al., Tumors with mixed cell phenotypes are more 2008). aggressive and are associated with a higher So far, no systemic therapy has been recognized as prevalence of vascular invasion and metastasis. effective for metastatic mucosal melanoma of the Usually the neoplastic proliferation lies along the head and neck. Combinations of cytotoxic junction between the epithelial and lamina propria, chemotherapy with immunotherapy have shown but in advanced, ulcerated lesions, this might be higher response rates (Bartell et al., 2008). Some difficult to be detected. targeted therapies have been considered as effective Melanin pigment is noted in almost 90% of lesions. for patients with c-Kit or BRAF gene mutations The Clark and Breslow classifications are the most (Lopez et al., in press; Warszawik-Hendzel et al., frequently used assessment systems for the 2014). prognosis of cutaneous melanoma, but they less applicable in the oral cavity due of its histological Prognosis peculiarity. Mucosal melanoma of the head and neck has a poor In 1995, the Western Society of Teachers of Oral prognosis with few long-term survivors. Pathology agreed that POMM lesions should be Undifferentiated tumor cell morphology, vascular considered separately from the cutaneous form. and neural invasion, tumor necrosis, thickness of the There are 3 histological stages of POMMs: stage 1, tumor, cervical lymph node metastasis are primary site; stage 2, with lymph node metastasis; considered to be independent predictors of outcome and stage 3, with distant metastasis. (Lopez et al., in press; Kerr et al., 2012; Prasad et al., Furthermore, a 3-level microstage system was 2002). Five-year survival rate have been reported to established: level 1, in situ melanoma with no be within the range of 4.5 to 48.0% (Shuman et al., evidence of invasion or with the presence of 2011; Gonzalez-Garcia et al., 2005; Rapidis et al., individual or agglomerated invasive melanocytes 2003). Prasad et al. (2012) investigating molecular with fewer than 10 atypical melanocytes near the predictors of prognosis in mucosal melanomas subepithelial junction; level 2, melanoma cells, reported that Bcl-2 expression is associated with limited to the lamina propria; and level 3, invasion better survival. Other factors associated with poor of the deep conjunctive tissue, including skeletal prognosis are loss of p16 expression and positivity muscle, bone, or cartilage. for p53, although these results did not reach There are yet several issues that must be addressed statistical significance. in the histological evaluation of head and neck PMMs: (1) the architecture of the lesion in small Embryonic origin biopsies, (2) difficulties in specimen representation, The cell of origin of Primary Oral Mucosal and (3) advanced disease stage that might be Melanoma (POMM) is the melanocyte, which are associated with tumor necrosis. cells derived from the neural crest and that migrate Histopathological aspects of mucosal melanomas to endodermal or ectodermal derived tissues, can be observed in Figures 2, 3 and 4. including mucosa (Barrett & Raja, 1997; Batsakis, 1999).

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Hybrid Head and Neck: Primary oral mucosal melanoma Coutinho-Camillo CM, et al.

Figure 2. Primary oral mucosal melanoma (level I): neoplastic nests at the epithelial/lamina propria junction. (H&E, original magnification X400)

Figure 3 Primary oral mucosal melanoma (level II): invasive melanoma with neoplastic cells detected in the lamina propria. (H&E, original magnification X400)

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Hybrid Head and Neck: Primary oral mucosal melanoma Coutinho-Camillo CM, et al.

Figure 4. Primary oral mucosal melanoma (level III): deeply invasive melanoma up to the bone structures. (H&E, original magnification X400)

mutation was observed in 25.0% of the samples and Genetics 21.4% of the cases showed BRAF codon 600 There are some signaling pathways involved in mutation (unpublished results). Prasad et al. (2004) mucosal melanoma pathogenesis. reported that cancer-testis antigens (CT7, MAGE- The mitogen-activated protein kinase (MAPK) A4, and NY-ESO-1) are frequently expressed in pathway (RAS/MEK/ERK) is a critical growth HNMM and may be potential targets for CTA based cascade in oral mucosal melanoma. Another immunotherapy. Gwosdz et al. (2006) examined by important pathway is the phosphotidylinositol-3- immunohistochemistry and sequence analysis of the kinase-PTEN pathway (PI3K/AKT/PTEN/mTOR), entire coding region of the p53 transcript in mucosal which is involved in the regulation of cell death. melanomas. Accumulation of the p53 protein These two signaling pathways can be triggered by occurred 58% of the samples and no mutation has activation of c-kit (Soma et al., 2014; Kerr et al 2012; been found. Prasad et al. (2012) also reported that Buery et al., 2011; Junkins-Hopkins, 2010) (Figure expression of bcl-2, p53 and loss of p16 expression 5). C-KIT regulates the activity of MITF are frequent and early events in POMM. bcl-2 (microphthalmia-associated transcription factor) a expression in the initial tumors was associated with transcription factor that is important for significantly longer overall and disease specific melanogenesis and melanocyte function. MITF survival. Bologna et al. (2013) evaluated the expression has been found in 40 to 91% of mucosal expression of integrins, claudins, and melanomas of the head and neck (Morris et al., 2008; immunoglobulin-like adhesion molecules in oral Prasad et al., 2001). mucosal melanomas and their association with High rates of c-kit protein expression has been clinical parameters. Positivity of integrin beta-3 and reported for mucosal melanomas and this CD166 was associated with extensive vascular immunohistochemical expression is associated with invasion and lower expression of CD54 was c-kit mutation (Rivera et al., 2008). associated with cases with extensive necrosis. Most A review of the literature report that 14% of mucosal cases with metastatic disease were negative for melanomas harbor activating C-KIT mutations; 5% CD66. Immunohistochemical results are shown in showed BRAF mutation and 14% oncogenic Figures 6 and 7. Hsieh et al. (2013) examined the mutations in NRAS, which is much lower than the central components of the CDKN2A and RAS-RAF- reported BRAF prevalence (56 to 59%) in cutaneous MEK-ERK cascades by immunohistochemistry and melanomas (Tacastacas et al., 2014; Cohen et al., found that the majority of the cases were positive for 2004). Our group also investigated mutational status BRAF and ERK2. This pattern was associated with of NRAS and BRAF genes in oral mucosal vascular invasion and metastasis. melanoma: mutation in NRAS codons 12 and 13 was observed in 14.3% of the samples; NRAS codon 61

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Hybrid Head and Neck: Primary oral mucosal melanoma Coutinho-Camillo CM, et al.

Figure 5. Signaling pathways involved in mucosal melanoma pathogenesis. The binding of the ligand to the KIT results in activation of the MAPK and PI3K

found in 10% of the mucosal melanomas and MYC Cytogenetics amplifications was found in 62.5% of the mucosal melanomas (Glatz-Krieger et al., 2006). Cytogenetics Morphological Among the 23 acral and mucosal melanomas Genome-wide alterations in the number of copies of studied, copy number changes in GAB2 were found DNA and mutational status of BRAF and N-RAS in in 26% and KIT in 13% (3 of 23) of the cases. 126 melanomas from four groups (30 melanomas Mutations in BRAF were identified in 30% (7 of 23) from skin with chronic sun-induced damage and 40 of the cases and NRAS, in 4% (1 of 23) of the cases melanomas from skin without such damage; 36 (Chernoff et al., 2009). melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas) were investigated. Genes involved and The results indicate that there are distinct genetic pathways in the development of melanoma and proteins implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in Genetic profiling of mucosal melanomas have BRAF or N-RAS (Curtin et al., 2005). Comparative identified a number of altered genes, such as KIT, genomic hybridization performed in primary BRAF and N-RAS, suggesting that molecular melanomas located on acral skin, mucosa, and skin pathways like the mitogen‑activated protein kinase with chronic sun-induced damage (CSD) revealed (MAPK) pathway (RAS/MEK/ERK) and the focal amplifications in chromosome 4q12.7, phosphotidylinositol-3-kinase-PTEN pathway suggesting the involvement of c-KIT (Curtin et al., (PI3K/AKT/PTEN/mTOR) might be used for 2006). Fluorescence in situ hybridization (FISH) potential targeted therapy. was used to assess copy number changes of the Unlike cutaneous melanoma, BRAF mutation are cyclin D1 (CCND1), MDM2, c-myc (MYC), and infrequent and KIT mutation seem to be frequently HER2 genes in melanomas of melanomas of altered (Lopez et al., in press; Soma et al., 2014; Kerr different location and different etiology. CCND1 et al 2012; Buery et al., 2011; Junkins-Hopkins, amplifications was 2010).

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Hybrid Head and Neck: Primary oral mucosal melanoma Coutinho-Camillo CM, et al.

Figure 6. Primary oral mucosal melanoma: expression of CD166 surrounding the membrane of neoplastic melanocytes. (Immunohistochemistry, original magnification X400)

Figure 7. Primary oral mucosal melanoma: a high expression of integrin beta 3 in a level III melanoma. Association with vascular invasion. (Immunohistochemistry, original magnification X250)

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Hybrid Head and Neck: Primary oral mucosal melanoma Coutinho-Camillo CM, et al.

KIT Bartell HL, Bedikian AY, Papadopoulos NE, Dett TK, Ballo MT, Myers JN, Hwu P, Kim KB. Biochemotherapy in Location patients with advanced head and neck mucosal melanoma. 4q12 Head Neck. 2008 Dec;30(12):1592-8 DNA / RNA Batsakis JG, Regezi JA, Solomon AR, Rice DH. The pathology of head and neck tumors: mucosal melanomas, This gene has 4 transcripts (splice variants). KIT-001 part 13. Head Neck Surg. 1982 May-Jun;4(5):404-18 has 21 coding exons and a transcript length of 5,186 bps. KIT-002 has 21 coding exons and a transcript Batsakis JG.. Pathology of tumors of the oral cavity. in Thawley SE, Panje WR, Batsakis JG, et al (eds): length of 3,470 bps. Comprehensive Management of Head and Neck Tumors. Protein Philadelphia, PA, Saunders,1999, pp 651-655. Proteins with 976 and 972 amino acids residues. C- Bologna SB, Nico MM, Hsieh R, Coutinho-Camillo CM, KIT gene encodes a tyrosine kinase receptor for the Buim ME, Fernandes JD, Sangueza M, Soares FA, Lourenço SV. Adhesion molecules in primary oral mucosal stem cell factor. The mitogen-activated protein melanoma: study of claudins, integrins and kinase (MAPK) pathway (RAS/MEK/ERK) and the immunoglobulins in a series of 35 cases Am J phosphotidylinositol-3-kinase-PTEN pathway Dermatopathol 2013 Jul;35(5):541-54 (PI3K/AKT/PTEN/mTOR) can be triggered by Buery RR, Siar CH, Katase N, Gunduz M, Lefeuvre M, Fujii activation of c-kit. High expression of KIT protein is M, Inoue M, Setsu K, Nagatsuka H. NRAS and BRAF observed in mucosal melanomas frequently mutation frequency in primary oral mucosal melanoma associated with gene mutation (Tacastacas et al., Oncol Rep 2011 Oct;26(4):783-7 2014; Rivera et al., 2008). Chernoff KA, Bordone L, Horst B, Simon K, Twadell W, Lee K, Cohen JA, Wang S, Silvers DN, Brunner G, Celebi JT. BRAF GAB2 amplifications refine molecular classification of Location melanoma Clin Cancer Res 2009 Jul 1;15(13):4288-91 7q34 Chidzonga MM, Mahomva L, Marimo C, Makunike-Mutasa R. Primary malignant melanoma of the oral mucosa J Oral DNA / RNA Maxillofac Surg 2007 Jun;65(6):1117-20 This gene has 5 transcripts (splice variants). BRAF- Cohen Y, Rosenbaum E, Begum S, Goldenberg D, Esche 001 has 18 coding exons and a transcript length of C, Lavie O, Sidransky D, Westra WH. Exon 15 BRAF 2,480 bps mutations are uncommon in melanomas arising in nonsun- Protein exposed sites Clin Cancer Res 2004 May 15;10(10):3444- 7 Protein with 766 amino acids residues. BRAF is a serine-threonine kinase that once activated leads to Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma J Clin activation of other kinases promoting cell survival. Oncol 2006 Sep 10;24(26):4340-6 The evidence of BRAF mutation in mucosal melanomas is controversial, varying from 3 to 10% Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Bröcker EB, LeBoit PE, Pinkel (Tacastacas et al., 2014; Buery et al., 2011; Cohen et D, Bastian BC. Distinct sets of genetic alterations in al., 2004). melanoma N Engl J Med 2005 Nov 17;353(20):2135-47 NRAS Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual Location and the future of TNM Ann Surg Oncol 2010 1p13.2 Jun;17(6):1471-4 DNA / RNA Gavriel H, McArthur G, Sizeland A, Henderson M. Review: This gene has 1 transcript (splice variant). NRAS- mucosal melanoma of the head and neck Melanoma Res 2011 Aug;21(4):257-66 001 has 7 coding exons and a transcript length of 4,449 bps Glatz-Krieger K, Pache M, Tapia C, Fuchs A, Savic S, Glatz D, Mihatsch M, Meyer P. Anatomic site-specific patterns of Protein gene copy number gains in skin, mucosal, and uveal Protein with 189 amino acids residues. NRAS is a melanomas detected by fluorescence in situ hybridization GTPase involved in signaling transduction and Virchows Arch 2006 Sep;449(3):328-33 control of cell growth (Tacastacas et al., 2014; Buery Gonzálezlez-García R, Naval-Gías L, Martos PL, Nam-Cha et al., 2011). SH, Rodríguez-Campo FJ, Mu@ntilde;oz-Guerra MF, Sastre-Pérez J. Melanoma of the oral mucosa Clinical cases and review of the literature Med Oral Patol Oral Cir References Bucal Ballantyne AJ. Malignant melanoma of the skin of the head Gwosdz C, Scheckenbach K, Lieven O, Reifenberger J, and neck. An analysis of 405 cases. Am J Surg. 1970 Knopf A, Bier H, Balz V. Comprehensive analysis of the p53 Oct;120(4):425-31 status in mucosal and cutaneous melanomas Int J Cancer 2006 Feb 1;118(3):577-82 Barrett AW, Raja AM. The immunohistochemical identification of human oral mucosal melanocytes. Arch Oral Hsieh R, Nico MM, Coutinho-Camillo CM, Buim ME, Biol. 1997 Jan;42(1):77-81 Sangueza M, Lourenço SV. The CDKN2A and MAP kinase

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pathways: molecular roads to primary oral mucosal Prasad ML, Patel SG, Shah JP, Hoshaw-Woodard S, melanoma Am J Dermatopathol 2013 Apr;35(2):167-75 Busam KJ. Prognostic significance of regulators of cell cycle and apoptosis, p16(INK4a), p53, and bcl-2 in primary Junkins-Hopkins JM. Malignant melanoma: molecular mucosal melanomas of the head and neck Head Neck cytogenetics and their implications in clinical medicine J Am Pathol 2012 Jun;6(2):184-90 Acad Dermatol 2010 Aug;63(2):329-32 Rapidis AD, Apostolidis C, Vilos G, Valsamis S. Primary Kerr EH, Hameed O, Lewis JS Jr, Bartolucci AA, Wang D, malignant melanoma of the oral mucosa J Oral Maxillofac Said-Al-Naief N. Head and neck mucosal malignant Surg 2003 Oct;61(10):1132-9 melanoma: clinicopathologic correlation with contemporary review of prognostic indicators Int J Surg Pathol 2012 Rivera RS, Nagatsuka H, Gunduz M, Cengiz B, Gunduz E, Feb;20(1):37-46 Siar CH, Tsujigiwa H, Tamamura R, Han KN, Nagai N. C-kit protein expression correlated with activating mutations in Krengli M, Jereczek-Fossa BA, Kaanders JH, Masini L, KIT gene in oral mucosal melanoma Virchows Arch 2008 Beldì D, Orecchia R. What is the role of radiotherapy in the Jan;452(1):27-32 treatment of mucosal melanoma of the head and neck? Crit Rev Oncol Hematol 2008 Feb;65(2):121-8 Epub 2007 Sep Schenck CH, Mandell M, Lewis GM. A case of monthly 5 unipolar psychotic depression with suicide attempt by self- burning: selective response to bupropion treatment Compr López F, Rodrigo JP, Cardesa A, Triantafyllou A, Devaney Psychiatry 1992 Sep-Oct;33(5):353-6 KO, Mendenhall WM, Haigentz M, Strojan P, Pellitteri PK, Bradford CR, Shaha AR, Hunt JL, de Bree R, Takes RP, Shuman AG, Light E, Olsen SH, Pynnonen MA, Taylor JM, Rinaldo A, Ferlito A. Update on primary head and neck Johnson TM, Bradford CR. Mucosal melanoma of the head mucosal melanoma Head Neck 2014 Sep 20 and neck: predictors of prognosis Arch Otolaryngol Head Neck Surg 2011 Apr;137(4):331-7 Lourenço SV, Fernandes JD, Hsieh R, Coutinho-Camillo CM, Bologna S, Sangueza M, Nico MM. Head and neck Soma PF, Pettinato A, Agnone AM, Donia C, Improta G, mucosal melanoma: a review Am J Dermatopathol 2014 Fraggetta F. Oral malignant melanoma: A report of two Jul;36(7):578-87 cases with BRAF molecular analysis Oncol Lett 2014 Sep;8(3):1283-1286 McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW. Incidence of noncutaneous melanomas in the U Sortino-Rachou AM, Cancela Mde C, Voti L, Curado MP. S Cancer Primary oral melanoma: population-based incidence Oral Oncol 2009 Mar;45(3):254-8 Meleti M, Leemans CR, Mooi WJ, Vescovi P, van der Waal I. Oral malignant melanoma: a review of the literature Oral Tacastacas JD, Bray J, Cohen YK, Arbesman J, Kim J, Oncol 2007 Feb;43(2):116-21 Koon HB, Honda K, Cooper KD, Gerstenblith MR. Update on primary mucosal melanoma J Am Acad Dermatol 2014 Mihajlovic M, Vlajkovic S, Jovanovic P, Stefanovic V. Aug;71(2):366-75 Primary mucosal melanomas: a comprehensive review Int J Clin Exp Pathol 2012;5(8):739-53 Wagner M, Morris CG, Werning JW, Mendenhall WM. Mucosal melanoma of the head and neck Am J Clin Oncol Morris LG, Wen YH, Nonaka D, DeLacure MD, Kutler DI, 2008 Feb;31(1):43-8 Huan Y, Wang BY. PNL2 melanocytic marker in immunohistochemical evaluation of primary mucosal Warszawik-Hendzel O, Sńowiń M, melanoma of the head and neck Head Neck 2008 Olszewska M, Rudnicka L. Melanoma of the oral cavity: Jun;30(6):771-5 pathogenesis, dermoscopy, clinical features, staging and management J Dermatol Case Rep 2014 Sep 30;8(3):60-6 Patel SG, Prasad ML, Escrig M, Singh B, Shaha AR, Kraus DH, Boyle JO, Huvos AG, Busam K, Shah JP. Primary This article should be referenced as such: mucosal malignant melanoma of the head and neck Head Neck 2002 Mar;24(3):247-57 Coutinho-Camillo CM, Louren SV, Soares FA. Hybrid Head and Neck: Primary oral mucosal melanoma. Atlas Prasad ML, Jungbluth AA, Patel SG, Iversen K, Hoshaw- Genet Cytogenet Oncol Haematol. 2016; 20(1):52-61. Woodard S, Busam KJ. Expression and significance of cancer testis antigens in primary mucosal melanoma of the head and neck Head Neck 2004 Dec;26(12):1053-7

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