Volume 1 - Number 1 May - September 1997

Volume 20 - Number 12 December 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It 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).

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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) Lymphomas Section Editor Antonino Carbone (Aviano, Italy) Myeloid Malignancies Section Editor Robert S. Ohgami (Stanford, California) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editors Cécile Badoual and Hélène Blons (Paris, France) Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts) Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland) Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy) Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil) DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) WNT pathway Section Editor Alessandro Beghini (Milano, Italy)

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] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] François IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, Desangles 91223 Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [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, 6500 HB Kessel Nijmegen, The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Oskar A. Haas Research Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Roderick Mc Leod Braunschweig, Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] 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 Cultures, Stefan Nagel 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, Memphis, Tennessee Susana Raimondi 38105-3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [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) - Italy; Roberta Vanni [email protected] Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants Franck Viguié Malades, 75015 Paris, France; [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 20, Number 12, December 2016 Table of contents

Gene Section

DAPK2 (death-associated protein kinase 2) 587 Mafalda Pinto, Valdemar Máximo OCA2 (OCA2 melanosomal transmembrane protein) 592 Kunal Ray, Mainak Sengupta, Sampurna Ghosh PARK7 (Parkinsonism associated deglycase) 595 Valentina La Cognata, Sebastiano Cavallaro RHOBTB3 (Rho-related BTB domain containing 3) 607 Shuo Cai, Francisco Rivero

Leukaemia Section

Disseminated Juvenile Xanthogranuloma 611 Samir Dalia, Luis Miguel Juarez Salcedo t(9;11)(p21;q23) KMT2A/MLLT3 613 Jeroen Knijnenburg, H. Berna Beverloo t(X;14)(q28;q11.2) TRA-TRD/MTCP1 616 Aurelia M. Meloni-Ehrig t(15;17)(q24;q21) PML/RARA 620 Pino J. Poddighe, Daniel Olde Weghuis

Cancer Prone Disease Section

Denys-Drash syndrome (DDS) 625 Maria Piccione, Emanuela Salzano Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

DAPK2 (death-associated protein kinase 2) Mafalda Pinto, Valdemar Máximo IPATIMUP Institute of Molecular Pathology and Immunology of the University of Porto, (MP, VM); I3S Institute for Innovation and Health Research, University of Porto (MP, VM); Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal (VM) [email protected]; [email protected]

Published in Atlas Database: April 2016 Online updated version : http://AtlasGeneticsOncology.org/Genes/DAPK2ID40263ch15q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66944/04-2016-DAPK2ID40263ch15q22.pdf DOI: 10.4267/2042/66944 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

Location (base pair): Chromosome 15:63,907,036- Abstract 64,072,033 reverse strand. GRCh38:CM000677.2 (Ensembl.org) Short communication on DAPK2, with data on DNA and on the protein encoded. DNA/RNA Keywords DAPK2; DRP1; DRP-1; calcium/calmodulin; DAPK2 is a gene that codes for a protein that serine/threonine; kinase; apoptosis belongs to the serine/threonine protein kinase family. Identity Transcription Other names: DRP1, DRP-1 DPAK2 has 13 transcripts (3 coding), 75 orthologues and 11 paralogues (MYLK4, MYLK3, STK17A, HGNC (Hugo): DAPK2 DAPK3, DAPK1, OBSCN, SPEG, TTN, MYLK, Location: 15q22.31 STK17B, MYKL2) (ENSG00000035664).

Blue highlighting indicates alternating exons; Red highlighting indicates amino acids encoded across a splice junction.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 587 DAPK2 (death-associated protein kinase 2) Pinto M, Máximo V

Schematic diagram of DAPK2 protein structure. The 42 KDa DAPK2 protein kinase bears three domain structures. A kinase domain on its N-terminal region determines specificity and allows for homodimerization through its basic loop. It is followed by a calcium/calmodulin (CaM)-regulated Serine/Threonine binding domain, which dictates kinase catalytic activity by unblocking substrate access when bound to Ca2+/CaM. Autophosphorylation of S308 decreases DAPK2 activity. The C-terminal dimerization domain allows for homodimerization. (Kawai T et al., 1999; Inbal B et al., 2000)

In mouse, DAPK2 is strongly and specifically Protein expressed in interstitial cells of the kidney cortex Description (Guay JA et al., 2014). DAPK2 encodes a 42 KDa protein kinase (Inbal B., Localisation 2000) that belongs to the serine/threonine protein Cytoplasm (Inbal B et al., 2000), cytoplasmic family of five proapoptotic proteins with tumor vesicles, inside autophagic vesicles (Inbal B et al., suppressor activity. DAPK2 is soluble and cytosolic 2002). (Inbal B., 2000). It contains highly-conserved N-terminal kinase Function catalytic domain, followed by a conserved DAPK2 is a regulator of apoptosis, autophagy calcium/calmodulin regulatory binding domain and and inflammation (Geering B 2015). a C-terminal homodimerization domain Apoptosis encompassing the last 40 aminoacids, predicted to DAPK2 overexpression induces cell apoptosis in 50 form two helices, which has no sequence homology to 60% (Inbal B et al., 2000). Depletion of the C- to known protein sequences. terminal tail of DAPK2 abolishes its apoptotic Autophosphorylation restrains the apoptotic activity activity, while further truncation of the CaM- of DAPK2 kinase by controlling dimerization and regulatory domain strongly enhances its apoptotic calmodulin binding (Shani G et al., 2001). effect (Inbal B et al., 2000). DAPK2 is a monomer in its activated state and a DAPK2 is a modulator of TRAIL signaling and homodimer when inhibited by autophosphorylation TRAIL-induced apoptosis. Genetic ablation of at Ser-308 (Shani G et al., 2001). The dimers of DAPK2 causes phosphorylation of NF-KB and its DAPK2 are formed through the association of two transcriptional activity in several cancer cell lines, opposed catalytic domains (Patel AK et al., 2001). leading to the induction of several proapoptotic DAPK2 is negatively regulated by the autoinhibitory proteins (TNFRSF10A (DR4) and TNFRSF10B CaM-binding domain and this inhibition is removed (DR5)) (Schlegel CR et al., 2014). by the binding of Ca2+/CaM (Inbal B et al., 2000). Autophagy That is, DAPK2 is activated by CaM in response to DAPK2 modulates MTOR activity by directly Ca2+ stimuli, and regulated by a double locking interacting and phosphorylating mTORC1. This way mechanism. DAPK2 is dephosphorylated at Ser-308 it suppresses mTOR activity to promote autophagy in response to activated Fas and TNF-alpha induction and autophagy levels under stress and receptors. steady-state conditions (Ber Y et al., 2015). UniProtKB: Q9UIK4 Expression of DAPK2 in its activated form triggers autophagy in a caspase independent way. DAPK2 Expression mediates the formation of autophagic vesicles during Widespread expression. Strong expression in heart, apoptosis (Inbal B et al., 2002). Expression of lung and skeletal muscle, but also expressed in dominant negative mutant of DAPK2 reduces colon, breast, spleen tissue and leukocytes (Kawai T autophagy (Inbal B et al., 2002). et al., 1999; Inbal B et al., 2000).

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 588

DAPK2 (death-associated protein kinase 2) Pinto M, Máximo V

Translation (370 aa)

Protein serine/threonine kinase activity Positive regulation of eosinophil and neutrophil In vitro kinase assays, using myosin light chain chemotaxis, and granulocyte maturation (MLC) as substrate, have shown both MLC DPAK2 inhibition blocks recruitment of neutrophils phosphorylation and DAPK2 autophosphorylation to the site of inflammation in a peritonitis mouse (Kawai T et al., 1999; Inbal B et al., 2000). DAPK2 model. functions in vitro as a kinase that is capable of DAPK2 functions in a signaling pathway that phosphorylating itself and an external substrate mediates motility in neutrophils and eosinophils in (Kawai T et al., 1999; Inbal B et al., 2000). response to intermediary chemoattractants, but not to Calmodulin binding end-target chemoattractants (Geering B et al., 2014). The addition of Ca2+/CaM to in vitro kinase assays DPAK2 regulates granulocytic motility by using myosin light chain (MLC) as substrate, lead to controlling cell spreading and polarization (Geering an increased amount of phosphorylated MLC, B et al., 2014) and may play a role in granulocyte suggesting that DPK2 is regulated by binding to maturation (Rizzi M et al., 2007). CaM (Kawai T et al., 1999; Inbal B et al., 2000). Regulation of erythropoiesis DPAK2 is negatively regulated by the autoinhibitory Among hematopoietic lineages, DPAK2 is CaM-binding domain and this inhibition is removed expressed predominantly in erythroid cells. DPAK2 by the binding of Ca2+/CaM (Inbal B et al., 2000). is substantially up-modulated during late Truncation of the CaM-regulatory region of DAPK2 erythropoiesis (Fang J et al., 2008). enhances the apoptotic effect (Inbal B et al., 2000). In UT7epo cells, siRNA knock-down of DAPK2 Oxidative stress regulation enhanced survival due to cytokine withdrawal, and DAPK2 regulates oxidative stress in cancer cells by DAPK2's phosphorylation and kinase activity also preserving mitochondrial function. Depletion of were erythropoietin (EPO)-modulated. DAPK2 DAPK2 leads to an increased production of therefore comprises a new candidate attenuator of mitochondrial superoxide anions and increased stress erythropoiesis (Fang J et al., 2008). oxidative stress (Schlegel CR et al., 2015). The physiological substrate of DAPK2 is unknown Cellular metabolism although it is known to phosphorylate the myosin DAPK2 kinase domain in important to maintain light chain in vitro (Inbal B et al., 2000). mitochondrial integrity and thus metabolism. INTERACTION Depletion of DPAK2 leads to metabolic alterations, YWHAB (14-3-3-β) (Yuasa K et al., 2015) and α- decreased rate of oxidative phosphorylation and actinin-1 are novel DAPK2 binding partners destabilized mitochondrial membrane potential (Geering B et al., 2015). (Schlegel CR et al., 2015). The interaction of DAPK2 with α-actinin-1 is Membrane blebbing localized to the plasma membrane, resulting in Interaction of DAPK2 with ACTA1 (α-actin-1) at massive membrane blebbing and reduced cellular the plasma membrane leads to massive membrane motility, whereas the interaction of DAPK2 with 14- blebbing (Geering B et al., 2015). 3-3- β is localized to the cytoplasm, with no impact Expression of DAPK2 in its activated form triggers on blebbing, motility, or viability (Geering B et al membrane blebbing and this process is caspase 2015). 14-3-3- proteins inhibit DAPK2 activity and independent (Inbal B et al., 2002). Dominant its apoptotic effects (Yuasa K et al., 2015). negative mutants of DAPK2 reduce membrane DAPK2 also interacts with RAD1, MAPK1 and blebbing during the p55/TRAF1 (TNF-receptor 1)- MLC1 (Steinmann S et al., 2015). induced apoptosis (Inbal B et al., 2002). Motility Homology Interaction of DAPK2 with α-actin-1 leads to DAPK3/ZIPK/DLK (Death-related protein 1); reduced cellular motility (Geering B et al., 2015). STK17A (DRAK1/STK17B (DRAK2) (DAPK- Intracellular signaling transduction related apoptosis inducing protein kinases 1 and 2) Depletion of DAPK2 leads to the activation of (Shobat G et al., 2002) classical stress-activated kinases, such as ERK, Mutations JNK and p38 (Schlegel CR et al., 2015).

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Germinal Geering B. Death-associated protein kinase 2: Regulator of apoptosis, autophagy and inflammation. Int J Biochem Cell No germline or somatic mutations have been Biol. 2015 Aug;65:151-4 described for DAPK2 gene. There are 4 structural Geering B, Stoeckle C, Rozman S, Oberson K, Benarafa C, variants are described for DPAK2 gene: nsv1567 Simon HU. DAPK2 positively regulates motility of and nsv1569 leading to loss (PubMed ID 18451855), neutrophils and eosinophils in response to intermediary and nsv1568 and esv1414761 leading to insertions chemoattractants. J Leukoc Biol. 2014 Feb;95(2):293-303 (PubMed IDs 18451855 and 17803354, Geering B, Zokouri Z, Hürlemann S, Gerrits B, Ausländer D, respectively) (Database of Genomic Variants). Britschgi A, Tschan MP, Simon HU, Fussenegger M. Identification of Novel Death-Associated Protein Kinase 2 Somatic Interaction Partners by Proteomic Screening Coupled with Bimolecular Fluorescence Complementation. Mol Cell Biol. Hypermethylation of the promoter region 2016 Jan 1;36(1):132-43 downregulates DAPK2 expression. Guay JA, Wojchowski DM, Fang J, Oxburgh L. Death associated protein kinase 2 is expressed in cortical Implicated in interstitial cells of the mouse kidney. BMC Res Notes. 2014 Jun 7;7:345 Hematological malignancies Humbert M, Federzoni EA, Britschgi A, Schläfli AM, Valk PJ, DAPK2 is a tumor suppressor gene. Promoter region Kaufmann T, Haferlach T, Behre G, Simon HU, Torbett BE, hypermethylation is one mechanism of DAPK2 Fey MF, Tschan MP. The tumor suppressor gene DAPK2 is inactivation in Hodgkin lymphoma-derived tumor induced by the myeloid transcription factors PU.1 and C/EBPα during granulocytic differentiation but repressed by cell lines (Tur MK et al., 2009). PML-RARα in APL. J Leukoc Biol. 2014 Jan;95(1):83-93 DAPK2 is up-regulated during normal myeloid Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A. DAP kinase differentiation and enhances neutrophil maturation and DRP-1 mediate membrane blebbing and the formation in myeloid leukemic cells (Rizzi M et al., 2007). of autophagic vesicles during programmed cell death. J Cell Acute promyelocytic leukemia (APL) patients have Biol. 2002 Apr 29;157(3):455-68 particularly low levels of DAPK2, where the Inbal B, Shani G, Cohen O, Kissil JL, Kimchi A. Death- predominant lesion causing its transcriptional associated protein kinase-related protein 1, a novel repression isPML-RARA. and SPI1 (PU.1) bind to serine/threonine kinase involved in apoptosis. Mol Cell Biol. binding sites in the DAPK2 promoter. Restoring 2000 Feb;20(3):1044-54 DAPK2 expression can rescue neutrophil Kawai T, Nomura F, Hoshino K, Copeland NG, Gilbert DJ, differentiation (Humbert M. et al., 2014). Jenkins NA, Akira S. Death-associated protein kinase 2 is a Low DAPK2 expression is associated with CEBPA- new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity. Oncogene. mutated AML patients and Humbert et al have found 1999 Jun 10;18(23):3471-80 that DAPK2 is induced by the myeloid transcription Patel AK, Yadav RP, Majava V, Kursula I, Kursula P. factors PU.1 and CEBPA during granulocyte Structure of the dimeric autoinhibited conformation of differentiation but repressed by PML-RARA in APL DAPK2, a pro-apoptotic protein kinase. J Mol Biol. 2011 Jun patients (Humbert M. et al., 2014). 10;409(3):369-83 CEBPA-dependent regulation of DAPK2 during Rizzi M, Tschan MP, Britschgi C, Britschgi A, Hügli B, Grob APL differentiation (Humbert M. et al., 2014). TJ, Leupin N, Mueller BU, Simon HU, Ziemiecki A, Torbett BE, Fey MF, Tobler A. The death-associated protein kinase Breast cancer 2 is up-regulated during normal myeloid differentiation and DAPK2 expression is regulated by MIR520H in enhances neutrophil maturation in myeloid leukemic cells. J breast cancer cells (Su CM. et al., 2016). Leukoc Biol. 2007 Jun;81(6):1599-608 Schlegel CR, Georgiou ML, Misterek MB, Stöcker S, Chater Obesity ER, Munro CE, Pardo OE, Seckl MJ, Costa-Pereira AP. DAPK2 regulates obesity-related attenuated DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function. Cell Death Dis. 2015 Mar autophagy in adipocytes – DAPK2 downregulation 5;6:e1671 associates with attenuated adipocyte autophagic clearance in human obesity (Soussi H et al., 2015). Shani G, Henis-Korenblit S, Jona G, Gileadi O, Eisenstein M, Ziv T, Admon A, Kimchi A. Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling References dimerization and calmodulin binding. EMBO J. 2001 Mar 1;20(5):1099-113 Ber Y, Shiloh R, Gilad Y, Degani N, Bialik S, Kimchi A. DAPK2 is a novel regulator of mTORC1 activity and Shohat G, Shani G, Eisenstein M, Kimchi A. The DAP- autophagy. Cell Death Differ. 2015 Mar;22(3):465-75 kinase family of proteins: study of a novel group of calcium- regulated death-promoting kinases. Biochim Biophys Acta. Fang J, Menon M, Zhang D, Torbett B, Oxburgh L, Tschan 2002 Nov 4;1600(1-2):45-50 M, Houde E, Wojchowski DM. Attenuation of EPO- dependent erythroblast formation by death-associated Soussi H, Reggio S, Alili R, Prado C, Mutel S, Pini M, protein kinase-2. Blood. 2008 Aug 1;112(3):886-90 Rouault C, Clément K, Dugail I. DAPK2 Downregulation Associates With Attenuated Adipocyte Autophagic Clearance in Human Obesity. Diabetes. 2015 Oct;64(10):3452-63

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Steinmann S, Scheibe K, Erlenbach-Wuensch K, Neufert C, apoptosis in Hodgkin lymphoma cells. J Immunother. 2009 Schneider-Stock R. Death-associated protein kinase: A Jun;32(5):431-41 molecule with functional antagonistic duality and a potential role in inflammatory bowel disease (Review). Int J Oncol. Yuasa K, Ota R, Matsuda S, Isshiki K, Inoue M, Tsuji A. 2015 Jul;47(1):5-15 Suppression of death-associated protein kinase 2 by interaction with 14-3-3 proteins. Biochem Biophys Res Su CM, Wang MY, Hong CC, Chen HA, Su YH, Wu CH, Commun. 2015 Aug 14;464(1):70-5 Huang MT, Chang YW, Jiang SS, Sung SY, Chang JY, Chen LT, Chen PS, Su JL. miR-520h is crucial for DAPK2 This article should be referenced as such: regulation and breast cancer progression. Oncogene. 2016 Mar 3;35(9):1134-42 Pinto M, Máximo V. DAPK2 (death-associated protein kinase 2). Atlas Genet Cytogenet Oncol Haematol. 2016; Tur MK, Neef I, Jost E, Galm O, Jäger G, Stöcker M, Ribbert 20(12):587-591. M, Osieka R, Klinge U, Barth S. Targeted restoration of down-regulated DAPK2 tumor suppressor activity induces

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 591 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Short Communication

OCA2 (OCA2 melanosomal transmembrane protein) Kunal Ray, Mainak Sengupta, Sampurna Ghosh Academy of Scientific and Innovative Research (AcSIR), Campus at CSIR - Central Road Research Institute, Mathura Road, New Delhi - 110 025, [email protected] (KR); University of Calcutta, Department of Genetics, 35, Ballygunge Circular Road, Kolkata - 700 019, [email protected]); [email protected] (MS, SG) India.

Published in Atlas Database: April 2016 Online updated version : http://AtlasGeneticsOncology.org/Genes/OCA2ID45789ch15q12.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66945/04-2016-OCA2ID45789ch15q12.pdf DOI: 10.4267/2042/66945 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 Location: 15q12 OCA2 gene (OCA2), having a chromosomal DNA/RNA location of 15q12-q13, encodes an integral membrane transporter protein playing a role in Description regulating the pH of melanosomes. In Chromosome: 15, the 344,486 bases long gene OCA2 is hypothesized to be involved in the transport starts from 27,754,873 bp from pter and ends at of tyrosine, the precursor to melanin synthesis, 28,099,358 bp from pter; Orientation: Minus strand. within the melanocyte. Defects in this gene are the It contains 24 exons and spans ~344.5 kb of the cause of oculocutaneous albinism type II; OCA II. genome. Keywords: OCA2, albinism, OCA II Transcription Identity The gene encodes a 3154 bp transcript. Alternative splicing results in at least two transcript Other names: SHEP1, EYCL2, EYCL3, BOCA, variants. BEY1, BEY2, EYCL, HCL3, PED, BEY, D15S12, Variant 2 lacks an alternate in-frame exon in the PEDH central coding region, compared to variant 1, HGNC (Hugo): OCA2 resulting in an isoform that is shorter than isoform 1.

Cytogenetic band showing OCA2 locus (Ref: http://www.genecards.org/cgi-bin/carddisp.pl?gene=OCA2&keywords=OCA2)

Protein

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 592 OCA2 (OCA2 melanosomal transmembrane protein) Ray K, et al.

Description http://cancer.sanger.ac.uk/cosmic/search?q=OCA2), but no causality have been reported. The gene encodes a protein containing 838 amino acids with molecular mass of 92850 Da. The OCA2 is thought to be a melanosomal multipass integral Implicated in membrane protein (with 12 predicted Melanoma transmembrane domains). OCA2 is characterized by the presence of a conserved consensus acidic Note dileucine-based sorting motif within the cytoplasmic In 2005, Jannot et al reported, based on allelic N-terminal region. A second dileucine signal within distribution between cases and controls, that this region confers steady-state lysosomal malignant melanoma and OCA2 are associated (p localization in melanocytes. It belongs to the CitM value=0.030 after correction for multiple testing). In (TC 2.A.11) transporter family. 2010 Duffy et al claimed the OCA2 variant Arg419Gln (rs1800407) to be a significant risk Expression factor for cutaneous malignant melanoma based on a Due to its localization in the melanosomal genome wide association study (GWAS). In 2011, membrane, OCA2 is thought to be expressed in the another GWAS identified a locus at chromosome melanocytes. 15q13.1 (HERC2/OCA2 region) in a discovery Localisation cohort of 1804 melanoma cases and 1026 controls, to be associated with melanoma (Amos et al., 2011). OCA2 is hypothesized to be present in the Co-segregation analysis in an OCA2 affected melanosomal membrane of the melanocytes. pedigree containing individuals diagnosed with both Function cutaneous and iris melanoma, revealed that OCA2 variants could act as contributors towards melanoma The precise function of OCA2 has not been predisposition (Hawkes et al., 2013). elucidated till date. However, the potential functions The OCA2 Arg419Gln SNP has also been found to include: a) normal biogenesis of melanosomes, b) for be associated with basal cell carcinoma of skin (OR, normal processing and transport of tyrosinase and other melanosomal proteins, and c) maintenance of 1.50; 95% CI, 1.06-2.13) (Nan et al., 2009) an acidic pH in melanosomes. References Homology Amos CI, Wang LE, Lee JE, Gershenwald JE, Chen WV, Its sequence predicts that OCA2 has a homology to Fang S, Kosoy R, Zhang M, Qureshi AA, Vattathil S, a superfamily of permeases. It has been proposed Schacherer CW, Gardner JM, Wang Y, Bishop DT, Barrett that OCA2 also regulates the post-translational JH, MacGregor S, Hayward NK, Martin NG, Duffy DL, Mann GJ, Cust A, Hopper J, Brown KM, Grimm EA, Xu Y, Han Y, processing of tyrosinase, which catalyzes the rate Jing K, McHugh C, Laurie CC, Doheny KF, Pugh EW, Seldin limiting steps in melanin biosynthesis and is a major MF, Han J, Wei Q. Genome-wide association study determinant of brown and/or blue eye color. identifies novel loci predisposing to cutaneous melanoma. Hum Mol Genet. 2011 Dec 15;20(24):5012-23 Mutations Duffy DL, Zhao ZZ, Sturm RA, Hayward NK, Martin NG, Montgomery GW. Multiple pigmentation gene Germinal polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J Invest Dermatol. 2010 Mutations in OCA2 are responsible for albinism Feb;130(2):520-8 known also as OCA2. A few OCA2 mutations have Hawkes JE, Cassidy PB, Manga P, Boissy RE, Goldgar D, been associated also with autosomal recessive ocular Cannon-Albright L, Florell SR, Leachman SA. Report of a albinism. While the degree of cutaneous pigment and novel OCA2 gene mutation and an investigation of OCA2 iris color may vary, the newborn with OCA2 nearly variants on melanoma risk in a familial melanoma pedigree. always have pigmented hair. Nevi and freckles are J Dermatol Sci. 2013 Jan;69(1):30-7 common. Visual acuity is better than in OCA1 and Jannot AS, Meziani R, Bertrand G, Gérard B, Descamps V, reaches 3/10. Africans with OCA2 appear with light Archimbaud A, Picard C, Ollivaud L, Basset-Seguin N, brown hair and skin, and gray irises. Eighty six Kerob D, Lanternier G, Lebbe C, Saiag P, Crickx B, Clerget- Darpoux F, Grandchamp B, Soufir N, Melan-Cohort. Allele mutations in OCA2 have been reported in Albinism variations in the OCA2 gene (pink-eyed-dilution locus) are Database associated with genetic susceptibility to melanoma Eur J (http://www.ifpcs.org/albinism/oca2mut.html). It is Hum Genet 2005 Aug;13(8):913-20 to be noted that Albinism Database has been updated Kim HK, Kim YS, Lee SH, Lee HH. Impact of a Delayed till 2009. Laparoscopic Appendectomy on the Risk of Complications in Acute Appendicitis: A Retrospective Study of 4,065 Somatic Patients Dig Surg 2016 Jul 6;34(1):25-29 Somatic mutations in OCA2 have been identified in Kunnus K, Zhang W, Delcey MG, Pinjari RV, Miedema PS, cancers Schreck S, Quevedo W, Schroeder H, Foehlisch A, Gaffney (http://www.cancerindex.org/geneweb/OCA2.htm, KJ, Lundberg M, Odelius M, Wernet P. Viewing the Valence

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OCA2 (OCA2 melanosomal transmembrane protein) Ray K, et al.

Electronic Structure of Ferric and Ferrous Hexacyanide in This article should be referenced as such: Solution From the Fe and Cyanide Perspectives J Phys Chem B 2016 Jul 5 Ray K, Sengupta M, Ghosh S. OCA2 (OCA2 melanosomal transmembrane protein). Atlas Genet Nan H, Kraft P, Hunter DJ, Han J. Genetic variants in Cytogenet Oncol Haematol. 2016; 20(12):592-594. pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians Int J Cancer 2009 Aug 15;125(4):909-17

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 594 Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS

Gene Section Review

PARK7 (Parkinsonism associated deglycase) Valentina La Cognata, Sebastiano Cavallaro Institute of Neurological Sciences, National Research Council, Catania (VLA, SC); Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania (VLA) - Italy. [email protected]; [email protected]

Published in Atlas Database: April 2016 Online updated version : http://AtlasGeneticsOncology.org/Genes/PARK7ID41639ch1p36.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66946/04-2016-PARK7ID41639ch1p36.pdf DOI: 10.4267/2042/66946

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 Identity PARK7 (also called DJ-1 or Parkinsonism Other names: DJ1, DJ-1, HEL-S-67p, RS, CAP1, associated deglycase) is a pleiotropic protein FLJ27376, FLJ92274, FLJ34360 belonging to the peptidase C56 family. It acts as HGNC (Hugo): PARK7 positive regulator of androgen receptor-dependent transcription, redox-sensitive chaperone, sensor for Location: Location Cytogenetic location: 1p36.23; oxidative stress, and apparently protects neurons Molecular location: Chromosome 1; Start 7961654; against oxidative stress and cell death. Dysfunctions Stop 7985282based on Genome Browser Human in PARK7 are related to autosomal recessive early- Dec. 2013 (GRCh38/hg38) Assembly [Link to onset Parkinson disease 7 and cancer forms. Here, chromosome band 1p36] we review some major data on PARK7, concerning Local order: PARK7 is flanked towards the the genetic structure, the transcription regulation, the telomeric direction by two protein-coding genes encoded protein and functions, and its implication in (UTS2 and TNFRSF9) and towards the centromeric human diseases. direction by ERRFI1. According to NCBI Keywords: PARK7, DJ-1, Autosomal Recessive MapViewer, a non-coding RNA (LOC105376694) is Early-Onset Parkinson Disease, Oncogene also present in this locus (Figure 1).

Figure 1 displays the human chromosome 1 (NCBI Reference Sequence NC_000001.11) and relative localization and orientation of PARK7 and flanking genes. PARK7 is represented in red. Further genes (UTS2, TNFRSF9, ERRFI1) and a non-coding RNA (LOC105376694) map in this locus.

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Figure 2 displays the two full-length Reference Sequences of PARK7 gene (NCBI - Nucleotide Database). Corresponding GenBank Accession Numbers are indicated on the left. Exons are represented as boxes (blue for coding regions and white for non-coding), whereas the dashed line indicates intronic regions. The green triangle specifies the start codon, while the red one designates the stop codon.

98680419, Stop Coordinate 98680983according to DNA/RNA Genome BrowserHuman Dec. 2013 (GRCh38/hg38) Description Assembly DJ-1 maps on the distal part of the short arm of Protein chromosome 1, cytoband 1p36.23 (Figure 1). It spans about 24 kb and includes eight exons (Figure Description 2). The first two exons (1A and 1B) are noncoding X-ray crystallographic examination of DJ-1 protein and alternatively spliced in the DJ-1 mRNAs structure indicates that it exists as a dimer (Figure (Bonifati, Rizzu, Squitieri, et al., 2003). 4)(Wilson et al., 2003). It contains domains found in Transcription heat shock chaperones and belongs to the ThiJ/PfpI Currently, the NCBI RefSeq database annotates two family. This family (pfam01965) includes: ThiJ, a representative transcripts as full-length PARK7 protein involved in thiamine biosynthesis in mRNAs (Figure 2). However, a total of 10 spliced prokaryotes; PfpI (so-called from P. furious protease variants is reported in the Ensembl database I) and other bacterial proteases; araC and other http://www.ensembl.org (Figure 3). The majority of bacterial transcription factors; and the glutamine mRNAs contain a 570 bp ORF, encoding a protein amidotransferases family (including bacteria of 189 aa. Two shorter transcripts (PARK7-003 catalases) (Bonifati, Rizzu, Squitieri, et al., 2003). lacking exon 4, and PARK7-010 starting at an inner Expression transcription point) produce smaller proteins (169 and 160 aa respectively) (Table 2 and Fig. 3). Other DJ-1 is a ubiquitous protein, highly expressed in transcripts do not encode proteins and are processed almost all cells and tissue (Figure 5). Distribution via the NMD (non-sense mediated decay) studies indicate that DJ-1 is preferentially expressed mechanism. in testis, brain and kidney. In the brain, DJ-1 is expressed in both neurons and glial cells. The Pseudogene expression level of DJ-1 is increased under oxidative PGOHUM00000239770: Chr. 12, Start Coordinate stress conditions both in PD and other 49988931, Stop Coordinate 49989471 according neurodegenerative diseases(Ariga et al., 2013). DJ-1 toGenome BrowserHuman Dec. 2013 is also frequently overexpressed in the several tumor (GRCh38/hg38) Assembly types (Cao et al., 2015). PGOHUM00000236716: Chr. 9, Start Coordinate

# Name Ensembl Transcript ID bp Biotype Protein 1 PARK7-004 ENST00000493373 624 Protein coding 189aa 2 PARK7-002 ENST00000338639 949 Protein coding 189aa 3 PARK7-007 ENST00000460192 567 Processed transcript No protein 4 PARK7-001 ENST00000493678 1088 Protein coding 189aa 5 PARK7-003 ENST00000377493 795 Protein coding 169aa 6 PARK7-008 ENST00000465354 949 Processed transcript No rotein 7 PARK7-005 ENST00000377491 977 Protein coding 189aa 8 PARK7-006 ENST00000377488 783 Protein coding 189aa 9 PARK7-009 ENST00000497113 670 Processed transcript No protein 10 PARK7-010 ENST00000469225 711 Protein coding 160aa

Table 1.

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Figure 3 displays the structures of the currently known PARK7 mRNA splicing variants listed in Ensembl. Each mRNA variant is indicated with a number corresponding to that indicated in Table 1. Transcript variants are classified as coding mRNAs (black) and non-coding (gray).

Localisation other cysteine residues then follow the same process of oxidation. Subcellular localization: DJ-1 is mainly localized in The regulation of transcription is mediated by DJ-1 the nucleus, cytoplasm, and mitochondria and is binding with various transcription factors without secreted into culture medium or serum, directly tie up to DNA. Transcription factors or cerebrospinal fluid, saliva and nipple fluid(Ariga, modified proteins identified so far include TP53, the 2015). DJ-1 is translocated from the cytoplasm to androgen receptorAR and its regulatory proteins, the nucleus upon addition of a mitogen to the culture polypyrimidine tract-binding protein-associated medium, while it translocates to mitochondria after splicing factor(SFPQ), KEAP1, an inhibitor for oxidative stress (Junn et al., 2009). nuclear factor erythroid-2 related factor 2 (NFE2L2), Function the sterol regulatory element-binding protein (SREBP), Ras-responsive element-binding protein The product of DJ-1 is an 189 amino acidic highly (RREB1), and signal transducer and activator of conserved multifunctional protein belonging to the transcription1 (STAT1) (Ariga, 2015). peptidase C56 family (Lev et al., 2006). It mainly DJ-1 is also involved in the activation or repression acts as regulator of transcription, redox-sensitive of cell growth and cell death signaling pathways. chaperone, sensor for oxidative stress, cysteine Specifically, this polypeptide modulates p53 protease, and seems to protect neurons from ROS- activity, the PI3K/Akt pathway by interacting with induced apoptosis (Figure 7) (Xu et al., 2005; Ariga PTEN, and intervenes in the Raf/Erk pathway et al., 2013). together with ras (Ariga, 2015). To this regard, it The oxidative stress sensor activity is carried out by should be reminded that the first identified DJ-1 three cysteine residues at C46, C53 and C106: under function was its oncogene activity transforming oxidative stress conditions, C106 is firstly oxidized mouse NIH3T3 cells in cooperation with activated from SH to SOH, SO2H and to SO3H form. The ras (Nagakubo et al., 1997).

Figure 4 shows the crystallographic structure of DJ-1 protein. This protein is a dimer composed of two portions, monomer A represented in purple and monomer B represented in green. Adapted from (Wilson et al., 2003).

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Figure 5 (adapted from PROTEOMICS DB - www.proteomicsdb.org) shows the central and peripheral distribution of DJ-1 in human tissues. It is a ubiquitous protein, expressed in almost all human body systems.

Figure 6 (fromGeneCards database http://www.genecards.org/ and based on Compartments http://compartments.jensenlab.org/) shows the subcellular localizations of DJ-1 into cellular structures. Data are derived from database annotations, automatic text mining of the biomedical literature, and sequence-based predictions. The confidence of each association is indicated with numbers (the higher number corresponds to a greater confidence).

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Epigenetics No currently known epigenetic mechanismsregulating PARK7. Implicated in Parkinson's Disease Mutations in PARK7 are the less common cause of autosomal recessive Parkinsonism (~ 1% of early- onset PD) (Lockhart et al., 2004; Moore et al., 2005). The first identified mutations were a large homozygous deletion and a missense mutation (L166P) identified in both Italian and Dutch consanguineous families (van Duijn et al., 2001; Bonifati, Rizzu, Squitieri, et al., 2003). The other observed familial mutations are summarized in Table 2. Familial amyloid polyneuropathy Transthyretin (TTR), a protein causing familial amyloidotic polyneuropathy (FAP), is a substrate of DJ-1 protease (Koide-Yoshida et al., 2007). In normal conditions, both TTR and DJ-1 are secreted into the culture medium. Under oxidative stress, Figure 7 summarizes the functions of DJ-1 and related TTR but not DJ-1 is secreted into the culture diseases. It is though that excess of activation or loss of function of DJ-1 triggers the onset of various diseases, medium, resulting in the aggregation of TTR protein. including cancer and oxidative stress-related diseases. Mirror images of both the expression patterns and Abbreviations: PD - Parkinson's Disease, FAP - familial solubility of DJ-1 and TTR have been observed in amyloid polyneuropathy; COPD - chronic obstructive tissues of FAP patients, and the unoxidized form of pulmonary disease. Adapted from (Ariga, 2015). DJ-1 is secreted into the serum of FAP patients. Homology These results suggest that oxidative stress abrogates The PARK7 Gene Tree shows a great evolutionary secretion of DJ-1 and that secreted DJ-1 degrades conservation across species (Figure 8). The internal aggregated TTR to protect against the onset of FAP nodes of the phylogenetic tree are annotated for (Koide-Yoshida et al., 2007). duplication (red boxes) and speciation (blue boxes) Chronic obstructive pulmonary events, which correspond to paralogs and orthologs disease genes respectively. Disease Mutations Chronic obstructive pulmonary disease (COPD) is caused by cigarette smoking and oxidative stress. Somatic Malhotra et al. assessed the expression of NFE2L2 See Table 2. (NRF2) and DJ-1 in non-COPD and smoker COPD lungs and in cigarette smoke-exposed human lung Germinal epithelial cells (Beas2B) and mice (Malhotra et al., A wide spectrum of mutations in PARK7 have been 2008). COPD patient lungs showed significantly identified in familial Parkinson's Disease patients decreased DJ-1 levels. from different ethnicities. Mutations include Exposure of Bea2B cells to cigarette smoke caused missense mutations in coding and UTR regions, oxidative modification and enhanced proteasomal frame-shifts, copy number variations, and splice degradation of DJ-1 protein. Disruption of DJ-1 in sites alterations (Table 2). mouse lungs, mouse embryonic fibroblasts, and Beas2B cells lowered NRF2 protein stability and Somatic impaired antioxidant induction in response to Along with the germinal mutations occurring in cigarette smoke. Overall, DJ-1 expression was Parkinson's Disease, genetic defects have also been negatively associated with severity of COPD observed in solid tumors. A list of the known cancer- (Malhotra et al., 2008). derived mutations is available at the COSMIC Database and is summarized in Figure 9.

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PARK7 Mutations Exon References Ex1-5del(g.07561_21658del14098) EX1-5 (Bonifati, Rizzu, van Baren, et al., 2003) Ex1-5dup (breakpoints not mapped) EX1-5 (Macedo et al., 2009) Ex2del (breakpoints not mapped) EX2 (Guo et al., 2010) Ex5del (breakpoints not mapped) EX5 (Djarmati et al., 2004) Ex5-7del (breakpoints not mapped) EX5-7 (Hedrich et al., 2004) c.-122_-107del (g.10539_10554del16) 5'UTR (Keyser et al., 2009) Leu10Pro (g.11658T>C) EX2 (Guo et al., 2008) Met26Ile (g.11707G>A) EX2 (Abou-Sleiman et al., 2003) Ala39Ser (g.14192G>T) EX3 (Tang et al., 2006) Glu64Asp (g.14269G>C) EX3 (Hering et al., 2004) Gly78 (g.18230C>T) EX2 (Abou-Sleiman et al., 2003) IVS4+8_9insA (g.18256_18257insA) IVS4 (Tarantino et al., 2009) (Abou-Sleiman et al., 2003), (Lockhart et al., Arg98Gln (g.19778G>A) EX5 2004), (Healy et al., 2004), (Clark et al., 2004), (Pankratz et al., 2006) Arg98(g.19779G>A) EX5 (Abou-Sleiman et al., 2003) Ala104Thr(g.19795G>A) EX5 Clark et al., 2004) IVS5+2_12del (g.19809_19819del11) IVS5 (Hedrich et al., 2004) Asp149Ala (g.33774A>C) EX7 (Abou-Sleiman et al., 2003) Pro158del (g.33799_33801delGCC) EX7 Macedo et al., 2009) Thr160 (g.33808C>A) EX7 (Pankratz et al., 2006) Glu163Lys (g.33815G>A) EX7 (Annesi et al., 2005) Leu166Pro (g.33825T>C) EX7 (Bonifati, Rizzu, van Baren, et al., 2003) Ala167 (g.33829A>G) EX7 (Abou-Sleiman et al., 2003) Ala171Ser (g.33839G>T) EX7 (Clark et al., 2004) Lys175Glu (g.33851A>G) EX7 (Nuytemans et al., 2009) (Macedo et al., 2009) , (Nuytemans et al., Ala179Thr (g.33863G>A) EX7 2009) Val186 (g.33886T>C) EX7 (Hering et al., 2004) c.*120insA (g.34018_34019insA) EX7 (Abou-Sleiman et al., 2003) c.*203G>A (g.34101G>A) EX7 (Abou-Sleiman et al., 2003)

Table 2 displays the currently known PARK7 genetic mutations related to familial Parkinson's Disease. Details are available at the Parkinson Disease Mutation Database (http://www.molgen.vib-ua.be/PDMutDB/).

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Figure 8. The PARK7 Gene Tree shows the maximum likelihood phylogenetic tree representing the evolutionary history of this gene, constructed using the alignment of a representative protein for each species (green bars). This Gene tree has been generated by Ensembl (GeneTree ENSGT00390000001231).

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Figure 9 shows the overall distribution of PARK7 somatic mutations in cancer listed in COSMIC Database (http://cancer.sanger.ac.uk/cosmic) (March 2016). The exact number of collected somatic mutations in different cancer types is indicated in the data labels.

Type II Diabetes activate the apoptotic pathway in the benign prostatic cells but not in PC-3 cells, which are The expression of DJ-1 is reduced in pancreatic islets resistant to their action (Hod, 2004). of patients with type 2 diabetes mellitus (T2DM). Under non-diabetic conditions, DJ-1 expression Renal carcinoma increases in mouse and human islets during aging. The expression level of DJ-1 mRNA in a series of Jain et al. demonstrated that, in mouse islets, DJ-1 176 renal cell carcinomas (RCC) has been measured prevents an increase in reactive oxygen species and by (Sitaram et al., 2009). The level of DJ-1 has been preserves mitochondrial integrity and physiology, demonstrated significantly elevated in clear cell prerequisites for glucose-stimulated insulin RCC compared with papillary RCC and kidney secretion(Jain et al., 2012). Accordingly, DJ-1- cortex tissue. deficient mice developed glucose intolerance and Hepatocellular carcinoma reduced βcell area as they age or gain weight. These data suggested that DJ-1 is more generally involved DJ-1 was found significantly up-regulated in 149 in age- and lifestyle-related human diseases and hepatocellular carcinomas (HCC). DJ-1 expression show that DJ-1 plays a key role in glucose correlates with preoperative alpha-fetoprotein, liver homeostasis (Jain et al., 2012). cirrhosis, vein invasion, differentiation and overall survival, thus suggesting DJ-1 as a candidate Stroke prognostic biomarker of HCC (S. Liu et al., 2010). Loss of DJ-1 increases the sensitivity to Ovarian carcinoma excitotoxicity and ischemia, whereas expression of DJ-1 can reverse this sensitivity and provide The expression and clinical role of DJ-1 and its protection (Aleyasin et al., 2007). Importantly, DJ-1 putative association with transcriptional regulators expression decreases markers of oxidative stress specific proteins (SP1 and SP3) were investigated in after stroke insult in vivo, suggesting that DJ-1 ovarian carcinoma by (Davidson et al., 2008). RT- protects through alleviation of oxidative stress PCR reactions and immunohistochemistry were used (Aleyasin et al., 2007). Consistent with this finding, to analyze the expression levels of DJ-1, Sp1 and (Aleyasin et al., 2007) demonstrated the essential Sp3 mRNAs and PTEN protein. DJ-1 expression role of the oxidation-sensitive cysteine-106 residue resulted positively associated with Sp1 expression in in the neuroprotective activity of DJ-1 after stroke. effusions, and with Sp1 and Sp3 expression in solid tumors. Overall, results show DJ-1 is frequently Prostate cancer expressed in advanced-stage ovarian carcinoma at all he intracellular level of the DJ-1 polypeptide in anatomical sites and is co-expressed with its prostatic benign hyperplasia BPH-1 cells is inducible transcriptional regulators Sp1 and Sp3. In contrast, and results markedly increased after exposure to PTEN expression is infrequent in this disease. stress-inducing agents (H 2 O 2 and mitomycin C). The expression of DJ-1 is relatively high in PC-3 Breast cancer cells at the constitutive level, and incubation with the Expression of DJ-1 was examined by same cytotoxic drugs does not further modulate the immunohistochemistry and in-situ hybridization in polypeptide expression. Both cytotoxic agents 273 breast invasive ductal carcinomas (IDCs) and 41

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breast ductal carcinomas in situ (DCISs) and in 2014).DJ-1 expression in endometrial cancer tissues cancer cell lines (MDA-MB-231). DJ-1 protein was higher than in tumor-adjacent tissues and expression resulted lower than adjacent non- normal endometrial tissues. At the same time, it was cancerous epithelium in 6 of the 41 DCISs and in 146 associated with signs of cancer progression, of the 273 IDCs. Patients with IDC and low DJ-1 including differentiation, myometrial invasion expression had significant shorter disease-free depth, and presence of lymph node metastasis. survival and overall survival. Low expression of DJ- Overall, high DJ-1 expression seems to be negatively 1 protein seems to be predictive of poor outcome in correlated with apoptosis, and it may be part of the patients with IDC (Tsuchiya et al., 2012). mechanisms for the development, invasion, and Furthermore, RS/DJ-1 was found to be secreted in metastasis in endometrial cancer (Morelli et al., the breast cell line SUM-44 and in sera of diagnosed 2014). patients with breast cancer (Le Naour et al., 2001). Thyroid cancer Acute leukemia A comparative proteome analysis was performed by DJ-1 was found overexpressed in acute leukemia (Giusti et al., 2008) in order to examine the global (AL) patient samples and leukemia cell lines, giving changes of fine needle aspiration fluid protein the first clue that DJ-1 overexpression might be patterns of two variants of malignant papillary involved in leukemogenesis and/or disease thyroid cancer PTC (classical variant and tall cell progression of AL (H. Liu et al., 2008). Inactivation variant) respect to the controls. Changes in protein of DJ-1 by RNA-mediated interference (RNAi) in expression were identified using two-dimensional leukemia cell lines K562 and HL60 resulted in electrophoresis (2DE) and peptide mass finger inhibition of the proliferation potential and printing via MALDI-TOF mass spectrometry (MS), enhancement of the sensitivity of leukemia cells to as well as Western blot analysis. A significant chemotherapeutic drug etoposide(H. Liu et al., statistical up-regulation of 17 protein spots including 2008). DJ-1 was observed in classical PTC and/or tall cell Cervical cancer variant PTC with respect to controls(Giusti et al., 2008). Normal cervical epithelium and patient-matched high-grade squamous intraepithelial lesions (HSIL) Pancreas adenocarcinoma with cervical carcinoma tissue were compared by To identify potential novel biomarkers for pancreatic using laser capture microdissection and 2-D DIGE ductal adenocarcinoma (PDAC) from pancreatic (Arnouk et al., 2009). Significant expression juice, (Tian et al., 2008) carried out gel changes were observed with 53 spots corresponding electrophoresis (DIGE) and tandem mass to 23 unique proteins, including DJ-1. Results were spectrometry (MS/MS) to compare the pancreatic confirmed by immunohistochemistry using either juice profiling from 9 PDAC patients and 9 cancer- frozen sections from the same cohort or formalin free controls. Of the differently expressed proteins, fixed paraffin embedded samples from a tissue three up-regulated proteins in pancreatic cancer juice microarray. These markers can have potential were selected for validation by Western blot and applications for increasing the predictive value of immunohistochemistry, including DJ-1. Up- current screening methods (Arnouk et al., 2009). regulation of DJ-1 was associated with better differentiation (Tian et al., 2008). In another study, Non-small cell lung carcinoma the DJ-1 protein expression in tissue specimens from A proteomic approach using two-dimensional gels 41 patients was evaluated by immunohistochemistry coupled with mass spectrometry was used in non- and associated with a negative impact of small cell lung carcinoma samples to identify chemotherapy with gemcitabine on patient's proteins altered when treated with paclitaxel, a survival. Therefore, DJ-1 has been suggested as chemotherapic that activates mitogen-activated prognostic markers that express resistance of protein kinase kinase (MEK)/extracellular signal- pancreatic cancer patients to chemotherapy with regulated kinase and a MEK inhibitor (MacKeigan gemcitabine (Tsiaousidou et al., 2013). et al., 2003). This combined treatment uniquely altered the proteins RS/DJ-1 (RNA-binding Laryngeal squamous cell carcinoma regulatory subunit/DJ-1 PARK7) and RhoGDIalpha A study conducted by (Shen et al., 2011)aimed to (MacKeigan et al., 2003). explore the correlation between DJ-1 gene and survivin gene BIRC5 in laryngeal squamous cell Endometrial cancer carcinoma. The expression levels of DJ-1 gene and RT-PCR and Western blotting were performed to survivin gene in 82 laryngeal carcinoma tissues from determine the DJ-1 expression in 100 surgical patients and 82 negative surgical margin tissue specimens of endometrial cancer tissues, paired samples were measured by immunohistochemistry tumor-adjacent tissues, and 30 surgical specimens of and the relationship with clinicopathologic normal endometrium tissues (Morelli et al., parameters was assessed. Positive correlations were

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found between expression levels and patients' PROTEOMICSDB (www.proteomicsdb.org) clinical parameters in laryngeal carcinoma tissues enables navigation of proteomes, provides biological and tumor stages, but not with lymph node insight and fosters the development of proteomic metastasis. The DJ-1 gene expression level was also technology, and is a good tool to visualize the tissue related to cell differentiation. DJ-1 and survivin play distribution of mRNAs and proteins in human. a vital role in the occurrence and development of laryngeal carcinoma. DJ-1 may promote the References carcinogenesis of laryngeal cells by up-regulating Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW. the survivin gene expression (Shen et al., 2011). The role of pathogenic DJ-1 mutations in Parkinson's Esophageal squamous cell disease. Ann Neurol. 2003 Sep;54(3):283-6 carcinoma Aleyasin H, Rousseaux MW, Phillips M, Kim RH, Bland RJ, Callaghan S, Slack RS, During MJ, Mak TW, Park DS. The The expression of DJ-1 in 81 esophageal squamous Parkinson's disease gene DJ-1 is also a key regulator of cell carcinoma (ESCC) tumors, 31 paired non stroke-induced damage. Proc Natl Acad Sci U S A. 2007 neoplastic esophageal epithelia, and 19 paired ESCC Nov 20;104(47):18748-53 lymph node metastases was analyzed by (Yuen et al., Annesi G, Savettieri G, Pugliese P, D'Amelio M, Tarantino 2008). They found that cytoplasmic DJ-1 expression P, Ragonese P, La Bella V, Piccoli T, Civitelli D, Annesi F, Fierro B, Piccoli F, Arabia G, Caracciolo M, Cirò Candiano was significantly higher in ESCC and ESCC lymph IC, Quattrone A. DJ-1 mutations and parkinsonism- node metastases than in non neoplastic esophageal dementia-amyotrophic lateral sclerosis complex. Ann epithelium. ESCC specimens with high distant Neurol. 2005 Nov;58(5):803-7 metastatic potential also had a significantly higher Ariga H. Common mechanisms of onset of cancer and level of nuclear DJ-1 expression. A high level of neurodegenerative diseases. Biol Pharm Bull. nuclear DJ-1 was significantly associated with 2015;38(6):795-808 poorer patient survival in the cohort (P = 0.028). DJ- Ariga H, Takahashi-Niki K, Kato I, Maita H, Niki T, Iguchi- 1 expression was significantly associated with pAkt, Ariga SM. Neuroprotective function of DJ-1 in Parkinson's whereas nuclear DJ-1 expression was significantly disease. Oxid Med Cell Longev. 2013;2013:683920 correlated with nuclear expression of DAXX. These Arnouk H, Merkley MA, Podolsky RH, Stöppler H, Santos C, results suggest that phosphatidylinositol 3-kinase Alvarez M, Mariategui J, Ferris D, Lee JR, Dynan WS. pathway and Daxx-regulated apoptosis might be Characterization of Molecular Markers Indicative of Cervical Cancer Progression. Proteomics Clin Appl. 2009 May important in DJ-1-mediated ESCC progression. In 5;3(5):516-527 conclusion, results suggest that DJ-1 plays a very important role in transformation and progression of Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, ESCC and may be used as a prognostic marker in van Dongen JW, Vanacore N, van Swieten JC, Brice A, ESCC. Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal recessive early- Other malignancies onset parkinsonism. Science. 2003 Jan 10;299(5604):256- Increased levels of DJ-1 expression have been 9 observed in other kinds of cancer cells and tissues, Cao J, Lou S, Ying M, Yang B. DJ-1 as a human oncogene including gastric cancer (Shimwell et al., 2012; Li et and potential therapeutic target. Biochem Pharmacol. 2015 al., 2013), supraglottic cancer (Zhu et al., 2012), Feb 1;93(3):241-50 cholangiocarcinoma (Kawase et al., 2009), Clark LN, Afridi S, Mejia-Santana H, Harris J, Louis ED, glioma/glioblastomas(Hinkle et al., 2011; Wang et Cote LJ, Andrews H, Singleton A, Wavrant De-Vrieze F, Hardy J, Mayeux R, Fahn S, Waters C, Ford B, Frucht S, al., 2013), bladder carcinoma (Lee et al., 2012) and Ottman R, Marder K. Analysis of an early-onset Parkinson's melanoma (Pardo et al., 2006). Increased levels of disease cohort for DJ-1 mutations. Mov Disord. 2004 DJ-1 expression in cancer cells are parallel to Jul;19(7):796-800 severity of cancer with poor prognosis, including Davidson B, Hadar R, Schlossberg A, Sternlicht T, metastasis and invasion (Ariga, 2015). Slipicevic A, Skrede M, Risberg B, Flørenes VA, Kopolovic J, Reich R. Expression and clinical role of DJ-1, a negative regulator of PTEN, in ovarian carcinoma. Hum Pathol. 2008 To be noted Jan;39(1):87-95 COMPARTMENTS (compartments.jensenlab.org) Djarmati A, Hedrich K, Svetel M, Schäfer N, Juric V, is any updated web resource that integrates evidence Vukosavic S, Hering R, Riess O, Romac S, Klein C, Kostic on protein subcellular localization from manually V. Detection of Parkin (PARK2) and DJ1 (PARK7) mutations in early-onset Parkinson disease: Parkin curated literature, high-throughput screens, mutation frequency depends on ethnic origin of patients. automatic text mining, and sequence-based Hum Mutat. 2004 May;23(5):525 prediction methods. It can be useful to display, with Giusti L, Iacconi P, Ciregia F, Giannaccini G, Donatini GL, a certain grade of confidence, the subcellular Basolo F, Miccoli P, Pinchera A, Lucacchini A. Fine-needle localization of a specific biological molecule. aspiration of thyroid nodules: proteomic analysis to identify cancer biomarkers. J Proteome Res. 2008 Sep;7(9):4079- 88

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Guo JF, Xiao B, Liao B, Zhang XW, Nie LL, Zhang YH, Shen Lev N, Roncevic D, Ickowicz D, Melamed E, Offen D. Role L, Jiang H, Xia K, Pan Q, Yan XX, Tang BS. Mutation of DJ-1 in Parkinson's disease. J Mol Neurosci. analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in 2006;29(3):215-25 Chinese patients with autosomal recessive early-onset Parkinsonism. Mov Disord. 2008 Oct 30;23(14):2074-9 Li Y, Cui J, Zhang CH, Yang DJ, Chen JH, Zan WH, Li B, Li Z, He YL. High-expression of DJ-1 and loss of PTEN Guo JF, Zhang XW, Nie LL, Zhang HN, Liao B, Li J, Wang associated with tumor metastasis and correlated with poor L, Yan XX, Tang BS. Mutation analysis of Parkin, PINK1 prognosis of gastric carcinoma. Int J Med Sci. and DJ-1 genes in Chinese patients with sporadic early 2013;10(12):1689-97 onset parkinsonism. J Neurol. 2010 Jul;257(7):1170-5 Liu H, Wang M, Li M, Wang D, Rao Q, Wang Y, Xu Z, Wang Healy DG, Abou-Sleiman PM, Jain S, Ahmadi KR, Wood J. Expression and role of DJ-1 in leukemia. Biochem NW. Assessment of a DJ-1 (PARK7) polymorphism in Biophys Res Commun. 2008 Oct 24;375(3):477-83 Finnish PD. Neurology. 2004 Jun 22;62(12):2335 Liu S, Yang Z, Wei H, Shen W, Liu J, Yin Q, Li X, Yi J. Hedrich K, Djarmati A, Schäfer N, Hering R, Wellenbrock C, Increased DJ-1 and its prognostic significance in Weiss PH, Hilker R, Vieregge P, Ozelius LJ, Heutink P, hepatocellular carcinoma. Hepatogastroenterology. 2010 Bonifati V, Schwinger E, Lang AE, Noth J, Bressman SB, Sep-Oct;57(102-103):1247-56 Pramstaller PP, Riess O, Klein C. DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early- Lockhart PJ, Lincoln S, Hulihan M, Kachergus J, Wilkes K, onset Parkinson disease. Neurology. 2004 Feb Bisceglio G, Mash DC, Farrer MJ. DJ-1 mutations are a rare 10;62(3):389-94 cause of recessively inherited early onset parkinsonism mediated by loss of protein function. J Med Genet. 2004 Hering R, Strauss KM, Tao X, Bauer A, Woitalla D, Mietz Mar;41(3):e22 EM, Petrovic S, Bauer P, Schaible W, Müller T, Schöls L, Klein C, Berg D, Meyer PT, Schulz JB, Wollnik B, Tong L, MacKeigan JP, Clements CM, Lich JD, Pope RM, Hod Y, Krüger R, Riess O. Novel homozygous p.E64D mutation in Ting JP. Proteomic profiling drug-induced apoptosis in non- DJ1 in early onset Parkinson disease (PARK7). Hum Mutat. small cell lung carcinoma: identification of RS/DJ-1 and 2004 Oct;24(4):321-9 RhoGDIalpha Cancer Res 2003 Oct 15;63(20):6928-34 Hinkle DA, Mullett SJ, Gabris BE, Hamilton RL. DJ-1 Macedo MG, Verbaan D, Fang Y, van Rooden SM, Visser expression in glioblastomas shows positive correlation with M, Anar B, Uras A, Groen JL, Rizzu P, van Hilten JJ, Heutink p53 expression and negative correlation with epidermal P. Genotypic and phenotypic characteristics of Dutch growth factor receptor amplification. Neuropathology. 2011 patients with early onset Parkinson's disease Mov Disord Feb;31(1):29-37 2009 Jan 30;24(2):196-203 Hod Y. Differential control of apoptosis by DJ-1 in prostate Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, benign and cancer cells. J Cell Biochem. 2004 Aug Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder 15;92(6):1221-33 RM, Biswal S. Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of Jain D, Jain R, Eberhard D, Eglinger J, Bugliani M, Piemonti its positive regulator, DJ-1 Am J Respir Crit Care Med 2008 L, Marchetti P, Lammert E. Age- and diet-dependent Sep 15;178(6):592-604 requirement of DJ-1 for glucose homeostasis in mice with implications for human type 2 diabetes. J Mol Cell Biol. 2012 Moore DJ, West AB, Dawson VL, Dawson TM. Molecular Aug;4(4):221-30 pathophysiology of Parkinson's disease Annu Rev Neurosci 2005;28:57-87 Junn E, Jang WH, Zhao X, Jeong BS, Mouradian MM. Mitochondrial localization of DJ-1 leads to enhanced Morelli M, Scumaci D, Di Cello A, Venturella R, Donato G, neuroprotection. J Neurosci Res. 2009 Jan;87(1):123-9 Faniello MC, Quaresima B, Cuda G, Zullo F, Costanzo F. DJ-1 in endometrial cancer: a possible biomarker to improve Kawase H, Fujii K, Miyamoto M, Kubota KC, Hirano S, differential diagnosis between subtypes Int J Gynecol Kondo S, Inagaki F. Differential LC-MS-based proteomics Cancer 2014 May;24(4):649-58 of surgical human cholangiocarcinoma tissues. J Proteome Res. 2009 Aug;8(8):4092-103 Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi- Ariga SM, Ariga H. DJ-1, a novel oncogene which Keyser RJ, van der Merwe L, Venter M, Kinnear C, Warnich transforms mouse NIH3T3 cells in cooperation with ras L, Carr J, Bardien S. Identification of a novel functional Biochem Biophys Res Commun 1997 Feb 13;231(2):509- deletion variant in the 5'-UTR of the DJ-1 gene. BMC Med 13 Genet. 2009 Oct 13;10:105 Nuytemans K, Meeus B, Crosiers D, Brouwers N, Goossens Koide-Yoshida S, Niki T, Ueda M, Himeno S, Taira T, D, Engelborghs S, Pals P, Pickut B, Van den Broeck M, Iguchi-Ariga SM, Ando Y, Ariga H. DJ-1 degrades Corsmit E, Cras P, De Deyn PP, Del-Favero J, Van transthyretin and an inactive form of DJ-1 is secreted in Broeckhoven C, Theuns J. Relative contribution of simple familial amyloidotic polyneuropathy. Int J Mol Med. 2007 mutations vs copy number variations in five Parkinson Jun;19(6):885-93 disease genes in the Belgian population Hum Mutat Le Naour F, Misek DE, Krause MC, Deneux L, Giordano TJ, Pankratz N, Pauciulo MW, Elsaesser VE, Marek DK, Halter Scholl S, Hanash SM. Proteomics-based identification of CA, Wojcieszek J, Rudolph A, Shults CW, Foroud T, Nichols RS/DJ-1 as a novel circulating tumor antigen in breast WC; Parkinson Study Group - PROGENI Investigators. cancer. Clin Cancer Res. 2001 Nov;7(11):3328-35 Mutations in DJ-1 are rare in familial Parkinson disease Neurosci Lett 2006 Nov 20;408(3):209-13 Lee H, Choi SK, Ro JY. Overexpression of DJ-1 and HSP90α, and loss of PTEN associated with invasive Pardo M, García A, Thomas B, Piñeiro A, Akoulitchev A, urothelial carcinoma of urinary bladder: Possible prognostic Dwek RA, Zitzmann N. The characterization of the invasion markers. Oncol Lett. 2012 Mar;3(3):507-512 phenotype of uveal melanoma tumour cells shows the presence of MUC18 and HMG-1 metastasis markers and leads to the identification of DJ-1 as a potential serum biomarker Int J Cancer 2006 Sep 1;119(5):1014-22

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Shen Z, Ren Y, Ye D, Guo J, Kang C, Ding H. Significance at mRNA and protein levels in ductal carcinoma of the and relationship between DJ-1 gene and surviving gene breast Histopathology 2012 Jul;61(1):69-77 expression in laryngeal carcinoma Eur J Histochem 2011 Mar 21;55(1):e9 Wang C, Fang M, Zhang M, Li W, Guan H, Sun Y, Xie S, Zhong X. The positive correlation between DJ-1 and β- Shimwell NJ, Ward DG, Mohri Y, Mohri T, Pallan L, Teng M, catenin expression shows prognostic value for patients with Miki YC, Kusunoki M, Tucker O, Wei W, Morse J, Johnson glioma Neuropathology 2013 Dec;33(6):628-36 PJ. Macrophage migration inhibitory factor and DJ-1 in gastric cancer: differences between high-incidence and low- Wilson MA, Collins JL, Hod Y, Ringe D, Petsko GA. The 1 incidence areas Br J Cancer 2012 Oct 23;107(9):1595-601 1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease Sitaram RT, Cairney CJ, Grabowski P, Keith WN, Hallberg Proc Natl Acad Sci U S A B, Ljungberg B, Roos G. The PTEN regulator DJ-1 is associated with hTERT expression in clear cell renal cell Xu J, Zhong N, Wang H, Elias JE, Kim CY, Woldman I, Pifl carcinoma Int J Cancer 2009 Aug 15;125(4):783-90 C, Gygi SP, Geula C, Yankner BA. The Parkinson's disease-associated DJ-1 protein is a transcriptional co- Tang B, Xiong H, Sun P, Zhang Y, Wang D, Hu Z, Zhu Z, activator that protects against neuronal apoptosis Hum Mol Ma H, Pan Q, Xia JH, Xia K, Zhang Z. Association of PINK1 Genet 2005 May 1;14(9):1231-41 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease Hum Mol Genet 2006 Jun Yuen HF, Chan YP, Law S, Srivastava G, El-Tanani M, Mak 1;15(11):1816-25 TW, Chan KW. DJ-1 could predict worse prognosis in esophageal squamous cell carcinoma Cancer Epidemiol Tarantino P, Civitelli D, Annesi F, De Marco EV, Rocca FE, Biomarkers Prev 2008 Dec;17(12):3593-602 Pugliese P, Nicoletti G, Carrideo S, Provenzano G, Annesi G, Quattrone A. Compound heterozygosity in DJ-1 gene Zhu XL, Wang ZF, Lei WB, Zhuang HW, Hou WJ, Wen YH, non-coding portion related to parkinsonism Parkinsonism Wen WP. Tumorigenesis role and clinical significance of DJ- Relat Disord 2009 May;15(4):324-6 1, a negative regulator of PTEN, in supraglottic squamous cell carcinoma J Exp Clin Cancer Res 2012 Nov 14;31:94 Tian M, Cui YZ, Song GH, Zong MJ, Zhou XY, Chen Y, Han JX. Proteomic analysis identifies MMP-9, DJ-1 and A1BG van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, as overexpressed proteins in pancreatic juice from Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld pancreatic ductal adenocarcinoma patients BMC Cancer GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, 2008 Aug 16;8:241 Heutink P. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36 Am J Hum Tsiaousidou A, Lambropoulou M, Chatzitheoklitos E, Genet 2001 Sep;69(3):629-34 Tripsianis G, Tsompanidou C, Simopoulos C, Tsaroucha AK. B7H4, HSP27 and DJ-1 molecular markers as This article should be referenced as such: prognostic factors in pancreatic cancer Pancreatology 2013 Nov-Dec;13(6):564-9 La Cognata V, Cavallaro S. PARK7 (Parkinsonism associated deglycase). Atlas Genet Cytogenet Oncol Tsuchiya B, Iwaya K, Kohno N, Kawate T, Akahoshi T, Haematol. 2016; 20(12):595-606. Matsubara O, Mukai K. Clinical significance of DJ-1 as a secretory molecule: retrospective study of DJ-1 expression

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RHOBTB3 (Rho-related BTB domain containing 3) Shuo Cai, Francisco Rivero Cardiff China Medical Research Collaborative Institute of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, (SC); Centre for Cardiovascular and Metabolic Research, The Hull York Medical School, University of Hull, Cottingham Road, Hull HU6 7RX, (FR) UK. [email protected]; [email protected]

Published in Atlas Database: April 2016 Online updated version : http://AtlasGeneticsOncology.org/Genes/RHOBTB3ID43467ch5q15.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66947/04-2016-RHOBTB3ID43467ch5q15.pdf DOI: 10.4267/2042/66947 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 RHOBTB3 is one of the three members of the Description RhoBTB family. All RhoBTB proteins are The RHOBTB3 gene spans over 65 Kbp genomic characterized by a GTPase domain followed by a DNA and consists of 12 exons. The first exon splits proline-rich region, a tandem of two BTB domains the translation initiation codon (Figure 1). The and a C-terminal putative RING finger domain. In coding sequence of RHOBTB3 is 1833 nucleotides RHOBTB3 the GTPase domain has ATPase activity. long (Ramos et al., 2002). RHOBTB3 is a putative tumour suppressor gene. Expression of RHOBTB3 has been found Transcription significantly decreased in the breast, kidney, uterus, There is no evidence of transcription variants. lung, and ovary tumors and in human renal carcinomas. The mechanism of RHOBTB3 protein Protein as a tumor suppressor may be related to its function as an adaptor of cullin 3-dependent ubiquitin ligases. Note RHOBTB3 targets cyclin E for degradation and RHOBTB3 is one of the three members of the facilitates entry into the G2 phase of the cell cycle. RhoBTB family in vertebrates. The RhoBTB family RHOBTB3 also builds a multiprotein complex that was identified during the study of the genes encoding maintains HIFα (hypoxia inducible factor α) levels Rho-related proteins in the lower eukaryote low by promoting its hydroxylation, ubiquitination Dictyostelium discoideum (Rivero et al., 2002). All and degradation. three RhoBTB proteins may be implicated in Keywords tumorigenesis (Berthold et al., 2008b). tumor suppressor, ubiquitin ligase, cullin 3, HIFα, Description cyclin E RHOBTB3 is 611 amino acids long. All RhoBTB proteins share the same domain architecture: a Identity GTPase domain is followed by a proline-rich region, HGNC (Hugo): RHOBTB3 a tandem of two BTB domains and a C-terminal region (Figure 2). Location: 5q15 The GTPase domain of RHOBTB3 is considerably Location (base pair): Starts at 95,713,522 bp from divergent and unlike the GTPase domain of pter and ends at 95,824,383 bp from pter.

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RHOBTB1 and RHOBTB2, which bind GTP, it diverse renal cell carcinoma subtypes (Zhang et al., binds and hydrolyses ATP (Espinosa et al., 2009). 2015). The proline-rich region links the GTPase to the first BTB domain. In RHOBTB1 and RHOBTB2 this Localisation region could act as a SH3 domain-binding site, The localisation of endogenous RHOBTB3 has not however in RhoBTB3 the proline-rich region is not been investigated. Available antibodies fail to very prominent. recognise any endogenous RHOBTB3 in fixed cells The BTB domain (broad complex, tramtrack and and tissues. In cells expressing epitope tagged bric-a-brac) is an evolutionary conserved protein- RHOBTB3 ectopically the protein tends to form protein interaction domain that participates in aggregates in a paranuclear pattern (Berthold et al., homomeric and heteromeric associations with other 2008). When expressed at moderate levels BTB domains. The BTB domain was also identified RHOBTB3 displays a vesicular pattern as a component of multimeric cullin 3-dependent predominantly surrounding the centrosome. ubiquitin ligase complexes. The first BTB domain is RHOBTB3 co-localises with Golgi apparatus bipartite, being interrupted by an insertion of markers. Some vesicles co-localize with early unknown function that is much shorter in RhoBTB3 endosome markers or in close vicinity to than in the two other members of the family. The microtubules or stress fibres (Berthold et al., 2008; BTB domains of RhoBTB allow the formation of Espinosa et al., 2009). homodimers and of heterodimers with other proteins Function of the RhoBTB family (Berthold et al., 2008). The C-terminus is a region conserved in all members Following functions have been proposed for of the RhoBTB subfamily. It predictably folds as 4 RHOBTB3. The molecular mechanisms by which consecutive alpha-helices and one beta-strand and RhoBTB3 exerts those roles are beginning to be may constitute a RING finger domain (Manjarrez et elucidated and in most cases may be related to its al., 2014). Many RING finger domains function as role in ubiquitination. ubiquitin ligases. RHOBTB3 bears a CAAX motif 1. RHOBTB3 as adaptor of cullin 3-dependent that is typical for classical Rho GTPases. This motif ubiquitin ligases. undergoes isoprenylation of the cysteine residue and The first BTB domain binds to the N-terminal region proteolytic cleavage of the last three residues and of CUL3 (cullin 3), but not other cullins. RHOBTB3 serves for localization of the protein to membranes, is itself a substrate for the cullin 3-based ubiquitin although it's not the only determinant for the Golgi ligase complex (Berthold et al., 2008). RhoBTB apparatus targeting of RHOBTB3 (Lu and Pfeffer, proteins appear to exist in an inactive state through 2013). an intramolecular interaction of the BTB domain region with the GTPase domain (Berthold et al., Expression 2008). RHOBTB3 is ubiquitously expressed, with high Several potential substrates of RHOBTB3- mRNA levels present in placenta, testis, pancreas, dependent ubiquitin ligase complex have been adrenal and salivary glands and neural and cardiac described, including LRRC41 (MUF-1) and cyclin E tissues. It is also expressed in fetal tissues (Ramos et and RHOBTB3 also participates in the degradation al., 2002; Nagase et al., 1998). of HIF1A (HIFα hypoxia inducible factor α). They Expression of the mouse Rhobtb3 gene has been have implications in tumorigenesis and are described investigated in great detail in a gene trap mouse below. strain that expresses β-galactosidase under the RHOBTB3 also interacts with the 5-HT7a receptor, control of the endogenous Rhobtb3 promoter (Lutz the most common splice variant of HTR7, the et al., 2014). Histochemical detection of β- serotonin receptor 7. This receptor is involved in a galactosidase expression revealed a profile wide variety of pathophysiological processes of the characterized by nearly ubiquitous expression of central nervous system. Interestingly, the 5-HT7a Rhobtb3 in the embryo, with particularly high levels receptor appears to interact with cullin 3 in bone, cartilage, all types of muscle, testis and independently of RHOBTB3, and RHOBTB3 restricted areas of the nervous system. In the adult apparently inhibits proteasomal degradation of the mouse expression declines considerably, but persists receptor (Mathys et al., 2012) at low levels in cardiac muscle, the tunica media of 2. RHOBTB3 roles in cell cycle regulation and blood vessels, the muscularis of hollow organs and tumorigenesis. cartilage, and at high levels in the seminiferous RHOBTB3, like RHOBTB1 and RHOBTB2, tubules and peripheral nerves. interacts with MUF1 (LLRC41, leucine rich repeat Expression of RHOBTB3 has been found decreased containing 41). MUF1 is a nuclear protein and in kidney, breast, uterus, lung and ovary tumors in a carries a BC-box that functions as a linker in cancer profiling array (Berthold et al., 2008) and in multicomponent cullin 5-dependent ubiquitin ligase complexes (Schenkov et al., 2012). MUF1 may be a

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RHOBTB3 (Rho-related BTB domain containing 3) Cai S, Rivero F

substrate for RhoBTB-Cullin 3 ubiquitin ligase reduces the formation of the RHOBTB3-dependent complexes. The function of MUF1 is unknown, but multicomponent complex, resulting in an it is suspected to be involved in the DNA damage accumulation of HIFα. response. A tumor suppressor role for RHOBTB3 has been RHOBTB3 binds cyclin E1 (CCNE1) (and to a lesser shown in xenograft experiments with Ras- extent CCNB1 (cyclin B1)), uncoupled from its transformed embryonic fibroblasts isolated from dependent kinaseCDK2. Cyclin E regulates the cell Rhobtb3 deficient mice or HeLa cells in which cycle transition from G1 to S phase and is degraded Rhobtb3 was silenced. The xenografts were larger before entry into G2 phase. RHOBTB3 targets cyclin and had increased levels of HIFα and its gene targets. E for ubiquitination by a cullin 3-dependent It has been proposed that RHOBTB3 inhibits ubiquitin ligase that localizes at the Golgi apparatus tumorigenesis by maintaining low HIFα levels and (Lu and Pfeffer, 2013). RhoBTB3 protein consequently suppressing the Warburg effect (Zhang accumulates during the S phase after the plateau of et al., 2015). cyclin E. Depletion of RHOBTB3 causes S-phase 3. RHOBTB3 and vesicle trafficking. arrest in cultured cells accompanied by increased RHOBTB3 is a component of a complex required for levels of cyclin E and increased activity of CDK2. retrograde transport to the Golgi complex that Therefore RHOBTB3 regulates the S/G2 transition contains RAB9A and the cargo selection protein of the cell cycle by targeting cyclin E for PLIN3 (TIP47), with which RHOBTB3 interacts ubiquitination. The RHOBTB3-CUL3 pathway (Espinosa et al., 2009). When RHOBTB3 is depleted constitutes an alternative ubiquitination route to the by gene silencing the Golgi apparatus becomes KITLG (SCF)- FBXW7 pathway, but these two fragmented (Lu and Pfeffer 2013) and the mannose- pathways may target different pools of cyclin E. This 6-P receptor adopts a disperse localization in Rab9 mechanism may contribute to the role of RHOBTB3 positive vesicles, indicative of altered retrograde as a tumor suppressor. Deregulation of cyclin E transport, but endocytosis and exocytosis are not levels can have a significant impact on cell changed (Espinosa et al., 2009). A model has been proliferation, as shown in a significant percentage of proposed in which Rab9 on vesicles travelling from breast cancers where high cyclin E correlates with late endosomes to the Golgi relieves the tumor stage and grade. autoinhibitory conformation of RHOBTB3 and Regulation of HIFα levels constitutes another case of allows maximal ATP hydrolysis. Activation of cross-talk between different ubiquitination RHOBTB3 releases TIP47, facilitating vesicle pathways. HIFs are key regulators of adaptive uncoating and membrane fusion (Pfeffer 2009). responses to low oxygen concentration. In the 4. Other roles. presence of oxygen their α-subunits are rapidly A case of a male carrying a balanced paracentric degraded through an ubiquitination-dependent inversion of chromosome 5 that disrupts RHOBTB3 proteasomal pathway after hydroxylation. Under has been reported. This patient showed asymmetric hypoxia conditions HIFs accumulate and bind to leg growth and large hands and behavior problems. hypoxia responsive elements of various genes, in It hasn't been determined whether disruption of many cases related to aspects of cancer growth. In RHOBTB3 is the cause of those alterations (Chen et fact, aberrant accumulation or activation of HIFs is al., 2010). closely linked to many types of cancer. The characterization of a gene trap knockout mouse Hydroxylated HIFα is targeted for ubiquitination by strain has shown that disruption of the Rhobtb3 gene the von Hippel-Lindau (VHL) protein, a component causes reduced perinatal viability, a postnatal growth of a CUL2 (cullin 2)-dependent ubiquitin ligase defect that persists in males after weaning and (Tanimoto et al., 2000). reduced testis size (Lutz et al., 2014). Ablation of RHOBTB3 acts as a scaffold for a multicomponent Rhobtb3 only caused very modest changes in the complex that regulates the degradation of HIFα. pattern of gene expression of adult heart and brain. RHOBTB3 binds the prolyl hydroxylase EGLN1 Lack of Rhobtb3 did not affect the rate of (PHD2) that promotes hydroxylation of HIFα proliferation of primary lung fibroblasts isolated (Zhang et al., 2015). The complex also binds VHL from 10-week-old animals (Lutz et al., 2014) but protein and facilitates ubiquitination of HIFα. higher proliferation rates have been reported in Additionally RHOBTB3 appears to heterodimerize mouse embryonic fibroblasts (Zhang et al., 2015). with LIMD1, an adaptor for PHD2 and VHL, and RHOBTB3 has been identified as a candidate blood this interaction enhances the activity of the complex. biomarker for hallucinations. Gene expression was The chaperone HSP90AA1 (Hsp90) is incorporated found decreased in high hallucination states (Kurian to the complex through interaction with HIFα and et al., 2011). RHOBTB3 has also been proposed as a does not seem to interact with RHOBTB3. Hsp90 candidate vulnerability gene for Alzheimer's disease may contribute to relieve the autoinhibitory (Miller et al., 2013). conformation of RHOBTB3, as it has been proposed Like other members of the RhoBTB family, for RHOBTB2 (Manjarrez et al., 2014). Hypoxia RHOBTB3 has no apparent influence on cell

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RHOBTB3 (Rho-related BTB domain containing 3) Cai S, Rivero F

morphology and actin organization (Berthold et al., Lutz J, Grimm-Günter EM, Joshi P, Rivero F. Expression 2008). analysis of mouse Rhobtb3 using a LacZ reporter and preliminary characterization of a knockout strain. Histochem Homology Cell Biol. 2014 Nov;142(5):511-28 There are three RhoBTB proteins in vertebrates: Manjarrez JR, Sun L, Prince T, Matts RL. Hsp90-dependent RHOBTB1, RHOBTB2 and RhOBTB3 (Figure 2). assembly of the DBC2/RhoBTB2-Cullin3 E3-ligase complex. PLoS One. 2014;9(3):e90054 RHOBTB2 is very similar to RHOBTB1, while RHOBTB3 displays very low similarity to these. Matthys A, Van Craenenbroeck K, Lintermans B, Haegeman G, Vanhoenacker P. RhoBTB3 interacts with the Orthologues have been found in amoebae and in 5-HT7a receptor and inhibits its proteasomal degradation. insects but they are absent in plants and fungi. Cell Signal. 2012 May;24(5):1053-63 Miller JA, Woltjer RL, Goodenbour JM, Horvath S, Mutations Geschwind DH. Genes and pathways underlying regional and cell type changes in Alzheimer's disease. Genome No pathogenic mutations have been identified to Med. 2013;5(5):48 date. Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O. Prediction of the Implicated in coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain Various cancers, including kidney, which code for large proteins in vitro. DNA Res. 1998 Oct breast, uterus, lung and ovary 30;5(5):277-86 Pfeffer SR. Multiple routes of protein transport from Expression of RHOBTB3 was found moderately but endosomes to the trans Golgi network. FEBS Lett. 2009 significantly decreased in breast, kidney, uterus, Dec 3;583(23):3811-6 lung, and ovary tumour samples in a cancer profiling Pfeffer SR. Multiple routes of protein transport from array. The decrease affected to 80% of kidney and to endosomes to the trans Golgi network. FEBS Lett. 2009 56% of breast cancer samples. The expression Dec 3;583(23):3811-6 changes correlated with those of CUL3 in the same Ramos S, Khademi F, Somesh BP, Rivero F. Genomic samples (Berthold et al., 2008) organization and expression profile of the small GTPases of the RhoBTB family in human and mouse. Gene. 2002 Oct Renal cell carcinoma 2;298(2):147-57 RHOBTB3 expression is significantly decreased in Rivero F, Dislich H, Glöckner G, Noegel AA. The clear cell renal cell carcinoma, papillary renal cell Dictyostelium discoideum family of Rho-related proteins. carcinoma, hereditary clear cell renal cell carcinoma Nucleic Acids Res. 2001 Mar 1;29(5):1068-79 and non-hereditary clear cell renal cell carcinoma Schenková K, Lutz J, Kopp M, Ramos S, Rivero F. subtypes (Zhang et al., 2015). MUF1/leucine-rich repeat containing 41 (LRRC41), a substrate of RhoBTB-dependent cullin 3 ubiquitin ligase References complexes, is a predominantly nuclear dimeric protein. J Mol Biol. 2012 Oct 5;422(5):659-73 Berthold J, Schenkova K, Rivero F. Rho GTPases of the Schenková K, Lutz J, Kopp M, Ramos S, Rivero F. RhoBTB subfamily and tumorigenesis. Acta Pharmacol Sin. MUF1/leucine-rich repeat containing 41 (LRRC41), a 2008 Mar;29(3):285-95 substrate of RhoBTB-dependent cullin 3 ubiquitin ligase Chen W, Ullmann R, Langnick C, Menzel C, et al.. complexes, is a predominantly nuclear dimeric protein. J Breakpoint analysis of balanced chromosome Mol Biol. 2012 Oct 5;422(5):659-73 rearrangements by next-generation paired-end sequencing. Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism Eur J Hum Genet. 2010 May;18(5):539-43 of regulation of the hypoxia-inducible factor-1 alpha by the Espinosa EJ, Calero M, Sridevi K, Pfeffer SR. RhoBTB3: a von Hippel-Lindau tumor suppressor protein. EMBO J. 2000 Rho GTPase-family ATPase required for endosome to Golgi Aug 15;19(16):4298-309 transport. Cell. 2009 May 29;137(5):938-48 Zhang CS, Liu Q, Li M, Lin SY, Peng Y, et al.. RHOBTB3 Espinosa EJ, Calero M, Sridevi K, Pfeffer SR. RhoBTB3: a promotes proteasomal degradation of HIFα through Rho GTPase-family ATPase required for endosome to Golgi facilitating hydroxylation and suppresses the Warburg transport. Cell. 2009 May 29;137(5):938-48 effect. Cell Res. 2015 Sep;25(9):1025-42 Kurian SM, Le-Niculescu H, Patel SD, Bertram D, et al.. Zhang CS, Liu Q, Li M, Lin SY, Peng Y, Wu D, Li TY, Fu Q, Identification of blood biomarkers for psychosis using Jia W, Wang X, Ma T, Zong Y, Cui J, Pu C, Lian G, Guo H, convergent functional genomics. Mol Psychiatry. 2011 Ye Z, Lin SC. RHOBTB3 promotes proteasomal Jan;16(1):37-58 degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect. Cell Res. 2015 Levin AA. [Clinical significance of the disorders of hydrolysis Sep;25(9):1025-42 and disaccharide absorption in the small intestine]. Klin Med (Mosk). 1974;52(8):33-7 This article should be referenced as such: Lu A, Pfeffer SR. Golgi-associated RhoBTB3 targets cyclin Cai S, Rivero F. RHOBTB3 (Rho-related BTB domain E for ubiquitylation and promotes cell cycle progression. J containing 3). Atlas Genet Cytogenet Oncol Haematol. Cell Biol. 2013 Oct 28;203(2):233-50 2016; 20(12):607-610.

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Leukaemia Section Short Communication

Disseminated Juvenile Xanthogranuloma Samir Dalia, Luis Miguel Juarez Salcedo Joplin, MO, USA; [email protected] (SD); Hematological Malignancies, Moffitt Cancer Center and Research Institute, Tampa, FL USA, [email protected] (LMJS)

Published in Atlas Database: March 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/DisseminJuvXanthogranulomID1716.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66948/03-2016-DisseminJuvXanthogranulomID1716.pdf DOI: 10.4267/2042/66948 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

presentation and phagocytosis. JXG is defined by Abstract pathological infiltration by histiocytes within effected tissues. Review on Disseminated Juvenile Xanthogranuloma, with data on clinics, and the Epidemiology genes involved. Preferentially affects children, usually occurs by 10 Keywords years of age, with one-half of reported cases Disseminated Juvenile Xanthogranuloma, occurring in the first year of life. Hystiocytes, skin lesions Twenty percent of the cases occur in adolescents and young adults. Male children are slightly more often Identity affected than female children, with reported ratios ranging from1.1 to 1.4. Other names Clinics JXG, Benign cephalic histiocytosis, Progressive nodular histiocytosis, Generalized (non-lipidemic) Skin and soft-tissue presentation are the most eruptive histiocytosis (skin), Xanthoma common sites of involvement and can include the disseminatum (skin plus mucosa lesions), Erheim- mucosal surface of the upper airway. Chester disease (adult form with bone and lung Cutaneous presentation consists of benign, usually involvement). asymptomatic, self-healing, red, yellow or brown maculopapular lesions primarily involving the head, Clinics and pathology neck, and trunk. These lesions are usually believed to be benign and Disease will regress spontaneously leaving a flat, atrophic scar or an area of altered pigmentation. Although Phenotype/cell stem origin systemic JXG without organ damage can have a Rudolf Virchow may have been the first to describe benign course, CNS disease may be difficult to treat a child with "cutaneous xanthomas" in 1871 as noted and is associated with severe morbidity (can cause in a 1954 report of this condition (Helwig and diabetes insipidus, seizures, hydrocephalus and Hackney, 1954). JXG is a histiocytic condition changes in the mental status) and mortality. (proliferation) in the spectrum of non-Langerhans If cytopenias are noted in these patients then bone histiocytosis that primarily affects children. The marrow involvement should be ruled out with a bone disease can be related with germline in marrow biopsy and aspirate. neurofibromatosis type 1 (NF1) that implicate the Liver infiltration may be noted in patients with potential role for MAPK hyperactivity in elevated liver function testing, hypoalbuminemia, pathogenesis. Histiocytes are cells with specific and an elevated erythrocyte sedimentation rate. histological and immunogenic properties, Hypercalcemia can also be seen in patients with contributing to the immune response through antigen JXG.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 611 Disseminated Juvenile Xanthogranuloma

Differential diagnosis Langerhan's cell histocytosis chemotherapy. Outcomes in older children remain is the disease most often confused with JXG. Others unclear due to the lack of published data on patients disorders in the differential include fibrohistocytic with JXG. lesion NOS, reticulohistiocytoma, hemangioendothelioma, Spitz nevus, malignant Genetics fibrous histiocytoma, and rhabdomyosarcoma or other solid tumor malignancies. High prevalence of BRAF V600E, LCH and other activating MAPK mutations Pathology JXG cells are small and oval with a bland, round to References oval nucleus and pink cytoplasm. Touton cells are Liu DT, Choi PC, Chan AY. Juvenile xanthogranuloma in seen at dermal sites. childhood and adolescence: a clinicopathologic study of 129 Immunohistochemistry reveals cells that express patients from the Kiel pediatric tumor registry. Am J Surg vimentin, lysozyme, CD14, CD68, CD163, stabilin Pathol. 2005 Aug;29(8):1117; author reply 1117-8 1 and factor XIIIa. CD1 is negative. Berliner N, Rollins BJ. Congenital and Acquired Disorders of Macrophages and Histiocytes. Hematol Oncol Clin North Treatment Am. 2015 Oct;29(5):xiii-xv Treatments include using treatments similar to Dalia S, Jaglal M, Chervenick P, Cualing H, Sokol L. Langerhans cell histiocytosis including agents such Clinicopathologic characteristics and outcomes of as vinblastine, prednisone, and methotrexate. histiocytic and dendritic cell neoplasms: the moffitt cancer Clinical trials and tertiary care center referrals are center experience over the last twenty five years. Cancers recommended for treatment and evaluation of JXG. (Basel). 2014 Nov 14;6(4):2275-95 Ferguson SD, Waguespack SG, Langford LA, Ater JL, Prognosis McCutcheon IE. Fatal juvenile xanthogranuloma presenting Patients with only skin or soft tissue involvement as a sellar lesion: case report and literature review. Childs have a high survival rate, and lesions can Nerv Syst. 2015 May;31(5):777-84 spontaneously disappear over time in a majority of This article should be referenced as such: cases. Infants with large retroperitoneal masses, Dalia S, Juarez Salcedo LM. Disseminated Juvenile liver, bone marrow, or central nervous system Xanthogranuloma. Atlas Genet Cytogenet Oncol involvement usually have good outcomes with Haematol. 2016; 20(12):611-612.

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Leukaemia Section Short Communication t(9;11)(p21;q23) KMT2A/MLLT3 Jeroen Knijnenburg, H. Berna Beverloo Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. [email protected]

Published in Atlas Database: March 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0911ID1001.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66949/03-2016-t0911ID1001.pdf DOI: 10.4267/2042/66949 This article is an update of : t(9;11)(p21;q23) KMT2A/MLLT3. Atlas Genet Cytogenet Oncol Haematol 2016;20(12) Huret JL. t(9;11)(p22;q23). Atlas Genet Cytogenet Oncol Haematol 1997;1(2)

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Abstract Clinics Review on t(9;11)(p21;q23), with data on clinics, Organomegaly, frequent central nervous system and the genes involved. (CNS) involvement, especially in de novo cases; no preceding myelodysplastic phase, unlike classic Keywords therapy related AML with chromosome 5 and/or 7 chromosome 9; chromosome 11; acute myeloid involvement, short interval from initial drug therapy leukemia; KMT2A; MLLT3. (may even be of 1-2 yrs). Patients may present with disseminated intravascular coagulation and may Clinics and pathology have tissue infiltration. Disease Cytology Acute myeloid leukemia (AML). Absence of trilineage dysplasia, unlike classic Phenotype/cell stem origin therapy related AML. Most often found in acute monocytic and Prognosis myelomonocytic leukaemias, although occasionally Survival is described as poor to intermediate, being also seen in AML with or without maturation (WHO superior to AML with other KMT2A translocations. 2008). M5 most often (especially M5a, M4); both found in Cytogenetics de novo and therapy related AML with antitopoisomerase II drugs (epipodophyllotoxins, Cytogenetics morphological anthracyclins, actinomycin D). May easily be overlooked. Previously described as Immunophenotype typically shows positivity for t(9;11)(p22;q23) based on band estimation, but CD11, CD13, CD15 and CD33, but less often shows nowadays it is known that MLLT3 is located in positivity for CD14, CD34 and lymphoid markers. 9p21.3 based on molecular positioning. Epidemiology Cytogenetics molecular May occur at any age, but is more common in FISH or RT-PCR is indicated in cases with poor children, being present in 5-12% of paediatric and 1- chromosome morphology or in cases where the 2% of adult AML, and equally common in males and translocation is expected in cases based on females. morphology, immunophenotype or clinical presentation.

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t(9;11)(p21;q23) G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (top 2), Courtesy Diane H Norback, Eric B Johnson, and Sara Morrison-Delap, UW Cytogenetic Services (middle 2 and bottom 2); R-banding (right): top: - Courtesy Pascale Cornillet-Lefebvre and Stéphanie Struski, center top: t(9;11)+der(9)t(9;11) - Courtesy Christiane Chharrin; bottom 2: - Courtesy Hossein Mossafa. FISH (left) - Courtesy Pascale Cornillet-Lefebvre and Stéphanie Struski. The probe is MLL; one signal is on the normal 11, one signal on the der(11), and one signal (arrow) on the der(9); FISH (right) - Courtesy Hossein Mossafa (AN: abnormal).

Additional anomalies KMT2A (myeloid/lymphoid or mixed None in 70% of cases, +8 in 20%, less frequently: lineage leukemia) additional trisomies of chromosome 6, 19 or 21. Location Variants 11q23.3 Complex 3 way translocations t(9;11;Var) involving Protein a (variable) third chromosome and insertions have Contains two DNA binding motifs (a AT hook, and been described, and showed that der(11) is the Zinc fingers), a DNA methyl transferase motif, a crucial on bromodomain; transcriptional regulatory factor; nuclear localisation. Genes involved and proteins Result of the chromosomal anomaly MLLT3 (myeloid/lymphoid or mixed- lineage leukemia (trithorax homolog, Hybrid gene Drosophila); translocated to, 3) Description Location 5' KMT2A- 3' MLLT3; variable breakpoints. 9p21.3 Fusion protein Protein Description Contains a nuclear targeting sequence; N-term -- AT hook and DNA methyltransferase from transcriptional activator; nuclear localisation. KMT2A (1444 amino acids) fused to the 192

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C-term amino acids from MLLT3 (as breakpoints Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner are variable, this is only an exemple); 180 kDa. T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Expression / Localisation Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield Nuclear localisation. CD. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010 To be noted Jan 21;115(3):453-74 You may also have a glance at 11q23 Joh T, Kagami Y, Yamamoto K, Segawa T, Takizawa J, Takahashi T, Ueda R, Seto M. Identification of MLL and rearrangements, which gives an overview of related chimeric MLL gene products involved in 11q23 translocation diseases. and possible mechanisms of leukemogenesis by MLL truncation. Oncogene. 1996 Nov 7;13(9):1945-53 References Sandoval C, Head DR, Mirro J Jr, Behm FG, Ayers GD, Raimondi SC. Translocation t(9;11)(p21;q23) in pediatric de Albain KS, Le Beau MM, Ullirsch R, Schumacher H. novo and secondary acute myeloblastic leukemia. Implication of prior treatment with drug combinations Leukemia. 1992 Jun;6(6):513-9 including inhibitors of topoisomerase II in therapy-related monocytic leukemia with a 9;11 translocation. Genes Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Chromosomes Cancer. 1990 May;2(1):53-8 Stein H, Thiele J, Vardiman JW.. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Edition; Lyon, France: IARC Press; 2008. Alonzo TA, Auvrignon A, Beverloo HB, Chang M, Creutzig U, Dworzak MN, Forestier E, Gibson B, Hasle H, Harrison This article should be referenced as such: CJ, Heerema NA, Kaspers GJ, Leszl A, Litvinko N, Nigro LL, Morimoto A, Perot C, Pieters R, Reinhardt D, Rubnitz JE, Knijnenburg J, Beverloo HB. t(9;11)(p21;q23) Smith FO, Stary J, Stasevich I, Strehl S, Taga T, Tomizawa KMT2A/MLLT3. Atlas Genet Cytogenet Oncol Haematol. D, Webb D, Zemanova Z, Zwaan CM, van den Heuvel- 2016; 20(12):613-615. Eibrink MM. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009 Sep 17;114(12):2489-96

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Leukaemia Section Review t(X;14)(q28;q11.2) TRA-TRD/MTCP1 / t(X;7)(q28;q34) TRB/MTCP1 Aurelia M. Meloni-Ehrig CSI Laboratories, Alpharetta, GA / e-Mail: [email protected]

Published in Atlas Database: March 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/tX14q28q11ID2051.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66950/03-2016-tX14q28q11ID2051.pdf DOI: 10.4267/2042/66950 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 Disease T-cell prolymphocytic leukemia (T-PLL) T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive post-thymic lymphoid neoplasm Phenotype/cell stem origin characterized by recurrent chromosome CD4+CD8- (65-70%) CD4+CD8+ (21-25%), or rearrangements that lead to activation of the TCL1A CD4-CD8+ (10-13%), CD7+ bright and surface (14q32.1) or the MTCP1 (Xq28) genes. In this CD3 negative in 20% of cases. report, we focus on the t(X;14)(q28;q11.2), which is The coexpression of CD4 and CD8 together with thought to occur in approximately 20% of T-PLL weak CD3 and strong CD7 expression suggest that cases and leads to overexpression of the MTCP1 the T-PLL cell stage of differentiation is between a gene by relocation to the T-cell receptor alpha/delta cortical thymocyte and a mature T-cell (Matutes, (TRA/D) located at 14q11.2 locus. A rare variant of 1998). the t(X;14) is the t(X;7)(q28;q34) also leading to overexpression of MTCP1 this time by relocation to the T-cell receptor beta (TRB) locus. Approximately 80% of T-PLL cases, however, are characterized by the inv(14)(q11.2q32.1) and variants, which lead to the activation of the TCL1A (14q32.1) gene by relocation to the TRA/D or TRB gene loci. The additional abnormalities in cases with MTCP1 or TCL1A related abnormalities are similar and include gain of 8q usually in the form of i(8q), as well as deletions 6q, 9p, 11q, and 13q. Keywords t(X;14)(q28;q11.2), t(X;7)(q28;q34), T-cell prolymphocytic leukemia (T-PLL), MTCP1, TCL1A, Ataxia Telangiectasia, ATM Partial karyotype of the t(X;14)(q28;q11.2) Clinics and pathology Etiology T-PLL accounts for about 2% of all mature lymphoid Note neoplasms. Most patients are older than 50 years. These translocations are known to occur in: However, some patients aged as young as 30 years T-cell prolymphocytic leukemia (T-PLL) have been reported. The disease affects more male Ataxia telangiectasia (AT) than female patients (3:1 ratio) (Matutes, 1998).

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t(X;14) full karyotype.

Epidemiology The disease is widespread and does not appear to have a geographic predilection or racial clustering. Clinics T-PLL is a rare and aggressive post-thymic lymphoid neoplasm characterized by a high white cell count (usually >100,000/μL) with associated anemia and thrombocytopenia (Magro et al, 1986). Often there is infiltration of the bone marrow, spleen, liver, lymph nodes, and skin. Patients often present with hepatosplenomegaly and generalized lymphadenopathy (Matutes et al, 1991). The median survival is usually < 1 year. However, occasional spontaneous remission has Cytology of typical T-PLL cells in peripheral blood. Cells are medium-sized with regular nuclear outline, single nucleolus, been reported in some cases. and intense basophilic cytoplasm. Morphologically, T-PLL includes 3 morphologic variants: typical, small cell, and cerebriform, all of Cytogenetics which have a similar clinical course and genetic Stimulation with a T-cell mitogen (typically PHA) is abnormalities (Matutes et al, 1986). necessary to obtain metaphase cells for analysis. Approximately 15% of patients may be Most cases of T-PLL have a complex karyotype. asymptomatic at diagnosis (indolent phase), which Inversion (14)(q11.2q32.1), which leads to might persist several years before progression occurs juxtaposition of the T-cell receptor TRA/D at (Matutes et al, 1998). 14q11.2 with the TCL1A gene at 14q32.1, is the most common abnormality present in approximately Cytology 70% of cases (Costa et al., 2003. Another 10% of T-PLL includes 3 morphologic variants: typical, patients have the variant t(14;14)(q11.2;q32.1) small cell, and cerebriform, all of which have a involving the same genes as the inv(14). Both similar clinical course and genetic abnormalities. aberrations lead to overexpression of the TCL1A Majority (75%) of T-PLL patients have the typical gene (Mossafa et al., 1994). The t(X;14)(q28;q11.2) variant where the cells show a regular nuclear is present in about 20% of the cases (de Oliveira et outline; 20% have the small cell variant; and 5% al., 2009). This translocation juxtaposes the TRA/D have cells with a more irregular nuclear shape with the MTCP1 gene at Xq28 and results in similar to the cerebriform cells seen in Sezary overexpression of the MTCP1 gene (Madani et al., syndrome (Costa et al, 2003). 1996; Soulier et al., 1994). Only few cases have been reported with the variant t(X;7)(q28;q34) involving

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MTCP1 and the T-cell receptor beta (TRB), which Various carcinomas are reported to occur in adults. also lead to overexpression of MTCP1 (De Diagnosis of AT relies on clinical findings, including Schouwer et al., 2000). slurred speech, truncal ataxia, and oculomotor ADDITIONAL ABNORMALITIES Karyotypes are apraxia; neuroimaging; and family history. complex in most cases. The most common Laboratory findings that support the diagnosis abnormalities involve chromosome 8, usually as include: severely depleted levels of intracellular i(8)(q10) in 45% of cases, but also t(8;8)(p12;q11) in ATM protein, elevated serum alpha-fetoprotein 15% of cases, +8 in 15%, and deletion 8p in 15% of concentration (Swift, 1990). cases (Mossafa et al., 1994). Furthermore, frequent losses involving 6q, 9p, 11q, 12p, 13q, 17p/TP53, Cytogenetics and 22q, and frequent gains of 6p and 7q have been Spontaneous chromatid/chromosome breaks, reported in most complex karyotypes (Matutes et al., triradials, quadriradials (less prominent phenomenon 1991; Costa et al., 2003). Mutations in the ATM than in Fanconi anemia), telomeric associations. The (ataxia telangiectasia mutated) gene, located in the best diagnosis test is on the (pathognomonic) highly 11q22.3 region have been associated with elevated level (10% of mitoses) of inv(7)(p14q35), inactivation or significantly reduced expression of t(14;14)(q11;q32), and other nonclonal stable the ATM protein, which is believed to function as a chromosome rearrangements involving 2p12, 7p14, tumor suppressor (Stankovic et al., 2001). 7q 35, 14q11, 14q32, and 22q11 (illegitimate Treatment recombinations between immunoglobulin superfamily genes Ig and TCR); normal level of T-PLL is a neoplasm characterized by an aggressive those rearrangements are: 1/500 [inv(14)), 1/200 course, poor response to conventional chemotherapy (t(7;14)], 1/10 000 (inv(7)) clonal rearrangements and a short median survival. Treatment with purine further occur in 10% of patients, but without analogs and the monoclonal antibody alemtuzumab manifestation of malignancy: t(14;14), inv(14), or has resulted in significantly higher response rates t(X;14) (Bartram et al., 1976; Taylor et al., 1992; and increased survival (Szuszies et al., 2014). Thick et al., 1994). However, responses are transient and allogeneic hematopoietic progenitor-cell transplantation Genes involved and remains the only potential curative option. The proportion of patients eligible for transplant is low, proteins owing to the older age group of patients, and nonmyeloablative transplantation is a promising MTCP1 (Mature T Cell Proliferation 1) alternative that needs to be explored. Location Disease Xq28 Ataxia telangiectasia (AT) Note The gene has two ORFs that encode two different Epidemiology proteins. The upstream ORF encodes a 13kDa AT onset occurs in early childhood and has an protein that is a member of the TCL1 gene family; incidence of approximately 1 in 40 000-100 000 live this protein may be involved in leukemogenesis births in the United States. AT is seen among all (Soulier et al., 1994). The downstream ORF encodes races and is most prominent among ethnic groups an 8kDa protein that localizes to mitochondria. with a high frequency of consanguinity. Alternative splicing results in multiple transcript Clinics variants. DNA/RNA AT is an autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated Complex alternative splicing : two donor sites in (ATM) gene. Classic ataxia-telangiectasia (A-T) is exon 1: transcripts A, the most abundant, ubiquitous, characterized by progressive cerebellar ataxia splicing from exon 1 to exon 6; transcripts B, rare : beginning between ages one and four years, splicing from exon 1 to exon 2. Initiation of the oculomotor apraxia, choreoathetosis, telangiectasias transcription : an alternative site of initiation of the of the conjunctivae, immunodeficiency, and transcription in intron 1 has been found in one tumor frequent infections. The disease is included in the with a translocation breakpoint in intron 1. group of chromosome instability syndromes Protein associated with an increased risk for malignancy, - p8 MTCP1: coded by transcripts A, 68 amino acids; particularly leukemia and lymphoma. AT children one domain formed by 3 alpha helices held together tend to develop B-cell acute lymphoblastic leukemia by two disulphide bridges in an antiparallel coiled- whereas T-cell acute lymphoblastic leukemia and T- coil motif. PLL tend to occur in teenager patients. - p13 MTCP1: coded by transcripts B, 107 amino acids; one domain with a b-barrel topology.

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t(X;14)(q28;q11.2) TRA-TRD/MTCP1 Meloni-Ehrig AM

TRA (T cell Receptor Alpha) restricted to mature T-cell proliferations with t(X;14) translocations. Blood. 1996 Mar 1;87(5):1923-7 Location Mossafa H, Brizard A, Huret JL, Brizard F, Lessard M, 14q11.2 Guilhot F, Tanzer J. Trisomy 8q due to i(8q) or der(8) t(8;8) Note is a frequent lesion in T-prolymphocytic leukaemia: four new cases and a review of the literature. Br J Haematol. 1994 The size of TCR alpha/delta (TRA/D) locus is about Apr;86(4):780-5 1 Mb. The TRD variable (V) diversity (D) joining (J) and constant region genes are situated within the Soulier J, Madani A, Cacheux V, Rosenzwajg M, Sigaux F, Stern MH. The MTCP-1/c6.1B gene encodes for a TRA locus between the TRA V and the TRA J cytoplasmic 8 kD protein overexpressed in T cell leukemia segments. The TRD locus contains three D segments bearing a t(X;14) translocation. Oncogene. 1994 and four J segments, whereas the TRA J region spans Dec;9(12):3565-70 approximately 80 Kb and contains at least 61 Swift M. Genetic aspects of ataxia-telangiectasia. segments. The TRA/D locus is transcribed in a Immunodefic Rev. 1990;2(1):67-81 centromere to telomere direction. Szuszies CJ, Hasenkamp J, Jung W, Koch R, Trümper L, DNA/RNA Wulf GG. Loss of donor chimerism in remission after allogeneic stem cell transplantation of T-prolymphocytic The TRD locus contains three D segments and four leukemia patients following alemtuzumab induction therapy. J segments, whereas the TRA J regions span Int J Hematol. 2014 Nov;100(5):425-8 approximately 80 Kb and contain at least 61 de Oliveira FM, Tone LG, Simões BP, Rego EM, Marinato segments. The TRA/D locus is transcribed in a AF, Jácomo RH, Falcão RP. Translocations centromere to telomere direction. t(X;14)(q28;q11) and t(Y;14)(q12;q11) in T-cell prolymphocytic leukemia. Int J Lab Hematol. 2009 Protein Aug;31(4):453-6 T-cell receptor alpha/delta chain. Costa D, Queralt R, Aymerich M, Carrió A, Rozman M, TRB (T cell Receptor Beta) Vallespí T, Colomer D, Nomdedeu B, Montserrat E, Campo E. High levels of chromosomal imbalances in typical and Location small-cell variants of T-cell prolymphocytic leukemia. 7q34 Cancer Genet Cytogenet. 2003 Nov;147(1):36-43 Note Magro CM, Morrison CD, Heerema N, Porcu P, Sroa N, The human TRB locus spans 620 kb and consists of Deng AC. T-cell prolymphocytic leukemia: an aggressive T cell malignancy with frequent cutaneous tropism. J Am Acad 82-85 genes. Enhancers sequences have been Dermatol. 2006 Sep;55(3):467-77 characterized at 5.5 kb 3' from TRBC2. Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla DNA/RNA R, Dearden C, Sempere A, Catovsky D. Clinical and The locus contains 2 types of coding elements : TCR laboratory features of 78 cases of T-prolymphocytic elements (64-67 variable genes TRBV, 2 clusters of leukemia. Blood. 1991 Dec 15;78(12):3269-74 diversity, joining and constant segments) and 8 Matutes E. T-cell Prolymphocytic Leukemia. Cancer trypsinogen genes. Control. 1998 Jan;5(1):19-24 Protein Stankovic T, Taylor AM, Yuille MR, Vorechovsky I. T-cell receptor beta chain. Recurrent ATM mutations in T-PLL on diverse haplotypes: no support for their germline origin. Blood. 2001 Mar References 1;97(5):1517-8 Taylor AM, Lowe PA, Stacey M, Thick J, Campbell L, Beatty Bartram CR, Koske-Westphal T, Passarge E. Chromatid D, Biggs P, Formstone CJ. Development of T-cell leukaemia exchanges in ataxia telangiectasia, Bloom syndrome, in an ataxia telangiectasia patient following clonal selection Werner syndrome, and xeroderma pigmentosum. Ann Hum in t(X;14)-containing lymphocytes. Leukemia. 1992 Genet. 1976 Jul;40(1):79-86 Sep;6(9):961-6 De Schouwer PJ, Dyer MJ, Brito-Babapulle VB, Matutes E, Thick J, Mak YF, Metcalfe J, Beatty D, Taylor AM. A gene Catovsky D, Yuille MR. T-cell prolymphocytic leukaemia: on chromosome Xq28 associated with T-cell antigen receptor gene rearrangement and a novel mode of prolymphocytic leukemia in two patients with ataxia MTCP1 B1 activation. Br J Haematol. 2000 Sep;110(4):831- telangiectasia. Leukemia. 1994 Apr;8(4):564-73 8 This article should be referenced as such: Madani A, Choukroun V, Soulier J, Cacheux V, Claisse JF, Meloni-Ehrig AM. t(X;14)(q28;q11.2) TRA-TRD/MTCP1. Valensi F, Daliphard S, Cazin B, Levy V, Leblond V, Daniel Atlas Genet Cytogenet Oncol Haematol. 2016; MT, Sigaux F, Stern MH. Expression of p13MTCP1 is 20(12):616-619.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 619 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Leukaemia Section Review t(15;17)(q24;q21) PML/RARA Pino J. Poddighe, Daniel Olde Weghuis Department of Clinical Genetics, VU University Medical Center, Amsterdam (PJP); Department of Human Genetics, Radboud University Nijmegen Medical Centre (DOW), The Netherlands. [email protected]; [email protected]

Published in Atlas Database: March 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1517ID1035.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66951/03-2016-t1517ID1035.pdf DOI: 10.4267/2042/66951

This article is an update of : Huret JL, Chomienne C. t(15;17)(q22;q21). Atlas Genet Cytogenet Oncol Haematol 1998;2(3)

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 Identity Review on t(15;17)(q24;q21), with data on clinics, The translocation, formerly known as and the genes involved. t(15;17)(q22;q21) or t(15;17)(q22;q12), has been Keywords renamed t(15;17)(q24;q21), since PML is located in chromosome 15; chromosome 17; PML; RARA; chromosome band 15q24, and RARA in acute promyelocytic leukaemia chromosome band 17q21.

t(15;17)(q24;q21) G- banding (left) - 2 top left: Courtesy Jean-Luc Lai and Alain Vanderhaegen, 2 bottom left: Courtesy Roland Berger ; R-banding (right) - top: Editor, middle: Courtesy Christiane Charrin, bottom: Courtesy Roland Berger.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 620 t(15;17)(q24;q21) PML/RARA Poddighe PJ, Weghuis DO

t(15;17)(q24;21) is associated conbsistently with AML M3. This chromosomal abnormality first appeared to be confined to the characteristic or morphologically typical M3 AML or "hypergranular promyelocytic leukemia", defined by bone marrow replacement with highly granulated blast cells. The nuclear size and shape is irregular and highly variable; they are often kidney- shaped or bilobed. The cytoplasm is completely occupied by densely packed or even coalescent large granules, staining bright pink, red or purple by MGG. In some cells the cytoplasm is filled with fine dust-like granules. Characteristic cells containing bundles of Auer rods ("faggot cells") randomly distributed in the cytoplasm, although frequent, are not present in all cases. Auer rods in M3 are usually larger than in other AML and they may have a characteristic morphology at the ultrastructural level. In some cases, the cytoplasmic granules are so large and/or numerous that they totally obscure the cell, rendering the nuclear cytoplasmic limit indistinct. In M3 AML, MPO is always strongly positive in all blast cells, with the reaction product covering the whole cytoplasm and often the nucleus too - Text and iconography Courtesy Georges Flandrin 2001.

Clinics and pathology Cytology Disease Large cells with myeloperoxidase positive Acute promyelocytic leukaemia (APL), subtype of cytoplasmic granulations (microgranular forms are acute myeloid leukaemia (AML). Mostly de novo; a called variant or hypogranular APL, and are often very few cases of t(15;17) in therapy-related hyperleucocytic); bundles of Auer rods. leukaemia (t-APL) have been reported. In sporadic The typical morphology shows abnormal, usually cases the t(15;17) can be present in chronic bilobed hypergranular promyelocytes. myelogenous leukemia (CML) in myeloid blast Sudan Black (SB) is always strongly positive in all crisis as an additional abnormality to the blast cells (WHO 2008). t(9;22)(q34;q11.2). Treatment Phenotype/cell stem origin One of the rare leukaemias where treatment is an t(15;17) is quasi pathognomonic of APL. Both emergency, as intra vascular coagulation is hypergranular or "typical" APL and microgranular prominent, causing a high rate (10 to 40%) of early (hypogranular) types exist. mortality, mainly due to cerebral haemorrhage. With Epidemiology the recent differentiation therapy using all-trans retinoic acid ATRA (with combined cytotoxic Found in 10% of adult AML; annual incidence: 1 per chemotherapy or arsenic trioxide (ATO)), complete 106, similar to the incidence of the t(8;21)(q22;q22). remission (CR) is obtained in more than 90% of The disease can occur at any age, but patients are cases; this is the only cancer which, to date, can be predominantly adult in mid-life; sex ratio 1M/1F treated by differentiation therapy. (WHO 2008). Clinics Prognosis Typical and microgranular APL are frequently The prognosis in APL, treated optimally with ATRA associated with disseminated intravascular and an anthracycline, is more favourable than for any coagulation (DIC). In microgranular APL, unlike other AML cytogenetic subtype, and cases of typical APL, the leukocyte count is very high, with relapsed or refractory APL show a generally good rapid doubling time. WBC and platelets may be response with arsenic trioxide therapy. lower than in other AMLs.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 621

t(15;17)(q24;q21) PML/RARA Poddighe PJ, Weghuis DO

FISH with the LSI PML/RARA Dual Color Dual Fusion Translocation Probe (Abbott) on a bone marrow cell sample, showing a metaphase spread and one interphase nucleus with two PML-RARA fusion signals (arrows), and one normal interphase cell with two red and two green signals. Courtesy Hossein Mossafa.

Expression of DC56 is associated with a less (RARA) gene on chromosome band 17q21 fuses favourable prognosis, (Ferrara et al 2000) while the with a nuclear regulatory factor gene on prognostic significance of FLT3 -ITD mutations in chromosome band 15q24 (PML gene) giving rise to this disease remains unclear (Kuchenbauer et al a PML-RARA fusion gene product. 2005). Survival at 1 yr and at 3 yrs are stable at 70%, Rare cases of APL lacking the classic translocation instead of a 30 to 40% 3 yr survival previously. in routine cytogenetic studies have been described with complex variant translocations (true variants) Cytogenetics involving both chromosomes 15 and 17 with an additional chromosome (three way translocations) or Cytogenetics morphological with submicroscopic insertion of RARA into PML Classic translocation t(15;17)(q24;q21). The leading to the expression of the PML-RARA translocation may be overlooked in traditional transcript; these latter cases are considered as cryptic karyotyping. Interphase FISH is indicated, or masked t(15;17)(q24;q21). Morphological preferably urgent (within 8 hours) on bone marrow analysis shows no major differences between the aspirate cells (see Figure 1). t(15;17)(q24;q21) positive group and the PML- Although primary anomaly in most cases, t(15;17) RARA positive patients without t(15;17)(q24;q21). can also occur in rare occurrences at acutisation (of Three way translocations demonstrated that the promyelocytic type, of course) of a CML with the crucial event lies on der(15), which receives the end usual t(9;22). part of chromosome 17. Additional anomalies A subset of patients, often with morphological features resembling APL, show variant Secondary cytogenetic abnormalities are noted in translocations involving RARA (17q21). These about 40% of cases, +8 most frequent (10-15%); del variant fusion partners include ZBTB16 (previously (7q) ; del(9q) rare. known as PLZF at 11q23) in t(11;17)(q23;q21), NPM1 at 5q35 in t(5;17)(q32;q12), and NUMA1 at Genes involved and 11q13 in t(11;17)(q13;q21) ID: 1126> and STAT5B proteins at 17q11.2 in dup(17)(q12q21). Some APL variants, including t(11;17)(q23;q12) with ZBTB16-RARA Note and cases with STAT5B-RARA fusions are resistant The sensitivity of APL cells (both hypergranular and to ATRA. hypogranular forms) to ATRA has led to the Mutations involving FLT3 occur in 34-45% of APL. discovery that the retinoic acid receptor alpha

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 622 t(15;17)(q24;q21) PML/RARA Poddighe PJ, Weghuis DO

PML and RARA breakpoints in the t(15;17) / 5' PML - 3' RARA fusion gene - Courtesy Hossein Mossafa.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 623

t(15;17)(q24;q21) PML/RARA Poddighe PJ, Weghuis DO

PML (promyelocytic leukemia) Oncogenesis Location Abnormal retinoic acid receptor with a dominant effect over RARa, antagonizing differentiation. 15q24.1 DNA/RNA References Numerous splices in 3'. Alcalay M, Zangrilli D, Pandolfi PP, Longo L, et al.. Protein Translocation breakpoint of acute promyelocytic leukemia Nuclear protein; contains zinc fingers and a leucine lies within the retinoic acid receptor alpha locus. Proc Natl zipper; transcription factor. Acad Sci U S A. 1991 Mar 1;88(5):1977-81 Berger R, Le Coniat M, Derré J, Vecchione D, Jonveaux P. RARA (Retinoic acid receptor, alpha) Cytogenetic studies in acute promyelocytic leukemia: a Location survey of secondary chromosomal abnormalities. Genes 17q21.2 Chromosomes Cancer. 1991 Sep;3(5):332-7 Protein Borrow J, Goddard AD, Sheer D, Solomon E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster Wide expression; nuclear receptor; binds specific region on chromosome 17. Science. 1990 Sep DNA sequences: HRE (hormone response 28;249(4976):1577-80 elements); ligand and dimerization domain; role in Fenaux P, Chastang C, Chomienne C, et al.. Treatment of growth and differentiation. newly diagnosed acute promyelocytic leukemia (APL) by all transretinoic acid (ATRA) combined with chemotherapy: Result of the chromosomal The European experience. European APL Group. Leuk Lymphoma. 1995 Feb;16(5-6):431-7 anomaly Fenaux P, Wang ZZ, Degos L. Treatment of acute promyelocytic leukemia by retinoids. Curr Top Microbiol Hybrid gene Immunol. 2007;313:101-28 Description Pandolfi PP, Alcalay M, Fagioli M, Zangrilli D, et al.. Variable breakpoint in PML between intron 3 and Genomic variability and alternative splicing generate exon 7a; constant breakpoint in intron 2 of RARa. multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute Transcript promyelocytic leukaemia. EMBO J. 1992 Apr;11(4):1397- 5' PML -3' RARa transcript is found in all cases, and 407 5' RARa - 3' PML transcript is detected in 2/3 of Warrell RP Jr, de Thé H, Wang ZY, Degos L. Acute cases. promyelocytic leukemia. N Engl J Med. 1993 Jul 15;329(3):177-89 Fusion protein de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. Description The t(15;17) translocation of acute promyelocytic leukaemia Variable, as breakpoints in PML are variable; e.g.: fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990 Oct 11;347(6293):558-61 932 amino acids; 103 kDa; N-term PML, with the DNA binding and the dimerization domains fused to This article should be referenced as such: most of RARa with the DNA and retinoid binding Poddighe PJ, Weghuis DO. t(15;17)(q24;q21) regions. PML/RARA. Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12):620-624.

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Cancer Prone Disease Section Short Communication

Denys-Drash syndrome (DDS) Maria Piccione, Emanuela Salzano Department of Sciences for Health Promotion and Mother and Child Care G. D'Alessandro, University of Palermo, Palermo, Italy. [email protected]; [email protected]

Published in Atlas Database: December 2015 Online updated version : http://AtlasGeneticsOncology.org/Kprones/DenysDrashID10036.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66952/12-2015-DenysDrashID10036.pdf DOI: 10.4267/2042/66952 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

Identity critical region are rarely reported: only 1 DDS case Other names was found carrier of 11p13-p12 deletion and none Drash syndrome with Frasier Syndrome (Jadresic et al.1991). Wilms tumor and pseudo- or true hermaphroditism However cytogenetic deletion involving 11p11 and Nephropathy, Wilms tumor, and genital anomalies 11p13 are described in sporadic Wilms Tumor and in Wilms tumor in association to WAGR (Wilms Note tumor, aniridia, genitourinary anomalies and mental Meacham Syndrome(OMIM # 608978) is an allelic retardation) Syndrome (OMIM #194072). disorder with some clinical features overlapping plus cardiac and pulmonary malformations. Genes involved and Inheritance To date about 150 patients with DDS have been proteins described and its prevalence is largerly unknown Gene-phenotype (Mueller 1994). The inheritance pattern is autosomal dominant, but most reported cases resulted from a de Denys-Drash syndrome 194080

novo mutation in germline cells or in earlier phases Frasier syndrome 136680 of embryonic development as postzygotic somatic Meacham syndrome 608978 event (Coppes et al.1992).

Mesothelioma, somatic 156240

Cytogenetics Nephrotic syndrome, type 4 256370

Deletion or chromosomal rearrangements of 11p13 Wilms tumor, type 1 194070

Comparison between Denys-Drash and Frasier Phenotypes.

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 625 Denys-Drash syndrome (DDS) Piccione M, Salzano E

WT1 (Wilms' tumor suppressor gene) expression depends on these alternatively spliced isoforms (Klamt et al 1998; Lefebvre et al. 2015). Location 11p13 References Note WT1 gene encodes for a DNA-binding protein Öçal G. Current concepts in disorders of sexual development. J Clin Res Pediatr Endocrinol. 2011;3(3):105- including four zinc-finger motifs at the C-terminus 14 and a proline/glutamine-rich DNA-binding domain Antonius T, van Bon B, Eggink A, van der Burgt I, Noordam at the N-terminus. It acts as trascriptional modulator K, van Heijst A. Denys-Drash syndrome and congenital that has an essential role in the normal development diaphragmatic hernia: another case with the 1097G > of the urogenital system. This gene has a biallelic, A(Arg366His) mutation. Am J Med Genet A. 2008 Feb and monoallelic expression from the maternal and 15;146A(4):496-9 paternal alleles in different tissues. Barbaux S, Niaudet P, Gubler MC, Grünfeld JP, et al.. Donor splice-site mutations in WT1 are responsible for DNA/RNA Frasier syndrome. Nat Genet. 1997 Dec;17(4):467-70 Description Jadresic L, Leake J, Gordon I, Dillon MJ, Grant DB, 10 exons, extending for 48 kb of genomic DNA. Pritchard J, Risdon RA, Barratt TM. Clinicopathologic Transcription review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome). J Pediatr. Alternative splicing at two sites results in four major 1990 Nov;117(5):717-25 different zinc finger protein isoforms (molecular Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta weights of between 52 and 54 kDa). P, Gessler M. Frasier syndrome is caused by defective Protein alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum Mol Genet. 1998 Apr;7(4):709- Description 14 Alternative splicing at the two sites generates 4 Koziell A, Grundy R. Frasier and Denys-Drash Syndromes major different isoforms, respectively either : different disorders or a part of a spectrum ? Arch Dis Child including or excluding exon 5 and including or 1999; 81:365-369. excluding three amino-acids - lysine, threonine and Lefebvre J, Clarkson M, Massa F, Bradford ST, Charlet A, serine (KTS positive or negative isoforms). The KTS Buske F, Lacas-Gervais S, Schulz H, Gimpel C, Hata Y, isoforms are highly conserved throughout evolution, Schaefer F, Schedl A. Alternatively spliced isoforms of WT1 indicating a very biological important function. control podocyte-specific gene expression Kidney Int. 2015 ; 88(2):321-31. Expression Nachtigal, M. W., Hirokawa, Y., Enyeart-VanHouten, D. L., Kidney, ovary, testis, liver, heart and hematopoietic Flanagan, J. N., Hammer, G. D., Ingraham, H. A. cells. Wilms'tumor 1 and Dax-1 modulate the orphan nuclear Localisation receptor SF-1 in sex-specific gene expression Cell 1998 ; 93: 445-454. Mainly nuclear, depending on the different isoforms. Niaudet P, Gubler MC. WT1 and glomerular diseases Function Pediatr Nephrol 2006; 21(11):1653-60. WT1 mediates trascriptional activation and/or Coppes, M. J., Liefers, G. J., Higuchi, M., Zinn, A. B., Balfe, repression of several gene targets. It particular seems J. W., & Williams, B. R.. Inherited WT1 mutation in Denys- to directly synergize with SF1 participating to Drash syndrome Cancer research 1992 ; 52.21 : 6125- steroidogenesis and in sexual differentiation by 6128. regulating expression of the polypeptide hormone Haber, D. A., Sohn, R. L., Buckler, A. J., Pelletier, J., Call, mullerian inhibiting substance. In addition WT1 K. M., Housman, D. E. Alternative splicing and genomic plays a key role in podocyte gene-expression and structure of the Wilms tumor gene WT1 Proc. Nat. Acad. subsequently in podocyte differentiation (Nachtigat Sci. 1991 ; 88: 9618-9622. et al 1998; Lefebvre et al. 2015). Koziell A, Charmandari E, Hindmarsh PC, Rees L, Scambler P, Brook CG.. Frasier syndrome, part of the Mutations Denys Drash continuum or simply a WT1 gene associated Denys-Drash WT1 mutations are clustered disorder of intersex and nephropathy? Clin Endocrinol particularly in the exons encoding Zf2 and Zf3in and (Oxf). 2000 ; 52(4):519-24. behave as dominant negatives. Most WT1 mutations Mueller, R. F. The Denys-Drash syndrome J. Med. Genet. in rasier patients affect the exon 9 donor splice site 1994 ; 31: 471-477. resulting in a functional imbalance of WT1 +KTS isoforms, as detected on dysgenetic gonads by This article should be referenced as such: RTPCR (Klam et al.1998; Haber et al.1991). In Piccione M, Salzano E. Denys-Drash syndrome (DDS). addition transcriptional profiling of mice lacking the Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12):625-626. WT1 alternative splice isoform (+KTS) seems to have a more restrictive podocyte set of genes whose

Atlas Genet Cytogenet Oncol Haematol. 2016; 20(12) 626

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