Number 1 May - September 1997

Volume 1 - Number 1 May - September 1997

Volume 24 - Number 8 August 2020 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, [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 Editors-in-Chief Jesús María Hernández Rivas (Salamanca, Spain) Paola Dal Cin (Boston, Massachusetts) Jean-Loup Huret (Poitiers, France) Hematology Section Editor Ana E. Rodríguez, Teresa Gonzalez (Salamanca, Spain) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editor Cécile Badoual (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) Epigenetics Section Editor Roberto Piergentili (Rome, Italy) Hematopoeisis Section Editor Olga Weinberg (Boston, Massachusetts) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren, Barnabas Nyesiga (Malmö, Sweden) Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223 François Desangles 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 Nijmegen, Kessel The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Research Oskar A. Haas 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, Braunschweig, Roderick Mc Leod 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, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 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] Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 24, Number 8, August 2020 Table of contents

Gene Section

THBS1 (thrombospondin-1) 291 Jeffrey S. Isenberg, David D. Roberts PARP1 (poly(ADP-ribose) polymerase 1) 300 Sinem Tunçer, Kubra Kavak

Leukaemia Section t(1;14)(p35;q32) LAPTM5/IGH 313 Jean Loup Huret Systemic EBV-positive T-cell lymphoma of childhood 315 Ashley M. Eckel, Karen M. Chisholm t(9;14)(p24;q12) STRN3/JAK2 320 Jean Loup Huret Primary Cutaneous CD8 Aggressive Epidermotropic Cytotoxic T Cell Lymphoma 322 Ana Marèa Corazón-Monzón, Luis Miguel Juárez-Salcedo, Samir Dalia Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review

THBS1 (thrombospondin-1) Jeffrey S. Isenberg, David D. Roberts Jeffrey S. Isenberg, Radiation Control Technologies, Inc., Loudonville, NY, USA; [email protected] (JSI); Biochemical Pathology Section, Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA; [email protected] (DDR)

Published in Atlas Database: October 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/THBS1ID42548ch15q15.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70774/10-2019-THBS1ID42548ch15q15.pdf DOI: 10.4267/2042/70774

This article is an update of : Roberts DD. THBS1 (thrombospondin-1). Atlas Genet Cytogenet Oncol Haematol 2005;9(3)

Abstract Identity Thrombospondins are encoded in vertebrates by a HGNC (Hugo): THBS1 family of 5 THBS genes. THBS1 is infrequently Location: 15q14 mutated in most cancers, but its expression is Other names positively regulated by several tumor suppressor genes and negatively regulated by activated THBS, TSP, THBS-1, TSP-1, TSP1 oncogenes and promoter hypermethylation. Local order Consequently, loss of thrombospondin-1 expression Telomeric to FLJ39531, centromeric to FSIP1 is frequently lost during oncogenesis and is (fibrous sheath interacting protein 1) correlated with a poor prognosis for some cancers. Thrombospondin-1 is a secreted protein that acts in DNA/RNA the tumor microenvironment to inhibit angiogenesis, regulate antitumor immunity, stimulate tumor cell Description migration, and regulate the activities of extracellular The THBS1 gene is 16,393 bases in size and is proteases and growth factors. composed of 22 exons. Differential effects of thrombospondin-1 on the Exons 2-21 encode the 5729 b mRNA. sensitivity of normal versus malignant cells to ischemic and genotoxic stress also regulate the Transcription responses to tumors to therapeutic radiation and Egr-1 and Sp1 sites function in the transcription of chemotherapy. THBS1 stimulated in most cell types by culture in Keywords the presence of serum (Shingu and Bornstein, 1994). thrombospondin-1, matricellular, tumor Transcription is regulated by JUN (c_jun orAP1) in angiogenesis, metastasis, resistance to genotoxic cooperation with the repressor Yin Yang-1 (YY1) therapy and by TP53.

Exon/intron organization of the THBS1 gene.

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Domain organization and localization of selected ligand binding sites in THBS1. THBS1 is a homotrimer linked via disulfide bonds.

USF2 and the aryl hydrocarbon receptor (AHR) induced by wounding, ischemia, ischemia mediate glucose-induced THBS1 transcription reperfusion, during tissue remodeling, in (Wang et al., 2004; Dabir et al., 2008). ID1 represses atherosclerotic lesions, rheumatoid synovium, THBS1 transcription (Volpert et al., 2002). glomerulonephritis, in response to high glucose and The ATF1 transcription factor also down-regulates fat, and in the stroma of many tumors. THBS1 transcription of THBS1 through an ATF/cAMP- expression increases with aging and in age-related responsive element-binding protein binding site conditions including type 2 diabetes and (Ghoneim et al., 2007). In contrast, MYC increases cardiovascular disease. THBS1 may also play a role turnover of thrombospondin-1 mRNA (Janz et al., in hematologic conditions such as sickle cell disease. 2000). Transcription of THBS1 in some human Conversely, most but not all malignant cells in cancers is suppressed through hypermethylation (Li tumors exhibit loss of THBS1 expression during et al., 1999; Yang et al., 2003). THBS1 expression is malignant progression (Isenberg et al., 2009). This also regulated post-transcriptionally by micro-RNAs loss is due to diminished positive regulation of the including MIR17HG (miR-17-92), MIR18A, THBS1 gene by suppressor genes such as TP53 and MIR19A, MIR27B, MIR98, miR-194, MIR221, and NME1 and increased negative regulation by MIRLET7I (let-7i-5p) (van Almen et al., 2011; oncogenes including RAS and MYC. THBS1 Sundaram et al.,, 2011; Italiano et al., 2012; Yang et expression is induced by TGF-beta, vitamin A, al., 2019; Miao et al., 2018; Farberov and Meidan progesterone, and retinoids and suppressed by 2018; Chen et al., 2017). nickel, ID1, and HGF (hepatocyte growth factor). Pseudogene Localisation None identified. THBS1 is secreted by many cell types in response to injury or specific cytokines, THBS1 is and present Protein transiently in extracellular matrix but is rapidly internalized for degradation by fibroblasts and Description endothelial cells. THBS1 is abundant in The THBS1 precursor contains 1170 amino acids; megakaryocytes and platelets and is constitutively 129,412 Da. The mature secreted protein comprises expressed at the dermal-epidermal boundary in skin residues 19-1170 after removal of the N-terminal and in subendothelial matrix of some blood vessels. signal peptide and assembles into a disulfide linked However, THBS1 levels are generally low or homotrimer. Secreted THBS1 is a glycoprotein with undetectable in most healthy adult tissues. a molecular mass of 150-180 kDa that contains Function approximately 12 Asn-linked mono-, bi- tri-, and tetraantennary complex oligosaccharides and THBS1 binds to extracellular matrix ligands variable numbers of C-mannosylated Trp residues in including fibrinogen, fibronectin, some collagens, the type 1 repeats, and O-fucosylation (Furukawa et latent and active TGFB1 (transforming growth al., 1989; Hofsteenge et al., 2001). factor-beta-1), TNFAIP6 (TSG6), heparin, plasmin, CTSG (cathepsin G), ELANE (neutrophil elastase), Expression some MMPs, tissue factor pathway inhibitor, and THBS1 is expressed in many tissues during heparan sulfate proteoglycans (Resovi et al., 2014). embryonic development but has limited expression THBS1 binds to cell surface receptors including in the healthy adult. THBS1 is the most abundant CD36, CD47, some syndecans, LRP1 (LDL protein in alpha granules of platelets, but normal receptor-related protein-1) (via CALR (calreticulin)) plasma levels are very low (typically 100-200 and the integrins ITGA5/ ITGB3 (alpha-5/beta-3), ng/ml). Expression in other cell types and tissues is ITGA3/ ITGB1 (alpha-3/beta-1), ITGA4/ITGB1

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(alpha-4/beta-1), and ITGA6/ITGB1 (alpha-6/beta- chemotherapy-mediated injury by promoting 1) (Calzada and Roberts, 2005). THBS1 is a slow protective autophagy and enhancing anabolic tight inhibitor of several proteases including metabolic repair pathways (Soto-Pantoja et al., 2012; plasmin, cathepsin G, and neutrophil elastase. Miller et al., 2015). Blocking the THBS1-CD47 axis THBS1 directly binds and activates latent TGFB1 also enhanced survival to lethal whole-body (Murphy-Ullrich and Suto, 2018). radiation (Soto-Pantoja et al., 2013). Conversely, THBS1 in a context-dependent and cell-specific interruption of THBS1-CD47 signaling increases manner stimulates or inhibits cell adhesion, radiation- and chemotherapy-mediated killing of proliferation, motility, and survival. THBS1 is a cancers (Maxhimer et al., 2009; Feliz-Mosquea et potent inhibitor of angiogenesis, but N-terminal al., 2018). This latter effect is mediated through proteolytic and recombinant parts of THBS1 have activation of T and NK cell killing of tumors (Soto- clear pro-angiogenic activities mediated by beta-1 Pantoja et al., 2014; Nath et al., 2019). integrins. In the immune system, THBS1 is a potent THBS1 is also a proximate inhibitor of stem cell self- inhibitor of T cell and dendritic cell activation and renewal (Kaur et al., 2013). Acting via its cell mediates clearance of apoptotic cells by phagocytes surface receptor CD47, THBS1 limits the expression (Soto-Pantoja et al., 2015). In the CNS, THBS1 of important self-renewal transcription factors secreted by astrocytes promotes synaptogenesis including POU5F1 (Oct3/4), SOX2, KLF4, and (Risher and Eroglu, 2012). MYC in nonmalignant cells (Kaur et al., 2013). Based on studies of Thbs1 null mice, platelet THBS1 However, the ability of THBS1 to limit stem cell is not essential for platelet aggregation, but THBS1 self-renewal is lost in cancer cells where MYC is null mice have impaired excisional but improved amplified or dysregulated, and loss of CD47 ischemic wound repair, increased retinal expression or function consequently can suppress angiogenesis, and are hyper-responsive to several cancer stem cells (Kaur et al., 2013; Lee et al., 2014; inflammatory stimuli (Soto-Pantoja et al., 2015). Kaur and Roberts, 2016). Time stimulates pathologic production of reactive oxygen species (ROS) by targeting NOX1. Homology Mitochondria from CD47 null mice produce less THBS1 is a member of the thrombospondin family ROS. Inhibition of H2S signaling contributes to the that also contains THBS2, THBS3, THBS4, and inhibition of T cell activation by THBS1 mediated COMP (cartilage oligomeric matrix protein) which through the CD47 receptor (Miller et al., 2015). arose from gene duplication of a single primordial THBS1 through interacting with CD47, plays a thrombospondin in insects (Adams and Lawler, broader role in primary non-cancer and cancer tissue 2012). The central type 1 repeats are also known as survival of genotoxic damage caused by ionizing thrombospondin-repeats (TSRs) and are shared with radiation and chemotherapy (Soto-Pantoja et al., the larger thrombospondin/properdin repeat 2015; Feliz-Mosquea et al., 2018). Animals lacking superfamily (Adams and Tucker, 2000; Apte 2009; either THBS1 or CD47 tolerated high-dose regional deLau et al., 2012). Orthologs of THBS1 are widely radiation with minimal soft-tissue injury or loss of conserved in mammals and have also been identified bone marrow (Isenberg et al., 2008). Suppressing in birds (Gallus gallus NP_001186382.1), THBS1-CD47 signaling renders non-cancer cells amphibians (Xenopus tropicalis XP_002937245.1) and tissues resistant to radiation- and and fish (Dania rerio XP_005160819.1).

Identified mutations in thrombospondin-1 in human cancers include 187 missense (green), 41 truncating nonsense (black), 3 inframe (brown), and 2 other (purple). Data is from The Cancer Genome Atlas (TCGA) using cBioPortal tools to analyze data from 10,953 patients.

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Frequency of THBS1 mutations in TCGA PanCancer data classified by cancer type using cBioPortal tools (green = mutation, purple = fusion, blue = deletion, red = amplification, grey = multiple alterations).

identified as a genetic risk factor of cerebral Mutations thrombosis in a Chinese population (Liu et al., 2004). Several noncoding SNPs in THBS1 have Germinal been associated with cancer risk as detailed below. Deep exon sequencing of THBS1 from 60,706 humans identified 4 putative loss of function Somatic mutations, which was significantly below the 37.6 The frequency of somatic THBS1 mutation in expected loss of function mutations for a non- human cancers is low. Somatic mutations have been essential gene of this size (Lek et al., 2016). The identified at a frequency of 1.9% in The Cancer resulting calculated probability that THBS1 is loss Genome Atlas (cbioprortal.org). A total of 233 intolerant (pLI =1.0) exceeds the pLI > 0.9 cut-off, mutations have been identified, most of which are which predicts a strong selective pressure against missense or nonsense. However, the random inactivation of this gene. The basis for this apparent distribution of these mutations indicates a lack of selective pressure against loss of THBS1 in humans cancer-specific mutation hotspots. THBS1 is most remains unclear. Thbs1-/- mice are viable and fertile frequently mutated in cutaneous melanomas (12%) but exhibit defects in inflammatory responses and followed by uterine cancers (7%), but rare or absent wound repair that may compromise their viability in other cancer types. The higher mutation rate of outside a protected laboratory environment (Lawler THBS1 in melanomas may simply reflect the high et al., 1998; Crawford et al., 1998; Lamy et al., 2007; overall mutation burden of this malignancy. Qu et al., 2018). Coding polymorphisms in THBS1 associated with altered disease risk in humans Epigenetics include a2210g (Asn700Ser), which is associated Most down-regulation of THBS1 in cancers is with premature familial myocardial infarction and epigenetic, resulting from promoter small for gestational age infants. This mutation alters hypermethylation (Yang et al., 2003), altered calcium binding to THBS1 and protein stability expression of regulatory noncoding RNAs (van (Carlson et al., 2008; Hannah et al., 2004). The Almen et al., 2011; Sundaram et al., 2011; Italiano coding polymorphism g1678a (Thr523Ser) was et al., 2012; Yang et al., 2019; Miao et al., 2018; Farberov and Meidan 2018; Chen et al., 2017), or

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altered levels of oncogenic transcription factor. strongest data is for colorectal carcinomas. Multiple Epigenetic silencing of THBS1 is associated with a independent studies have shown significant poor prognosis in several cancers (Guerrero et al., association of reduced THBS1 expression with 2008; Isenberg et al., 2009). increased invasion, microvascular densities, and poor prognosis (Miyanaga et al., 2002; Maeda et al., Implicated in 2001; Isenberg et al., 2009; Teraoku et al., 2016). Increased circulating levels of THBS1 were also a Gastric carcinoma favourable prognostic marker in patients with colon Disease cancer (HR 0.43, p = 0.007) (Marisi et al., 2018). THBS1 rs1478605 T>C Oncogenesis Carriers of the CC genotype exhibited a decreased The specific role of THBS1 in colorectal risk of developing gastric cancer compared to the oncogenesis has been studied in the APCMin/+ mouse carriers of the CT and TT genotypes [adjusted OR, model. Mice lacking THBS1 on the ApcMin/+ 0.56; 95% confidence interval (CI), 0.39-0.79; background exhibited increased intestinal adenoma P=0.001] (Hong et al., 2015). The CC genotype of formation with increased vascularization compared rs1478605 was negatively associated with gastric to Thbs1+/+: ApcMin/+ mice, consistent with the cancer lymph node metastasis (OR, 0.41; 95% CI, known anti-angiogenic activity of THBS1 (Gutierrez 0.23-0.71; P=0.001) and was associated with a et al., 2003). Lack of THBS1 also decreased reduced risk of lymph node metastasis in male colorectal carcinogenesis in mice exposed to the patients (OR, 0.27; 95% CI, 0.14-0.52; P carcinogen azoxymethane in combination with oral THBS1 rs2292305 T>C, rs1478604 A>G administration of dextran sulfate to induce intestinal Significant association was found between the inflammation (Lopez-Dee, et al., 2015). Again, homozygous CC variant of THBS1 (rs2292305 angiogenesis was increased in the lesions formed in T>C) and development of highly differentiated the Thbs1-/- mice. However, the protective role of gastric carcinoma (Lin et al., 2012). The rs1478604 THBS1 expression to limit colorectal carcinogenesis A>G variant was associated with invasion and was lost when ApcMin/+ mice were fed a high fat lymph node metastasis in gastric cancer. Based on Western diet, and metabolomic analysis identified logistic regression and stratification analysis, systemic alterations including in eicosanoid rs1478604 A>G was more strongly associated with metabolism that may mediate this effect (Soto- lymph node metastasis in highly differentiated Pantoja et al., 2016). gastric cancer. Oncogenesis Various cancers The mechanism by which this polymorphism Disease regulates carcinogenesis remains to be determined. Cancer progression associated with loss of THBS1 Bladder cancer expression in the absence of known gene mutations. Prognosis Disease Studies have shown associations of decreased THBS1 696 C/T polymorphism (rs2664139) THBS1 with poor prognosis in various cancers Compared with the CT/TT genotypes, the CC including non-small cell lung carcinoma (Rouanne et genotype was associated with a significantly al., 2016), pancreatic adenocarcinoma, gastric increased risk of bladder cancer (adjusted odds ratio (Nakao, et al., 2011), invasive cervical carcinoma, [OR] 1.43, 95% CI 1.01-2.04) (Gu et al., 2014). and oral squamous cell carcinomas (Isenberg et al., Oncogenesis 2009). Reports are mixed regarding THBS1 as a The mechanism by which this polymorphism prognostic factor in breast cancers (Rice et al., 2002). regulates carcinogenesis remains to be determined. Stromal THBS1 expression in breast cancer was Colorectal cancer inversely related to lymph node involvement (Ioachim et al., 2012). Evidence indicates that the Cancer progression associated with loss of THBS1 failure of THBS1 to protect in breast cancer is due to expression in the absence of known gene mutations. an escape mechanism involving increased VEGFA Prognosis expression (Fontana et al., 2005). Hypermethylation Mutation of THBS1 is rare in most cancers, but loss of THBS1 was associated with a poor prognosis in of THBS1 expression due to hypermethylation, prostate cancers (Guerrero et al., 2008). However, transcriptional regulation by oncogenes or tumor THBS1 was positively correlated with invasion in suppressor genes, or altered mRNA stability is hepatocellular carcinomas (Poon et al 2004). commonly reported (Isenberg et al., 2009). Evidence is mixed regarding the clinical significance Decreased THBS1 expression has been correlated of THBS1 expression in prostate cancer, and with malignant progression and decreased survival urothelial cancer (Miyata and Sakai, 2013). in several cancers (Isenberg et al., 2009). To date, the Oncogenesis

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Several transgenic mouse models support an indirect decreased and/or eliminated local binding of the tumor suppressor activity of THBS1. Mice lacking transcription factors SP1 and MAZ in aortic smooth THBS1 developed tumors earlier in a tp53 null muscle cells. The mutation was confirmed to not background (Lawler et al., 2001). Loss of THBS1 alter splicing of THBS1 mRNA but is predicted to expression was associated with local invasive alter gene expression. behavior, tumor neovascularization, and metastasis. The mutation was found in multiple members of the A study of UVB-induced skin carcinogenesis in single proband family with nine members diagnosed wildtype versus Thbs1-/- hairless SKH1 mice found with PAH but absent in healthy and chronic disease that the protective activity of the flavone apigenin control cohorts. Some of the affected family was lost in the absence of THBS1 (Mirzoeva et al., members were known to have BMPR2 mutations 2018). The protective role of THBS1 to limit that are associated with PAH risk, and two family carcinogenesis in skin was associated with decreased members with the THBS1 mutation but lacking the levels of circulating inflammatory cytokines and BMPR2 mutation were not diagnosed with PAH. infiltrating macrophages and neutrophils. Therefore, THBS1 was proposed to be a modifier Conversely, transgenic mice overexpressing THBS1 gene. Because only one family was reported to date, in skin or mammary tissue were resistant to chemical the relative risk associated with this mutation or oncogene-driven carcinogenesis (Streit et al., remains to be determined. 1999; Rodriguez-Manzaneque et al., 2001). In Post-refractive surgery chronic addition to inhibiting the angiogenic switch required for tumor growth and hematologic metastasis, over- ocular surface inflammation expression of THBS1 in tumor cells was associated Disease with increased M1 polarization of tumor-associated THBS1 SNPs (rs1478604 T >?C, rs2228262 macrophages in xenograft tumors, and THBS1 missense AAT> AGT, rs2292305 missense ACA> treatment increased superoxide production and GCA) killing of tumor cells by macrophages in vitro Increased risk for developing chronic inflammation (Martin-Manos et al., 2008). in patients undergoing refractive eye surgery or receiving corneal allografts. Familial pulmonary artery Prognosis hypertension Patients with the minor alleles were more susceptible Disease to developing chronic keratoconjunctivitis THBS1 missense mutant Asp362Asn (rs1478604: odds ratio [OR], 2.5; 95% confidence The THBS1 missense mutation (Asp362Asn) alters interval [CI], 1.41-4.47; P = 2.5 × 10-3; rs2228262 a residue in the first type 1 repeat of THBS1 and rs2292305: OR, 1.9; 95% CI, 1.05-3.51; P = 4.8 (Maloney et al., 2012). The Asp362Asn THBS1 × 10-2. The rs1478604 A SNP was significantly mutant had less than half of the ability of wild-type associated with increased risk of corneal allograft THBS1 to activate latent TGFB1. Mutant 362Asn rejection (odds ratio [OR], 1.58; 95% confidence THBS1 also lost the ability to inhibit growth of interval [CI], 1.02-2.45; P = 0.04) (Contreras-Ruiz et pulmonary arterial smooth muscle cells and was over al., 2014; Winton et al., 2014 three-fold less effective at inhibiting endothelial cell Familial premature myocardial growth. The mutation was found in two unrelated probands infarction, Small for gestational age from 60 familial pulmonary arterial hypertension (SGA) infants (PAH) kindreds but not in any healthy or chronic Disease disease control cohorts. Several affected family THBS1 variant A2210G (Ser700Asn) members carried a mutation in BMPR2, which is The THBS1 S700N variant is a significant risk factor known to be associated with PAH risk, and one for familial premature myocardial infarction in both family member with the THBS1 mutation but homozygous and heterozygous carriers of the variant lacking the BMPR2 mutation was not diagnosed allele (Topol et al., 2001; Zwicker et al., 2006; with PAH. Therefore, the THBS1 mutation alone Stenina et al., 2004). may not be sufficient to cause PAH, and THBS1 was Paternal and neonatal THBS1 A2210G was also proposed to be a modifier gene for familial PAH. associated with small gestational age. Maternal The frequency of other common THBS1 THBS1 A2210G was associated with reduced polymorphisms did not differ between PAH and maternal birth weight adjusted for gestational age at control cohorts. delivery (P = 0.03) (Andraweera et al., 2011). THBS1 intronic mutation (IVS8+255 G/A) Prognosis THBS1 intronic mutation (IVS8+255 G/A) was identified in a proband with familial pulmonary The THBS1 S700N variant may be a general risk hypertension (Maloney et al., 2012). This mutation factor for vascular disorders throughout life.

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Sickle cell disease breast cancer growth while preventing cardiac toxicity by regulation of autophagy Breast Cancer Res Treat 2018 Disease Nov;172(1):69-82 THBS1 SNPs (rs1478605 T > C and rs1478604 T Fontana A, Filleur S, Guglielmi J, Frappart L, Bruno-Bossio > C) G, Boissier S, Cabon F, Clézardin P. Human breast tumors The THBS1 SNPs rs1478604 (minor allele override the antiangiogenic effect of stromal frequencies (MAF) 0.291) and rs1478605 (MAF thrombospondin-1 in vivo Int J Cancer 2005 Sep 20;116(5):686-91 0.286) were negatively associated [OR 0.45 (95% CI 0.19, 1.08; p=0.069) and OR 0.33 (95% CI 0.12, Furukawa K, Roberts DD, Endo T, Kobata A. Structural study of the sugar chains of human platelet thrombospondin 0.88; p=0.017, respectively)] with tricuspid Arch Biochem Biophys 1989 Apr;270(1):302-12 regurgitant velocity (TRV) ≥2.5 in sickle cell disease patients (Jacob et al., 2017). Elevated TRV is a Ghoneim C, Soula-Rothhut M, Blanchevoye C, Martiny L, Antonicelli F, Rothhut B. Activating transcription factor-1- marker of pulmonary dysfunction. Of note, mediated hepatocyte growth factor-induced down- rs1478605 and rs1478604 are proximal to the regulation of thrombospondin-1 expression leads to thyroid THBS1 transcription start site and may alter THBS1 cancer cell invasion J Biol Chem 2007 May expression in patients with sickle cell disease. 25;282(21):15490-7 Gonzalez-Gomez P, Bello MJ, Arjona D, Alonso ME, Lomas References J, Amiñoso C, de Campos JM, Sarasa JL, Gutierrez M, Rey JA. CpG island methylation of tumor-related genes in three Adams JC, Lawler J. The thrombospondins. Cold Spring primary central nervous system lymphomas in Harb Perspect Biol. 2011 Oct 1;3(10):a009712 immunocompetent patients Cancer Genet Cytogenet 2003 Apr 1;142(1):21-4 Adams JC, Tucker RP. The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in Gu J, Tao J, Yang X, Li P, Yang X, Qin C, Cao Q, Cai H, neuronal development. Dev Dyn. 2000 Jun;218(2):280-99 Zhang Z, Wang M, Gu M, Lu Q, Yin C. Effects of TSP-1-696 C/T polymorphism on bladder cancer susceptibility and Andraweera PH, Dekker GA, Thompson SD, North RA, clinicopathologic features Cancer Genet 2014 McCowan LM, Roberts CT. A functional variant in the Jun;207(6):247-52 thrombospondin-1 gene and the risk of small for gestational age infants. J Thromb Haemost. 2011 Nov;9(11):2221-8 Guerrero D, Guarch R, Ojer A, Casas JM, Ropero S, Mancha A, Pesce C, Lloveras B, Garcia-Bragado F, Puras Apte SS. A disintegrin-like and metalloprotease (reprolysin- A. Hypermethylation of the thrombospondin-1 gene is type) with thrombospondin type 1 motif (ADAMTS) associated with poor prognosis in penile squamous cell superfamily: functions and mechanisms. J Biol Chem. 2009 carcinoma BJU Int 2008 Sep;102(6):747-55 Nov 13;284(46):31493-7 Hannah BL, Misenheimer TM, Pranghofer MM, Mosher DF. Calzada MJ, Roberts DD. Novel integrin antagonists A polymorphism in thrombospondin-1 associated with derived from thrombospondins Curr Pharm Des familial premature coronary artery disease alters Ca2+ 2005;11(7):849-66 binding J Biol Chem 2004 Dec 10;279(50):51915-22 Carlson CB, Liu Y, Keck JL, Mosher DF. Influences of the Hofsteenge J, Huwiler KG, Macek B, Hess D, Lawler J, N700S thrombospondin-1 polymorphism on protein Mosher DF, Peter-Katalinic J. C-mannosylation and O- structure and stability J Biol Chem 2008 Jul fucosylation of the thrombospondin type 1 module J Biol 18;283(29):20069-76 Chem 2001 Mar 2;276(9):6485-98 Chen L, Xu J, Chu X, Ju C. MicroRNA-98 interferes with Hong BB, Chen SQ, Qi YL, Zhu JW, Lin JY. Association of thrombospondin 1 expression in peripheral B cells of THBS1 rs1478605 T>C in 5'-untranslated regions with the patients with asthma Biosci Rep 2017 Aug 30;37(4) development and progression of gastric cancer Biomed Rep Contreras-Ruiz L, Ryan DS, Sia RK, Bower KS, Dartt DA, 2015 Mar;3(2):207-214 Masli S. Polymorphism in THBS1 gene is associated with Ioachim E, Damala K, Tsanou E, Briasoulis E, Papadiotis E, post-refractive surgery chronic ocular surface inflammation Mitselou A, Charhanti A, Doukas M, Lampri L, Arvanitis DL. Ophthalmology 2014 Jul;121(7):1389-97 Thrombospondin-1 expression in breast cancer: prognostic significance and association with p53 alterations, tumour Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N. Thrombospondin- angiogenesis and extracellular matrix 1 is a major activator of TGF-beta1 in vivo Cell 1998 Jun 26;93(7):1159-70 components Histol Histopathol 2012 Feb;27(2):209-16 Dabir P, Marinic TE, Krukovets I, Stenina OI. Aryl hydrocarbon receptor is activated by glucose and regulates Isenberg JS, Martin-Manso G, Maxhimer JB, Roberts DD. the thrombospondin-1 gene promoter in endothelial cells Regulation of nitric oxide signalling by thrombospondin 1: Circ Res 2008 Jun 20;102(12):1558-65 implications for anti-angiogenic therapies Nat Rev Cancer 2009 Mar;9(3):182-94 Farberov S, Meidan R. Fibroblast growth factor-2 and transforming growth factor-beta1 oppositely regulate miR- Italiano A, Thomas R, Breen M, Zhang L, Crago AM, Singer 221 that targets thrombospondin-1 in bovine luteal S, Khanin R, Maki RG, Mihailovic A, Hafner M, Tuschl T, endothelial cells Biol Reprod 2018 Mar 1;98(3):366-375 Antonescu CR. 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The thrombospondin-1 N700S polymorphism 23;269(51):32551-7 is associated with early myocardial infarction without altering von Willebrand factor multimer size Blood 2006 Soto-Pantoja DR, Sipes JM, Martin-Manso G, Westwood B, Aug 15;108(4):1280-3 Morris NL, Ghosh A, Emenaker NJ, Roberts DD. Dietary fat overcomes the protective activity of thrombospondin-1 de Lau WB, Snel B, Clevers HC. The R-spondin protein signaling in the Apc(Min/+) model of colon cancer family Genome Biol 2012;13(3):242 Oncogenesis 2016 May 30;5(5):e230 van Almen GC, Verhesen W, van Leeuwen RE, van de Vrie Stenina OI, Byzova TV, Adams JC, McCarthy JJ, Topol EJ, M, Eurlings C, Schellings MW, Swinnen M, Cleutjens JP, Plow EF. Coronary artery disease and the thrombospondin van Zandvoort MA, Heymans S, Schroen B. 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Gene Section Review

PARP1 (poly(ADP-ribose) polymerase 1) Sinem Tunçer, Kubra Kavak Vocational School of Health Services, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey Biotechnology Application and Research Center, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey; [email protected] (ST); Department of Molecular Biology and Genetics, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey; [email protected] (KK)

Published in Atlas Database: November 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/PARP1ID586ch1q42.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70775/11-2019-PARP1ID586ch1q42.pdf DOI: 10.4267/2042/70775

Abstract Identity PARP1 (poly(ADP-ribose) polymerase 1) is a Other names nuclear protein involved in the regulation of various PARP-1, ADPRT, ARTD1, PPOL, ADP- biological processes including apoptosis, DNA Ribosyltransferase NAD(+), Poly(ADP repair for the maintenance of genome integrity, Ribosyl)Transferase, Poly(ADP-Ribose) epigenetic marking of chromatin, assembly of Synthetase, EC 2.4.2., PADPRT-1, EC 2.4.2, higher-order chromatin structures, transcriptional ADPRT1, PARP activation, differentiation, proliferation, and cell HGNC (Hugo): PARP1 cycle. Particularly, due to its decisive role in several DNA repair pathways, the inhibition of PARP1 has Location: 1q42.12 emerged as a prominent therapeutic option in cancer Local order treatment, by improving the efficiency of Starts at 226360691 and ends at 226408093 chemotherapeutics or radiation therapy. (GRCh38.p13 Assembly) (Figure 1). Keywords Note PARylation, DNA repair, cancer, inflammation, PARP1 has been found to be related with almost all neurodegenerative diseases, viral infections the biological events and signalling pathways.

Figure 1. Genomic location of human PARP1 (Chromosome 1 - NC_000001.11, GRCh38.p13 Assembly)

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 300 PARP1 (poly(ADP-ribose) polymerase 1) Tunçer S, Kavak K

2013). PARP1, the first PARP purified and cloned DNA/RNA from human, is a constitutive and the best studied Note member of the PARP family of proteins (Citarelli et The poly (ADP-ribose) polymerase (PARP) proteins al., 2010). have been characterized as enzymes that catalyse the The PARP1 gene is conserved in chimpanzee, attachment of the ADP-ribose subunits to itself and Rhesus monkey, dog, cow, mouse, rat, chicken, to multiple target proteins by using NAD+ as the zebrafish, fruit fly, mosquito, C.elegans, A.thaliana, substrate (Citarelli, Teotia, & Lamb, 2010; Ray rice, and frog (Table 1). Chaudhuri Nussenzweig, 2017). This post- transcriptional modification is called Poly(ADP- Gene Species Gene Symbol Identity (%) DNA ribosyl)ation (PARylation) (Citarelli et al., 2010). vs. P.troglodytes PARP1 99,2 PARylation is a reversible modification: it is vs. M.mulatta PARP1 97,7 accomplished by the concerted actions of poly(ADP- ribose) polymerase (PARP) enzymes and poly(ADP- vs. C.lupus PARP1 88,4 ribose) (PAR) hydrolysing enzymes such as PAR vs. B.taurus PARP1 88,4 glycohydrolase (PARG) and ADP-ribosyl hydrolase vs. M.musculus Parp1 86,5 3 (ADPRHL2) (Virág, Robaszkiewicz, Rodriguez- vs. R.norvegicus Parp1 86,1 Vargas, Oliver, 2013). The removal of terminal vs. G.gallus PARP1 75,2 ADP-ribose unit is achieved by the hydrolytic vs. X.tropicalis parp1 72 activity of macrodomain proteins (MACROD1, MACROD2, and OARD1) (Perina et al., 2014). vs. D.rerio parp1 69,5 PARylation is a widely used process in eukaryotes. vs. D.melanogaster Parp 49,5 In eukaryotic species, the distribution of PARP vs. A.gambiae AgaP_AGAP003230 53,1 proteins strictly follows the distribution of PARGs vs. C.elegans pme-1 48,2 and at least one of the macrodomain proteins is also vs. A.thaliana PARP1 50,2 always present (Perina et al., 2014). On the other hand, PARP proteins are less common in bacteria vs. O.sativa Os07g0413700 51,7 and are thought to be acquired through horizontal Table 1. Pairwise alignment of PARP1 gene (in distance from human) (HomoloGene:1222, NCBI). gene transfer (Alemasova & Lavrik, 2019; Perina et al., 2014). In thermophilic archaeon Sulfolobus solfataricus, a protein with oligo(ADP-ribosyl) Description transferase activity was identified (Faraone- The PARP1 gene is a protein-coding gene. It is Mennella, Gambacorta, Nicolaus, Farina, 1998) and located at 1q42.12 on the minus strand and consists in a number of dsDNA viruses have also been found of 23 exons spanning ∼43 kb (starts at 226360691 to possess PARP homologues (Perina et al., 2014). and ends at 226408093; GRCh38.p13 Assembly, Based on the sequence homology, humans are NCBI). assumed to express 17 defined PARPs (Vyas, Chesarone-Cataldo, Todorova, Huang, Chang,

Figure 2. Display of human PARP1 gene transcript exons (Ensembl release 98 - September 2019)

Name/Gene ID Description Location (bp) Aliases

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PARP1P2 (ID: ADPRTP2, poly(ADP-ribose) polymerase 1 pseudogene 2 Chr 14, NC_000014.9 (63123001..63123935) 145) PPOLP2 PARP1P1 (ID: poly(ADP-ribose) +B7:D7polymerase 1 Chr 13, NC_000013.11 ADPRTP1, 144) pseudogene 1 (110936624..110940232) PPOLP1 Table 2. Transcripts of human PARP1 gene (Ensembl release 98 - September 2019)

Transcription (Dash et al., 2017; J. Lai et al., 2019; Wielgos et al., 2017). This gene has 10 transcripts (splice variants) depending on Ensembl release 98 - September 2019 Pseudogene (Table 2 and Figure 2). There are two known pseudogenes of PARP1: The human PARP1 promoter region does not contain PARP1P1 and PARP1P2 located on chromosomes typical regulatory elements, such as TATA or CAAT 13 and 14, respectively (Table 3). A germline, two- boxes. allele (A/B) polymorphism of PARP1P1 on A near 40-base-pair region surrounding the chromosome 13q34-qter has been identified. In the transcription start site described as containing a near- B-allele, a 193 bp deletion was determined and this consensus initiator element capable of initiating deletion has been shown to be associated with cancer RNA polymerase II transcription (Abbotts Wilson, predisposition to multiple myeloma, monoclonal 2017). gammopathies, prostate cancer, and lung cancers in Detailed analyses of the promoter regions of PARP1 African Americans. On the other hand, more recent genes in humans, rats, and mice showed that PARP1 studies do not support the earlier findings which promoter sequences have binding sites for suggest that the PARP1P1 genotype plays a critical transcription factors SP1, AP-2, YY1, ETS1, and role in cancer susceptibility (Lockett, Snowhite, Hu, NF1. 2005). Analyses, comprising a larger cohort that is In the distal promoter region of human PARP1 gene selected based on case/control differences rather Candidate binding sites for several other factors than racial/ethnic differences, are needed to clarify if including CDE, KLF4 (GKLF), BARB, RRM1 there is any significant role of this pseudogene in (MAZF), RREB1, HOX, GSX1 (GSH-1), CEBPB, cancer predisposition. NFIL3 (E4BP4), STAT6, cETSZ-1, PBX1, LEF1 (TCF), NF-kB, REL, ZNF148 (ZBP-89), KLF6 Protein (CPBP), USF, CDF-1, EGR1, and IKZF1 (Ikaros 1) were also identified (Doetsch, Gluch, Poznanovic, Note Bode, & Vidakovic, 2012). Encoded proteins by PARP1 gene in human are Additionally, at the post-transcriptional level, miR- given in Table 4 and PARP1 protein similarity across 124, MIR223, let-7a, miR-7-5p, and MIR125B2 species are given in Table 5. were shown to regulate cellular PARP1 expression

PARP1-201 ENST00000366790.3 570 - - Protein coding PARP1-202 ENST00000366792.3 553 - - Protein coding PARP1-203 ENST00000366794.10 3978 CCDS1554 NM_001618.4 Protein coding PARP1-204 ENST00000463968.5 830 - - lncRNA PARP1-205 ENST00000468608.1 438 - - lncRNA PARP1-206 ENST00000469663.1 542 - - lncRNA PARP1-207 ENST00000490921.5 3165 - - lncRNA PARP1-208 ENST00000491816.1 416 - - lncRNA PARP1-209 ENST00000498787.1 628 - - lncRNA PARP1-210 ENST00000629232.1 477 - - Protein coding

Table 3. Pseudogenes of human PARP1 gene (GRCh38 Assembly, NCBI)

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Isoelectric Molecular Name Transcript ID Protein Charge CCDS UniProt RefSeq Point Weight PARP1- 17,324.99 ENST00000366790.3 155aa 10,0 9,4862 - Q5VX85 - 201 g/mol PARP1- 12,234.02 ENST00000366792.3 108aa 3,0 7,7272 - Q5VX84 - 202 g/mol PARP1- 113,083.79 A0A024R3T8 ENST00000366794.10 1014aa 31,5 9,3322 CCDS1554 NM_001618.4 203 g/mol P09874 PARP1- 12,234.02 ENST00000629232.1 108aa 3,0 7,7272 - Q5VX84 - 210 g/mol

Table 4. Protein products of human PARP1 gene (Ensembl release 98 - September 2019

Gene Species Gene Symbol Identity (%) PROTEIN vs. P.troglodytes PARP1 99 vs. M.mulatta PARP1 98,2 vs. C.lupus PARP1 94,1 vs. B.taurus PARP1 90,4 vs. M.musculus Parp1 92,2 vs. R.norvegicus Parp1 91,6 vs. G.gallus PARP1 79,5 vs. X.tropicalis parp1 75,7 vs. D.rerio parp1 72,1 vs. D.melanogaster Parp 43,8 vs. A.gambiae AgaP_AGAP003230 46,5 vs. C.elegans pme-1 41,1 vs. A.thaliana PARP1 42,3 vs. O.sativa Os07g0413700 42,7 Table 5. Pairwise alignment of PARP1 protein sequences (in distance from human) (HomoloGene:1222, NCBI)

Figure 3. Domain organization of PARP1: ZF1-3: zinc finger domains 1-3; BRCT: BRCA1 C terminus domain; WGR: tryptophan- glycine-arginine rich domain; PRD: PARP regulatory domain; ART: catalytic domain, highly-conserved in other ADP-ribosyl transferases; NLS: Nuclear Localization Signal. The figure is modified from (Abbotts Wilson, 2017).

Description 2016). DBD contains two zinc finger domains PARP1 encodes poly (ADP-ribosyl) transferase (EC (ZFI/ZF1 and ZFII/ZF2; also known as Zn1 and 2.4.2.30) (NCBI Homo sapiens Annotation Release Zn2). Langelier et al. reported that the ZF2 domain 109). Poly (ADP-ribose) polymerase1 (PARP1) is an exhibits high binding affinity to DNA compared to isoform of the PARP enzyme family (Pacher Szabó, the ZF1 domain and Gradwohl et al. showed that 2007). Full length PARP1 protein comprises three disruption of the metal-binding ability of the ZF2 major functional domains: an amino-terminal DNA- dramatically reduces the binding to target DNA binding domain, a carboxy-terminal catalytic (Gradwohl et al., 1990). In addition, in both in vitro domain (CD; also called as CAT), and a central auto and in vivo, the ZF1 domain was found to be modification domain (called as AMD or AD) necessary for DNA-dependent PARP1 activity (Altmeyer, Messner, Hassa, Fey, & Hottiger, 2009; whereas the ZF2 domain was not required strictly Gross, Kotova, Maluchenko, Pascal, & Studitsky, (Langelier, Planck, Roy, & Pascal, 2011). An

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additional zinc finger domain (ZFIII/ZF3; also Compared to normal counterparts, enhanced PARP1 known as Zn3) presents after DBD and it mediates expression is found in various types of tumors, but inter-domain contacts, important for the PARP1 the most striking differences in PARP1 expression activation. (Langelier et al., 2011; Tao, Gao, have been found in breast, ovarian, endometrial, Hoffman, Liu, 2008). A bipartite nuclear localization lung, skin cancers and non-Hodgkin's lymphoma signal (NLS) also lies in DBD and contains a caspase (Galia et al., 2012; Ossovskaya, Koo, Kaldjian, cleavage site DEVD214 (Castri et al., 2014). The Alvares, Sherman, 2010). AMD region is located in the central region of the Localisation enzyme and the region has acceptor amino acids for the covalent attachment of PAR. Moreover, a weak PARP1 is primarily localized to the nucleus, but a leucine-zipper motif has been described in the distinct fraction was also detected in the amino-terminal region of the AMD, which suggests mitochondria. Unlike nuclear PARP1, mitochondrial that this motif may function in homo- and/or hetero- PARP1 has been shown to affect mitochondrial dimerization. The AMD of PARP1 also includes a DNA repair negatively (Szczesny, Brunyanszki, breast cancer 1 protein (BRCA1) C-terminus Olah, Mitra, Szabo, 2014). (BRCT) domain as well as an unstructured loop that PARP1 is one of several known cellular substrates of connects the AMD with the PARP homology CASP3 and CASP7 (caspase 3 and caspase 7) and domain (Altmeyer et al., 2009). The carboxy- cleavage of PARP1 by these caspases is considered terminal CD is the most conserved region across to be a hallmark of apoptosis. Upon cleavage, two PARP family of proteins in different species. This specific fragments of PARP1 are generated: an 89 domain has the 'PARP signature' characterized by kDa fragment containing AMD and the catalytic NAD acceptor sites and critical residues involved in domain of the enzyme and a 24 kDa containing the initiation (the attachment of the first ADP-ribose DBD. The 89 kDa fragment has a greatly reduced moiety onto an acceptor amino acid), elongation (the DNA binding capacity and is liberated from the addition of further ADP-ribose units onto already nucleus into the cytosol. On the other hand, the 24 existing ones) and branching (the generation of kDa cleaved fragment with 2 zinc-finger motifs does branching points) of PAR (Altmeyer et al., 2009; not leave the nucleus where it binds to nicked DNA Simonin et al., 1990). Followed by the CD, there is irreversibly and therefore acts as a trans-dominant a WGR region, named after the identification of inhibitor of active PARP1 (Chaitanya, Alexander, conserved amino acid sequence in the motif: Babu, 2010). Tryptophan-W, Glycine-G, Arginine-R. WGR Function region functions in DNA binding and inter-domain contacts essential for DNA damage-dependent ADP-ribosylation is a posttranslational + activation (Altmeyer et al., 2009; Dawicki-McKenna modification. By using the oxidized form of NAD + et al., 2015; Langelier, Planck, Roy, Pascal, 2012). as a substrate, PARP enzymes bind and cleave NAD The domain organization of PARP1 is shown in to nicotinamide (NAM) and ADP-ribose (ADPR) Figure 3. and catalyze the covalent binding of ADPR units PARP1 is known to be activated by mono-ADP- onto glutamate, aspartate, tyrosine, lysine, and serine ribosylation, acetylation, increased cellular calcium residues of target proteins (Rodrèguez-Vargas, concentration, or by binding to tyrosyl tRNA Oliver-Pozo, & Dantzer, 2019). PARP1, PARP2, synthase. On the other hand, self-PARylation and tankyrase 1 (TNKS), and tankyrase 2 (TNKS2) sumoylation were shown to inhibit PARP1 activity. synthesize branched PAR polymers and the PARP1 can also be phosphorylated in a reversible remaining PARP enzymes are either mono or oligo manner and the phosphorylation can activate (e.g., ADPR-transferases. No enzymatic activity has been AMP-activated protein kinase [AMPK]) or inhibit identified for ZC3HAV1 (PARP13) (Bai, 2015). (e.g., protein kinase C) PARP-1 activity (Bai, 2015). PARP1 is the prototype member of the PARP family In addition, physical interactions with other proteins, of enzymes and more than 80% of stimulated and including histones, HPF1, HMGN1, XPA, NEIL1, basal cellular PARP activity are exerted by PARP1 OGG1, DDB2, TP53, and MAPK1 (ERK2) found to (Bai, 2015; Rajamohan et al., 2009). regulate PARP1 activity (Alemasova Lavrik, 2019). Although PARP1 has been long defined as a DNA- It was also reported that dimerization of PARP1 damage response protein, recent investigations enhances its enzymatic activity while further highlight multiple functions of PARP1 including multimerization or dissociation to single PARP1 transcription, replication, aging, viral protection, cell molecules leads to decreased enzymatic activity cycle regulation, modification of chromosome (Alemasova Lavrik, 2019). structure, differentiation, inflammation, metabolic regulation, proteasomal degradation, and RNA Expression processing (Bai, 2015; Rodrèguez-Vargas et al., PARP1 is an abundantly and ubiquitously expressed 2019) (Figure 4). protein in most tissues (Schiewer & Knudsen, 2014). PARP1 functions in DNA repair

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Genotoxic stress results in various types of DNA synthesis, ribosome biogenesis, and mRNA lesions, including DNA single-strand breaks (SSBs) regulation (Ke et al., 2019; Ryu, Kim, Kraus, 2015). and double-strand breaks (DSBs). If not repaired, Accordingly, PARP1 can regulate gene expression at accumulated damage can disrupt genomic integrity. the post-transcriptional level. Fortunately, cells have evolved different DNA- Cell death and PARP1 damage repair responses that repair these DNA As mentioned before, PARP1 is known to be cleaved lesions to insure genomic stability (C. Liu, Vyas, and inactivated by active caspases 3 and 7 and this Kassab, Singh, Yu, 2017). cleavage is accepted as a 'hallmark of apoptosis' PARP1 recognizes both SSBs and DSBs and (Castri et al., 2014; Desroches & Denault, 2019). transfers the ADP-ribose moiety of NAD+ to the side The cleavage causes the formation of 24 kDa and 89 chains of asparagine, aspartic acid, glutamic acid, kDa fragments. Depending on the intensity and type arginine, lysine, serine and cysteine residues on its of stimuli resulting in the cleavage, two main target proteins. Through their PAR-binding consequences have been reported: (1) reduced domains, these PAR chains form a platform and PARylation during DNA repair processes; (2) the recruit DNA repair proteins. Therefore, PARP1 is an modification of PARP1 transcriptional activity important DNA damage sensor for both SSBs and (Castri et al., 2014). DSBs (Ray Chaudhuri Nussenzweig, 2017). Recent studies indicate that PARP1 hyperactivation, PARP1 modulates chromatin structure and ie. excessive PARylation by PARP1, can lead transcription 'parthanatos', a form of necrotic cell death which PARP1 functions in chromatin compaction, PAR induces the nuclear translocation of apoptosis- decondensation and it modulates epigenetic marks inducing factor ( AIFM1) from mitochondria to via PARylating histones and chromatin remodeling initiate chromatinolysis and cell death independently enzymes (Quénet, El Ramy, Schreiber, Dantzer, of caspase activation. For a long time, it has been 2009). Being as a component of enhancer/promoter- thought that the cell death caused by excessive binding complexes, besides its effects on chromatin activation of PARP occurs via the catalytic structure, PARP1 can bind to most of the RNA consumption of NAD+ followed by ATP reduction polymerase II transcribed genes and mediate around and bioenergetic collapse. However, Andrabi et al. 3.5% of all transcribed RNAs covering a broad range showed that not the decreased NAD+, but PAR- of functions from inflammation to metabolism (Ke, dependent inhibition of hexokinase activity leads to Zhang, Lv, Zeng, & Ba, 2019; Kraus, 2008). PARP1 defects in glycolysis and therefore causes the can also enhance the accessibility of promoters via bioenergetic collapse. On the other hand, PARP1 histone and nucleosome replacements and can activity is kept at much lower levels during normal enhance transcription by replacing negative unstressed cellular conditions (Andrabi et al., 2014; transcriptional cofactors with positive ones (Kraus & Dawicki-McKenna et al., 2015; Gupte, Liu, Kraus, Hottiger, 2013; Muthurajan et al., 2014). 2017). Recent findings described new roles of PARP1 in the regulation of RNA binding proteins, rRNA

Figure 4. Multifaceted nature of PARP-1: PARP1 functions in DNA repair, chromatin modification, inflammation, transcriptional regulation, and cell death. DBS: Double Strand Break; BER: Base Excision Repair; SSB: Single Strand Break; SPR: Short-Patch Repair; LPR: Long-Patch Repair. The figure is modified from (Swindall, Stanley, Yang, 2013).

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Figure 5. The Role of PARP1 in human organs. The figure is modified from (Bai, 2015).

and in vivo PARP inhibitor resistance. The results Mutations reveal that point mutations in the ZnF domains were Note sufficient for the inhibitor resistance (Pettitt et al., A list of PARP1 mutations in cancer can be found in: 2018). COSMIC, the Catalogue of Somatic Mutations in Polymorphisms: In addition to mutations, through Cancer, modulation of PARP1 expression level and enzyme https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln activity, PARP1 gene polymorphisms can affect the =PARP1 outcome and response to therapy of cancer. For example, PARP1 SNP rs1805407, found in perfect Germinal linkage disequilibrium with two PARP1 promoter Parp1-/- mice are viable, fertile, normal in size and do SNPs (rs2077197 and rs6665208), was shown to be not display any gross physical or behavioral associated with higher PARP1 expression abnormalities (Tha Jackson Laboratory; (Abecassis et al., 2019). In another study, expression www.jax.org/strain/002779). quantitative trait locus (eQTL) analysis in melanocytic cell types revealed that presence of the Somatic 1q42.1 melanoma risk allele (rs3219090[G]) is Lys933Asn and Lys945Asn mutations were found to correlated with higher PARP1 levels. Furthermore, a be significantly correlated with colorectal cancer proteomic screen identified that RECQL helicase (CRC) in the Saudi population. Since these binds to the insertion allele of PARP1 (indel SNP mutations were identified to be localized in PARP1 rs144361550) in melanoma cells and primary human catalytic domain (CD), mutations of these lysine melanocytes (J. Choi et al., 2017). In another study, residues were suggested to affect the PARP1 using a new data integrative approach applied on catalytic activity (Alshammari, Shalaby, Alanazi, multi-modal -omics, and clinical data, Abecassis et Saeed, 2014). al. demonstrated that response to chemotherapy is In addition, Val762Ala polymorphism in the CD has directly linked to the gene expression, four been reported as the most common variant of PARP1 methylation variables and PARP1 SNP rs1805407 in associated with an increased risk of many tumors a cohort of metastatic melanoma patients (Abecassis (Toss Laura, 2013). et al., 2019). According to the results of another Using genome-wide and high-density CRISPR-Cas9 genotyping study, Val762Ala, Asp81Asp, and 'tag-mutate-enrich' mutagenesis screens, Pettitt et al. Lys352Lys polymorphisms and the haplotype- identified PARP1 mutant alleles that cause in vitro ACAAC in PARP1 are associated with reduced risk

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of non-Hodgkin lymphoma in Korean males (Jin et and neurodegenerative diseases such as Parkinson's al., 2010). In a case-control study conducted in the disease (PD), Amyotrophic lateral sclerosis (ALS) Hexi area of China, PARP1 2819G allele was shown and Alzheimer's disease (AD) (Martire, Mosca, & to be associated with an increased risk of gastric d'Erme, 2015; Palazzo, Mikolcevic, Mikoc, Ahel, cancer (He, Liu, Shan, Zhu, Li, 2012). 2019). Neurological disorders can be characterized In addition, PAR metabolism is also involved in by aggregation of cytotoxic proteins, enhanced malignancies. For instance, PARylation of proteins levels of oxidative stress followed by DNA damage, in peripheral blood leukocytes was shown to be PARP1 activation, and excess of cellular levels of reduced by more than 50% in head, neck, breast and PAR (Palazzo et al., 2019). For instance, in PD, cervical cancers (Lakadong, Kataki, Sharan, 2010). intracellular monomericSNCA (alpha-synuclein) forms higher-ordered protein aggregates which can Implicated in spread from cell to cell. These α-synuclein aggregates can activate nitric oxide synthase which PARP1 has been implicated in several human enhances the production of NOS. NOS can cause pathologies (Figure 5). Defects in PARP1 function DNA damage and activation of PARP1 and nuclear have been shown to be associated with several production of PAR. PAR is transported into the diseases, such as conditions or diseases related with cytosol where it interacts with α-synuclein and chronic inflammation, neurodegenerative disorders, further accelerates fibrillization and misfolding of cardiovascular diseases, and cancer. this cytotoxic protein α-synuclein in a pathogenic Cardiovascular diseases loop. Ultimately, accumulation of pathologic α- Myocardial infarction (MI) is a common synuclein results in cell death via parthanatos and cardiovascular disease characterized by the neuronal dysfunction (Kam et al., 2018). induction of inflammation and apoptosis of A growing number of evidence shows that cardiomyocytes because of the diminished levels of mitochondrial function is strictly controlled by oxygen and nutrients in the myocardial tissue. In a PARP1 which is responsible for about more than rat model of MI, Wang et al. suggested that oxidative 90% of PARylation in the brain (Pieper et al., 2000). DNA damage caused by the generation of reactive In addition to oxidative stress which is able to species during the onset of MI can cause excessive activate PARP1, recent studies claim that PARP1 is activation of PARP1 followed by an imbalance of a critical component of a molecular interactions cell survival mechanisms that contribute to the death network responsible in the nervous system disorders of cardiomyocytes. The authors showed that related to mitochondrial function. It was suggested inhibition of iNOS (Inducible nitric oxide synthase), that deleterious consequences of PARP1 activation an important member of inflammatory cytokines on mitochondrial function are caused by its regulated by PARP1 via the NF- kB pathway, or interaction with SIRT1 (Sirtuin 1). In addition, the inhibition of PARP1 was able to reduce the level of interaction of PARP1 with promoters of nuclear apoptosis caused by the ischemic myocardial genes encoding for mitochondrial transcription damage (J. Wang et al., 2015). factors and mtDNA repair proteins were identified More recently, it has been shown that PARP1 can (Czapski et al., 2018). affect cardiac functions also via autophagy Viral Infections activation. Therefore, inhibition of PARP1 was A broad range of DNA and RNA viruses are known suggested to be protective against cardiac ischemia to activate DNA repair pathways in the absence of injury by repressing autophagy (C. Wang, Xu, host DNA damage. PARP1 is known to be recruited Zhang, Zhang, Huang, 2018). to the Kaposi's sarcoma-associated herpesvirus and Diabetes and Obesity Epstein-Barr virus genomes and it prevents viral PARP1 has been suggested to play an important role replication by modifying viral proteins involved in in adipogenesis and cellular metabolism (Erener, genome replication and partitioning. On the other Hesse, Kostadinova, & Hottiger, 2011; Jokinen, hand, hepatitis B virus was found to require PARP1 Pirnes-Karhu, Pietiläinen, & Pirinen, 2017; Luo et for efficient transcription. Additionally, PARP1 al., 2017). In their in vivo study, Devalaraja- inhibits the expression of retrotransposons in Narashimha and Padanilam showed that knock out Drosophila and retroviruses in avian cells (Gutierrez, of Parp reversed resistance to diet-induced obesity Valdes, Serguera, & Llano, 2016). It has been by decreasing energy expenditure in mice reported that efficient HIV-1 (Human (Devalaraja-Narashimha Padanilam, 2010). Immunodeficiency Virus-1) integration and transcriptional activation also require PARP1 Central Nervous System Disorders activity (Ha et al., 2001; Yu, Liu, Yang, & Zhou, PARP1 activation is known to be associated with the 2018). Recently, PARP1 was shown as a cofactor in pathogenesis of several central nervous system the activity of the influenza A virus polymerase disorders, including ischemia, neuroinflammation, (Westera et al., 2019). In another study, Shou et al.

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showed that PARP1 functions as a regulator of NF- the most advanced pancreatic intraepithelial kB by promoting its nuclear translocation and by neoplasia lesions (Greer & Whitcomb, 2007). In facilitating its binding to the NF-kB response BRCA1/2 mutated tumors, which homologous sequences in macrophages upon vaccinia virus recombination ca not be utilized to repair DSBs, infection; therefore PARP1 can provide viral control inhibitors of PARP are suggested to target tumor through natural killer (NK) cell recruitment to the cells to terminate their BER rescue pathway thus site of infection (Shou, Fu, Huang, Yang, 2019) leading to accumulation of DNA damage, genomic Gastric cancer instability and eventually cell death (Fogelman et al., 2011; Yuan, Liao, Hsueh, Mirshahidi, 2011). Depending on the survival analysis, upregulation of PARP1 expression was shown to be correlated with Non-Hodgkin's lymphoma poor overall survival rates of gastric cancer patients PARP1 expression is known to be enhanced in non- (Afzal et al., 2019). Enhanced PARP1 expression Hodgkin's lymphoma (Ossovskaya et al., 2010). was found to be significantly associated with Diffuse large B cell lymphoma (DLBCL) is the most Helicobacter pylori infection, decreased common subtype of non-Hodgkin's lymphoma. differentiation, increased depth of invasion, presence Expression of LIM-domain only 2 (LMO2) is one of of lymphatic invasion and lymph node metastasis, the best prognostic markers of longer survival and advanced tumor-node-metastasis stage (Y. Liu following therapy. Very recently, LMO2 expression et al., 2016). was found to lead dysfunction in homolog Lung cancer recombination (HR) and tumor cell sensitization to genotoxic agents and PARP1/2 inhibitors were In lung adenocarcinoma patients, PARP1 was shown to enhance this effect further. Therefore, claimed to enhance tumor metastasis through Parvin et al. suggested that the utilization of PARP supporting several metastatic features, including inhibitors in combination with anoikis resistance, invasion, extravasation and self- immunochemotherapy in LMO2-expressing tumors renewal (E. B. Choi et al., 2016). such as DLBCL, follicular lymphoma, and T-ALL Ovarian cancer and Breast cancer (Parvin et al., 2019). BCL6 is one of the therapeutic targets in lymphoma. Breast Cancer Susceptibility Genes BRCA1 and As a transcription factor, BCL6 is expressed in BRCA2 are tumor suppressors that function in the germinal centre B cells and it is fundamental for the repair DSBs via the homologous recombination formation of germinal centres and the production of (HR) repair pathway. In BRCA mutant tumor cells, high-affinity antibodies. On the other hand, during PARP inhibition was shown to induce 'synthetic terminal differentiation to plasma cells, BCL6 has to lethality' resulting in profound tumor cell be transcriptionally downregulated. BCL6 is known cytotoxicity without harming normal cells (Jiang, Li, to be highly expressed in B cell non-Hodgkin's Li, Bai, Zhang, 2019). lymphoma and in a subset of cases of diffuse large In addition to malignant tissues of BRCA-mutant, cell lymphoma. PARP1 was shown to bind in a triple-negative, and receptor-positive breast sequence-specific manner at the BCL6 locus and carcinoma, PARP1 is overexpressed significantly in contributes to the regulation of BCL6 transcription uterine carcinoma and ovarian carcinoma. As in (Ambrose, Papadopoulou, Beswick, Wagner, 2007). breast carcinoma, ovarian cancer cells show high sensitivity to drugs designed for PARP1 inhibition Melanoma (Iqbal et al., 2012; Thompson & Easton, 2003; L. Melanoma is characterized by defects in repair and Wang et al., 2017). cell cycle regulation. Malfunctioning in nucleotide Pancreatic cancer excision repair is thought to play an important role BRCA2 mutation carriers have a more than 3 fold in melanoma. Since BRCA2 mutations are known to risk of developing pancreatic cancer and women be associated with melanoma, PARP inhibitors were with BRCA 1/2 mutation were shown to have an introduced into melanoma therapy. However, use of approximate 2.5 fold increase in the incidence of PARP inhibitors in melanoma therapy ended with pancreatic cancer (Breast Cancer Linkage controversial clinical observations. In an in vitro Consortium, 1999; Iqbal et al., 2012; Thompson melanoma model, Cseh et al. showed that Easton, 2003). In the context of familial pancreatic pharmacologic PARP inhibition triggers cancer, studies have shown that pedigrees with mitochondrial events known to be associated with germline mutations in BRCA1 and BRCA2 have an cell survival, but also enhances the cytotoxic effects increased lifetime risk of pancreatic cancer. A of cytostatic compounds (Cseh et al., 2019). These germline mutation in one of these genes represents findings may explain the controversial results about the earliest risk factor in many familial pancreatic the use of PARP inhibitors in the treatment of cancer kindreds. In patients with sporadic pancreatic malignancies. cancer, BRCA1/2 were also found to be mutated in

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Colorectal cancer Alshammari AH, Shalaby MA, Alanazi MS, Saeed HM. Novel mutations of the PARP-1 gene associated with Colitis is the inflammation of the inner lining of the colorectal cancer in the Saudi population Asian Pac J colon caused by several inflammatory factors like Cancer Prev 2014;15(8):3667-73 infection, ischaemia, and allergic reactions. Chronic Altmeyer M, Messner S, Hassa PO, Fey M, Hottiger MO. inflammatory disorders, including inflammatory Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 bowel diseases, Crohn's disease (CD) and ulcerative and identification of lysine residues as ADP-ribose acceptor sites Nucleic Acids Res 2009 Jun;37(11):3723-38 colitis (UC), are thought to result from a dysregulated mucosal immune response to Ambrose HE, Papadopoulou V, Beswick RW, Wagner SD. commensal gut microbiota in genetically susceptible Poly-(ADP-ribose) polymerase-1 (Parp-1) binds in a sequence-specific manner at the Bcl-6 locus and individuals. Colorectal cancer (CRC) is well known contributes to the regulation of Bcl-6 transcription to be associated with long-standing and extensive Oncogene 2007 Sep 13;26(42):6244-52 colitis (Palazzo et al., 2019). PARP1 is Andrabi SA, Umanah GK, Chang C, Stevens DA, overexpressed in human CRC and elevated PARP1 Karuppagounder SS, Gagné JP, Poirier GG, Dawson VL, expression is correlated with disease progression. Dawson TM. Poly(ADP-ribose) polymerase-dependent Although PARP1 has been reported to support the energy depletion occurs through inhibition of glycolysis Proc focal inflammation during the tumor progression, Natl Acad Sci U S A 2014 Jul 15;111(28):10209-14 protective effects of PARP1 against DNA alkylation Bai P. Biology of Poly(ADP-Ribose) Polymerases: The and oxidation damage during the initial steps of CRC Factotums of Cell Maintenance Mol Cell 2015 Jun 18;58(6):947-58 have also been shown. Mechanistically, the pro- inflammatory functions of PARP1 were shown to be Breast Cancer Linkage Consortium. Cancer risks in BRCA2 related with the modulation of NF-kB activity and mutation carriers J Natl Cancer Inst 1999 Aug 4;91(15):1310-6 stimulation of IL6-STAT3-cyclin D1 axis (Dörsam et al., 2018). Castri P, Lee YJ, Ponzio T, Maric D, Spatz M, Bembry J, Hallenbeck J. Poly(ADP-ribose) polymerase-1 and its Prostate cancer cleavage products differentially modulate cellular protection through NF-kappaB-dependent signaling Biochim Biophys n vivo and in vitro studies showed that PARP1 can Acta 2014 Mar;1843(3):640-51 modulate androgen receptor ( AR) functions by Chaitanya GV, Steven AJ, Babu PP. PARP-1 cleavage recruiting to the AR function sites, and therefore by fragments: signatures of cell-death proteases in promoting AR occupancy and AR functions neurodegeneration Cell Commun Signal 2010 Dec 22;8:31 (Schiewer et al., 2012). Choi EB, Yang AY, Kim SC, Lee J, Choi JK, Choi C, Kim Silencing of PARP1 was reported to downregulate MY. PARP1 enhances lung adenocarcinoma metastasis by epithelial-mesenchymal transition (EMT) markers, novel mechanisms independent of DNA repair Oncogene inhibit PI3K, suppress the expression of EGFR and 2016 Sep 1;35(35):4569-79 p-GSK3B (Ser9) in in vivo and in vitro prostate Choi J, Xu M, Makowski MM, Zhang T, Law MH, Kovacs cancer models (Y. Lai et al., 2018). MA, Granzhan A, Kim WJ, Parikh H, Gartside M, Trent JM, Teulade-Fichou MP, Iles MM, Newton-Bishop JA, Bishop DT, MacGregor S, Hayward NK, Vermeulen M, Brown KM. To be noted A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF Nat The design of PARP1 inhibitors and clinical trials of Genet 2017 Sep;49(9):1326-1335 PARP1 inhibitors in cancer have been receiving considerable attention. Citarelli M, Teotia S, Lamb RS. 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Mol Cell Biol 2009 Aug;29(15):4116-29 of apoptosis Mol Med Rep 2015 Mar;11(3):1768-76 Ray Chaudhuri A, Nussenzweig A. The multifaceted roles Wang L, Liang C, Li F, Guan D, Wu X, Fu X, Lu A, Zhang of PARP1 in DNA repair and chromatin remodelling Nat G. PARP1 in Carcinomas and PARP1 Inhibitors as Rev Mol Cell Biol 2017 Oct;18(10):610-621 Antineoplastic Drugs Int J Mol Sci 2017 Oct 8;18(10) Rodríguez-Vargas JM, Oliver-Pozo FJ, Dantzer F. PARP1 Westera L, Jennings AM, Maamary J, Schwemmle M, and Poly(ADP-ribosyl)ation Signaling during Autophagy in García-Sastre A, Bortz E. Poly-ADP Ribosyl Polymerase 1 Response to Nutrient Deprivation Oxid Med Cell Longev (PARP1) Regulates Influenza A Virus Polymerase Adv Virol 2019 Jun 9;2019:2641712 2019 Mar 19;2019:8512363 Ryu KW, Kim DS, Kraus WL. New facets in the regulation Wielgos ME, Rajbhandari R, Cooper TS, Wei S, Nozell S, of gene expression by ADP-ribosylation and poly(ADP- Yang ES. Let-7 Status Is Crucial for PARP1 Expression in ribose) polymerases Chem Rev 2015 Mar 25;115(6):2453- HER2-Overexpressing Breast Tumors Mol Cancer Res 81 2017 Mar;15(3):340-347

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Yu D, Liu R, Yang G, Zhou Q. The PARP1-Siah1 Axis This article should be referenced as such: Controls HIV-1 Transcription and Expression of Siah1 Substrates Cell Rep 2018 Jun 26;23(13):3741-3749 Tunçer S, Kavak K. PARP1 (poly(ADP-ribose) polymerase 1). Atlas Genet Cytogenet Oncol Haematol. Yuan Y, Liao YM, Hsueh CT, Mirshahidi HR. Novel targeted 2020; 24(8): 301-312. therapeutics: inhibitors of MDM2, ALK and PARP J Hematol Oncol 2011 Apr 20;4:16

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 312 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Leukaemia Section Short Communication t(1;14)(p35;q32) LAPTM5/IGH Jean Loup Huret R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation at Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russian Federation / e-mail: [email protected]

Published in Atlas Database: October 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0114p35q32LAPTM5-IGHID1486.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70776/10-2019-t0114p35q32LAPTM5-IGHID1486.pdf DOI: 10.4267/2042/70776

carcinoma (Hu et al., 2018), data extracted from Abstract http://atlasgeneticsoncology.org/Bands/1p35.html. Review on t(1;14)(p35;q32), with data on clinics, Genes involved and and the genes involved. Keywords proteins Chromosome 1; chromosome 14; LAPTM5; IGH; LAPTM5 (lysosomal protein Mature B-cell neoplasms transmembrane 5) Clinics and pathology Location 1p35.2 Disease Protein Mature B-cell neoplasms 262 amino acids, contains 5 trans-membrane helices. Epidemiology Membrane protein that localizes to intracellular vesicles, lysosomes in particular. LAPTM5 may play A t(1;14)(p35;q32) LAPTM5/IGH was found in a an important role as a negative regulator of T cell or multiple myeloma cell line (Hayami et al., 2003). B cell receptor-mediated signaling. Two other cases of t(1;14)(p35;q32), but without Overexpression of LAPTM5 induces lysosomal cell gene assessment were described: a male patient, with death. LAPTM5 transcription is often decreased in Binet stage 1 chronic lymphocytic leukemia (CLL), various types of cancer cell lines, in non-small cell and with mutated NOTCH1 (Giudice et al., 2018), lung cancer and esophageal squamous cell and a female aged 55-year old female patient with carcinoma tumors. follicular lymphoma (Slavutsky et al., 1987). Low expression is associated with poor prognosis. LAPTM5 functions as a tumor suppressor (Nuylan Genetics et al., 2016). To be noted is that a PHC2 (1p35.1) / HSP90AA1 IGH (Immunoglobulin Heavy) (14q32.31) fusion was found in prostate cancer Location (Yoshihara et al., 2015) and a PPP2R5C (14q32.31) 14q32.33 / CCDC28B (1p35.2) fusion in hepatocellular

Result of the chromosomal anomaly

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 313 del(5q) in acute lymphoblastic leukemia (ALL) Zamecnikova A, al Bahar S

Hybrid gene Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna R, Kim H, Verhaak RG. The landscape and therapeutic Description relevance of cancer-associated transcript fusions. The rearrangement occurred between the switch Oncogene. 2015 Sep 10;34(37):4845-54 region of IGH and the first intron of LAPTM5. Hayami Y, Iida S, Nakazawa N, Hanamura I, Kato M, LAPTM5 was interrupted within its coding region Komatsu H, Miura I, Dave BJ, Sanger WG, Lim B, Taniwaki and was not expressed (Hayami et al., 2003). M, Ueda R. Inactivation of the E3/LAPTm5 gene by chromosomal rearrangement and DNA methylation in Fusion protein human multiple myeloma. Leukemia. 2003 Aug;17(8):1650- 7 Oncogenesis Nuylan M, Kawano T, Inazawa J, Inoue J.. Down-regulation Inactivation of LAPTM5 of LAPTM5 in human cancer cells. Oncotarget. 2016 May 10;7(19):28320-8. doi: 10.18632/oncotarget.8614. References Hu X, Wang Q, Tang M, Barthel F, Amin S, Yoshihara K, Slavutsky I, Labal de Vinuesa M, Estévez ME, Sen L, Lang FM, Martinez-Ledesma E, Lee SH, Zheng S, Verhaak Dupont J, Larripa I. Chromosome studies in human RGW.. TumorFusions: an integrative resource for cancer- hematologic diseases: non-Hodgkin's lymphomas. associated transcript fusions. Nucleic Acids Res. 2018 Jan Haematologica. 1987 Jan-Feb;72(1):29-37 4;46(D1):D1144-D1149. doi: 10.1093/nar/gkx1018. Giudice ID, Rigolin GM, Raponi S, Cafforio L, Ilari C, Wang This article should be referenced as such: J, Bordyuh M, Piciocchi A, Marinelli M, Nanni M, Tavolaro S, Filetti M, Bardi A, Tammiso E, Volta E, Negrini M, Huret JL. t(1;14)(p35;q32) LAPTM5/IGH. Atlas Genet Saccenti E, Mauro FR, Rossi D, Gaidano G, Guarini A, Cytogenet Oncol Haematol. 2020; 24(8): 314-314. Rabadan R, Cuneo A, Foà R. Refined karyotype-based prognostic stratification of chronic lymphocytic leukemia with a low- and very-low-risk genetic profile. Leukemia. 2018 Feb;32(2):543-546

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Leukaemia Section Review Systemic EBV-positive T-cell lymphoma of childhood Ashley M. Eckel, Karen M. Chisholm Department of Laboratory Medicine, University of Washington, Seattle, WA, USA; [email protected] (AME); Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA; [email protected] (KMC)

Published in Atlas Database: October 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/EBVT-LymphomaChildID1763.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70777/10-2019-EBVT-LymphomaChildID1763.pdf DOI: 10.4267/2042/70777

Note Abstract While this review focuses on systemic EBV-positive Review on systemic EBV positive T-cell lymphoma T-cell lymphoma of childhood, EBV infection is of childhood, with data on clinical findings, associated with multiple other non-malignant and pathology and genetic alterations. malignant disorders. For this particular diagnosis, it is important to distinguish this type of lymphoma Keywords from acute self-limited infectious mononucleosis childhood, EBV, hemophagocytosis, with EBV-infected B cells, and the other EBV- lymphoproliferative, lymphoma, T-cell, positive lymphoproliferative disorders (LPD) which Other names include aggressive NK-cell leukemia, extranodal Systemic EBV-positive T-cell lymphoma of NK/T-cell lymphoma, nasal type, and chronic active childhood has also been termed fulminant EBV- EBV infection (CAEBV) of T- and NK-cell type positive T-cell lymphoproliferative disorder of (cutaneous and systemic forms). It is frequently childhood, sporadic fatal infectious mononucleosis, particularly challenging to differentiate systemic fulminant hemophagocytic syndrome in children, EBV-positive T-cell lymphoma of childhood from and fatal EBV-associated hemophagocytic acute EBV-associated hemophagocytic syndrome. Use of the term 'severe chronic active lymphohistiocytosis (EBV-HLH), and the EBV (severe CAEBV)' is discouraged for this entity. differentiation is often not ultimately made in many cases (Coffey et al. 2019; Smith et al. 2014). It is also Clinics and pathology important to distinguish this entity from chronic active EBV infection of T- and NK-cell type, which Disease can show a broad range of clinical manifestations, Systemic EBV-positive T-cell lymphoma of from indolent, localized forms such as hydroa childhood is a rapidly progressive, fatal disease of vacciniforme-like lymphoproliferative disorder and children and young adults characterized by severe mosquito bite allergy to more systemic monoclonal expansion of EBV-positive T cells with disease manifestations characterized by symptoms an activated cytotoxic phenotype in tissues or similar to systemic EBV-positive T-cell lymphoma peripheral blood. of childhood. Correlation of morphological, It has a fulminant clinical course typically associated immunophenotype and clinical with hemophagocytic syndrome. The prognosis is features is critical for accurate diagnosis in these generally poor, and there is no standard treatment, cases and these disorders may be a biologic although therapy may include allogeneic continuum, rather than discrete entities. hematopoietic stem cell transplantation.

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 315 Systemic EBV-positive T-cell lymphoma of childhood. Eckel AM, Chisholm KM

Phenotype/cell stem origin hepatosplenomegaly, and jaundice with or without minimal lymphadenopathy. The cell of origin is thought to be transformed, High EBV viral loads, and elevated liver enzymes activated cytotoxic T cells. are common. In serological tests for EBV, IgM Etiology antibodies against the viral capsid antigen (VCA) are Epstein-Barr virus (EBV) is a herpesvirus with a often low to absent in the majority of patients; yet double-stranded DNA genome. EBV was first IgG antibodies against VCA are often positive discovered from cells isolated from African patients (Kikuta et al., 1993). Pancytopenia and with Burkitt's lymphoma and was later recognized to coagulopathies have also been reported in several of be highly prevalent worldwide (Epstein et al. 1964), the patients. Similarly, fever, hepatosplenomegaly, causing chronic latent infection with lifelong and frequent lymphadenopathy are also present in persistence in more than 90% of the world's reported cases arising from patients with CAEBV. population. EBV has been linked to several (Coffey et al. 2019; Kikuta et al. 1993; Quintanilla- malignancies, including nasopharyngeal carcinoma, Martinez et al. 2000; Zhu et al. 2019). Patients in gastric carcinoma and either group generally develop hemophagocytic lymphomas/lymphoproliferative diseases including lymphohistiocytosis, sepsis, and multiorgan Burkitt lymphoma, classical Hodgkin lymphoma, dysfunction, which ultimately lead to death usually post-transplantation lymphoproliferative disorders, within days to weeks. NK/T cell lymphoma (nasal type), aggressive NK- Cytology cell leukemia, angioimmunoblastic T cell The lymphocytes in this disorder are generally lymphoma. It is thought that these disorders arise described as small and lacking significant atypia due to impaired balance between the host immune (Quintanilla-Martinez et al. 2000). Some cases are response and EBV virus. Given the racial reported to show atypical pleomorphic medium to predispositions to some of these disorders, including large-sized lymphoid cells (Hong et al. 2013; Yoshii systemic EBV-positive T-cell lymphoma of et al. 2012). Findings of cytologic atypia, if present, childhood, it is postulated that there may be genetic may be indistinguishable from those of infectious defects in host immune responses to EBV that mononucleosis. increase susceptibility to transformation. Additionally, there are genetically different strains Pathology of EBV, which may have different propensities for By morphology, there is an increase in small contributing to cancer development (Rickinson et al. lymphoid cells and histiocytes, usually accompanied 1987; Yakovleva et al. 2015). by hemophagocytosis in the liver, spleen, lymph Epidemiology nodes, and bone marrow. Skin and lungs may also be Systemic EBV-positive T-cell lymphoma of involved. childhood is extremely rare but reports of this Bone marrow biopsies tend to show histiocytic disease have most frequently been in Asians hyperplasia, prominent hemophagocytosis, and an including individuals from Japan and China (Kikuta interstitial lymphocytic infiltrate (Figure 1). (Coffey et al. 1993; Su et al. 1994; Suzuki et al. 2004; Yoshii et al. 2019; Quintanilla-Martinez et al. 2000). et al. 2012; Zhu et al. 2019). Additional reports have Multiple reports describe lymph nodes as being described the disorder in several individuals from largely unremarkable with preserved architecture Mexico, Central and South America, and occasional and open sinuses, although occasional cases have individuals whose ethnic origin is described as been described to have partial or more complete White, not further specified (Coffey et al. 2019; destruction with paracortical expansion by a Quintanilla-Martinez et al. 2000). It occurs most prominent infiltration of small to medium-size often in children and young adults. atypical lymphocytes and areas of necrosis (Coffey et al. 2019; Hong et al. 2013; Quintanilla-Martinez Clinics et al. 2000; Zhu et al. 2019). Variable sinus The disease usually occurs in previously healthy histiocytosis with erythrophagocytosis has been children or adolescents shortly after acute primary described. EBV infection; however, it has also been described The liver in reported cases demonstrates infiltration as an evolution from chronic active EBV infection. of small lymphocytes in portal, lobular, and While reports of the disease are rare, accumulated sinusoidal areas. data from several individual patients suggests that Cholestasis, steatosis, hepatocyte necrosis, and the disease generally develops within days to weeks hemophagocytosis can also be seen (Figure 2) of infectious mononucleosis symptoms. Patients (Coffey et al. 2019; Quintanilla-Martinez et al. 2000, progress to increasing malaise, high fever, Yoshii et al. 2012).

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 316 Systemic EBV-positive T-cell lymphoma of childhood. Eckel AM, Chisholm KM

Figure 1: Bone marrow biopsy from a patient diagnosed with systemic EBV-positive T-cell lymphoma of childhood. (A) Numerous scattered intermediate and large sized atypical lymphoid cells and histiocytes with decreased background hematopoiesis. The atypical lymphoid cells are positive for (B) CD8 and (C) EBER. (D) CD163 highlights numerous macrophages, some with hemophagocytosis.

Figure 2: At autopsy, the liver of this 3 year old with systemic EBV positive T-cell lymphoma demonstrated (A) multiple mass forming vasculocentric foci of necrosis (right in photomicrograph) with interspersed atypical lymphocytes at the junction of viable and necrotic liver. (B) These atypical lymphocytes expressed EBV by EBER in situ hybridization.

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Systemic EBV-positive T-cell lymphoma of childhood. Eckel AM, Chisholm KM

The spleen can show inconspicuous to markedly EPSTEIN MA, ACHONG BG, BARR YM. VIRUS depleted white pulp, with a prominent lymphoid PARTICLES IN CULTURED LYMPHOBLASTS FROM BURKITT'S LYMPHOMA. Lancet. 1964 Mar infiltration and hemophagocytosis in the splenic 28;1(7335):702-3 sinusoids and occasionally necrosis (Quintanilla- Hong M, Ko YH, Yoo KH, Koo HH, Kim SJ, Kim WS, Park Martinez et al. 2000). H. EBV-Positive T/NK-Cell Lymphoproliferative Disease of Cytogenetics Childhood. Korean J Pathol. 2013 Apr;47(2):137-47 No consistent chromosomal aberrations have been Jones JF, Shurin S, Abramowsky C, Tubbs RR, Sciotto CG, Wahl R, Sands J, Gottman D, Katz BZ, Sklar J. T-cell identified, although cases with chromosomal lymphomas containing Epstein-Barr viral DNA in patients aberrations are generally fatal (Smith et al. 2014). with chronic Epstein-Barr virus infections N Engl J Med The finding of chromosomal aberrations has been 1988 Mar 24;318(12):733-41 suggested as a feature to support a diagnosis of Kanegane H, Bhatia K, Gutierrez M, Kaneda H, Wada T, systemic EBV-positive T-cell lymphoma of Yachie A, Seki H, Arai T, Kagimoto S, Okazaki M, Oh-ishi childhood over EBV-HLH (Kim et al. 2019). T, Moghaddam A, Wang F, Tosato G. A syndrome of peripheral blood T-cell infection with Epstein-Barr virus Genes (EBV) followed by EBV-positive T-cell lymphoma Blood he infiltrating T lymphocytes show monoclonal 1998 Mar 15;91(6):2085-91 rearrangements of the TCR genes, although notably Kikuta H, Sakiyama Y, Matsumoto S, Oh-Ishi T, Nakano T, this can also been seen in about half of EBV-HLH Nagashima T, Oka T, Hironaka T, Hirai K. Fatal Epstein- Barr virus-associated hemophagocytic syndrome Blood cases (Coffey et al. 2019; Kim et al. 2019; Yoshii et 1993 Dec 1;82(11):3259-64 al, 2012). All cases of systemic EBV-positive T-cell lymphoma of childhood harbour EBV in a clonal, Kim WY, Montes-Mojarro IA, Fend F, Quintanilla-Martinez L. Epstein-Barr Virus-Associated T and NK-Cell episomal form (Jones et al. 1988; Kikuta et al. 1993; Lymphoproliferative Diseases Front Pediatr 2019 Mar Suzuki et al. 2004). 15;7:71 Treatment Kimura H, Ito Y, Kawabe S, Gotoh K, Takahashi Y, Kojima S, Naoe T, Esaki S, Kikuta A, Sawada A, Kawa K, Ohshima At present, there is no effective, standard treatment. K, Nakamura S. EBV-associated T/NK-cell CHOP-like regimens or immunosuppressive lymphoproliferative diseases in nonimmunocompromised therapies are options, but most patients experience hosts: prospective analysis of 108 cases Blood 2012 Jan recurrence. Few cases have been reported to respond 19;119(3):673-86 to an etoposide- and dexamethasone-based regimen Quintanilla-Martinez L, Kumar S, Fend F, Reyes E, Teruya- typically used for HLH (Coffey et al. 2019; Smith et Feldstein J, Kingma DW, Sorbara L, Raffeld M, Straus SE, Jaffe ES. Fulminant EBV(+) T-cell lymphoproliferative al. 2014). Additionally, treatment with SMILE disorder following acute/chronic EBV infection: a distinct regimen (dexamethasone, methotrexate, ifosfamide, clinicopathologic syndrome Blood 2000 Jul 15;96(2):443- L-asparaginase, and etoposide) has been reported in 51 rare patients (Yoshida et al. 2017). The ultimate goal Rickinson AB, Young LS, Rowe M. Influence of the Epstein- is to get the patients to allogeneic hematopoietic Barr virus nuclear antigen EBNA 2 on the growth phenotype stem cell transplantation (Coffey et al. 2019). of virus-transformed B cells J Virol 1987 May;61(5):1310-7 Evolution Smith MC, Cohen DN, Greig B, Yenamandra A, Vnencak- Jones C, Thompson MA, Kim AS. The ambiguous boundary The disease usually occurs shortly after acute between EBV-related hemophagocytic lymphohistiocytosis primary EBV infection in previously healthy and systemic EBV-driven T cell lymphoproliferative disorder children or adolescents but has also been described Int J Clin Exp Pathol 2014 Aug 15;7(9):5738-49 evolving from a multi-year long course of chronic Su IJ, Chen RL, Lin DT, Lin KS, Chen CC. Epstein-Barr active EBV infection. virus (EBV) infects T lymphocytes in childhood EBV- associated hemophagocytic syndrome in Taiwan Am J Prognosis Pathol 1994 Jun;144(6):1219-25 The prognosis is poor with a generally fulminant Suzuki K, Ohshima K, Karube K, Suzumiya J, Ohga S, clinical course with most patients succumbing to the Ishihara S, Tamura K, Kikuchi M. Clinicopathological states of Epstein-Barr virus-associated T/NK-cell disease within days to weeks. The disease is usually lymphoproliferative disorders (severe chronic active EBV complicated by hemophagocytic syndrome. infection) of children and young adults Int J Oncol 2004 May;24(5):1165-74 References Yakovleva LS, Senyuta NB, Goncharova EV, Scherback LN, Smirnova RV, Pavlish OA, Gurtsevitch VE. [Epstein- Coffey AM, Lewis A, Marcogliese AN, Elghetany MT, Punia Barr Virus LMP1 oncogene variants in cell lines of different JN, Chang CC, Allen CE, McClain KL, Gaikwad AS, El- origin] Mol Biol (Mosk) 2015 Sep-Oct;49(5):800-10 Mallawany NK, Curry CV. A clinicopathologic study of the spectrum of systemic forms of EBV-associated T-cell Yoshida M, Osumi T, Imadome KI, Tomizawa D, Kato M, lymphoproliferative disorders of childhood: A single tertiary Miyazawa N, Ito R, Nakazawa A, Matsumoto K. Successful care pediatric institution experience in North America. treatment of systemic EBV positive T-cell lymphoma of Pediatr Blood Cancer. 2019 Aug;66(8):e27798 childhood using the SMILE regimen Pediatr Hematol Oncol 2018 Mar;35(2):121-124

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 318 Systemic EBV-positive T-cell lymphoma of childhood. Eckel AM, Chisholm KM

Yoshii M, Ishida M, Hodohara K, Okuno H, Nakanishi R, This article should be referenced as such: Yoshida T, Okabe H. Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood: Report of a Eckel AM, Chisholm KM. Systemic EBV-positive T-cell case with review of the literature Oncol Lett 2012 lymphoma of childhood. Atlas Genet Cytogenet Oncol Sep;4(3):381-384 Haematol. 2020; 24(8):316-319. Zhu YY, Duan YT, Song LL, Tao J, Guan YJ, Liu W, Li YG, Shi LH. [Clinicopathological Analysis of Children's Systemic EBV-Positive T-Cell Lymphoma] Zhongguo Shi Yan Xue Ye Xue Za Zhi 2019 Aug;27(4):1131-1137

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Leukaemia Section Short Communication t(9;14)(p24;q12) STRN3/JAK2 Jean Loup Huret [email protected] Published in Atlas Database: October 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0914p24q12STRN3-JAK2ID1683.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70778/10-2019-t0914p24q12STRN3-JAK2ID1683.pdf DOI: 10.4267/2042/70778

This article is an update of : Huret JL. Infant leukaemias. Atlas Genet Cytogenet Oncol Haematol 1999;3(2)

849-1124)). JAK Homology domains are the Abstract following: JH7 aa 25-137; JH6: aa 144-284; JH5: aa Review on t(9;14)(p24;q12), with data on clinics, 288-309; JH4: aa 322-440; JH3: aa 451-538; JH2: aa and the genes involved. 543-824; JH1: aa 836-1123. Keywords JAK2 is a member of the Janus kinase (JAKs) family of non-receptor protein tyrosine kinases ( JAK1, Chromosome 9; Chromosome 14; STRN3; JAK2 JAK2, JAK3, TYK2) .Janus kinases are protein tyrosine kinases of the non-receptor type that Clinics and pathology associates with the intracellular domains of cytokine Disease receptors including the receptors for interleukins, interferons, growth hormone, erythropoietin, and Acute lymphoblastic leukemia (ALL). leptin. Mediates signaling transduction. Janus Epidemiology kinases are constitutively bound to the cytoplasmic Only 1 case to date, a 12 year-old female patient with region of cytokine receptors. Binding of cytokines high-risk B-lineage ALL (Roberts et al., 2012). induces cytokine receptor dimerization, facilitating trans-phosphorylation of the associated JAKs and Genes involved and JAK/STAT signaling. Erythropoietin receptor (EPOR) and growth hormone receptor (GHR) bind proteins JAK2 exclusively. JAK2 is frequently mutated in myeloproliferative Note disorders. JAK2-V617F mutation occurs at the stem There was a IKZF1 deletion and p.Leu117fs (Frame cell level and is present in hematopoietic stem cell shift) mutation. progenitors (Strehl et al., 2006; Gangat and Tefferi, JAK2 (janus kinase 2) 2008; Hubbard, 2017). Location 9p24.1 STRN3 (striatin 3) Protein Location 14q12 1132 amino acids (aa); 130,7 kDa; JAK2 contains an Protein Interaction with cytokine/interferon/growth 797 amino acids (aa), contains caveolin-binding and hormone receptors region (aa 1-239), a FERM calmodulin-binding regions in the N-term (aa 71-79 domain: (aa 37-380), a central Src homology 2 and 166-183 respectively), a coiled-coil domain (aa (SH2) domain (aa 401-482), and two C-terminal 77-136, which allow homo- and hetero- domains: a tyrosine kinase domain JH1 (also termed oligomerization), and 6 WD repeats (from aa 478 to PTK or TyrKc domain (aa 545-809)), and a tyrosine aa 796; WD-repeat domain enables proteins to kinase-like domain JH2 (also termed STYKc (aa establish multiple protein-protein interactions).

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 320 Infant leukaemias, Congenital leukaemias, Neonatal Chisholm KM leukaemias

STRN3 is a member of striatin family ( STRN, Berry EM. Problem-oriented article summary. Lancet. 1985 STRN3, STRN4) which function as scaffold in Aug 24;2(8452):452 different signal transduction pathways STRN and Hubbard SR. Mechanistic Insights into Regulation of JAK2 STRN3 are the constituents of a multiprotein Tyrosine Kinase. Front Endocrinol (Lausanne). 2017;8:361 assembly called striatin-interacting phosphatase and Hubbard SR. Mechanistic Insights into Regulation of JAK2 kinase (STRIPAK). STRIPAK are regulators of cell Tyrosine Kinase. Front Endocrinol (Lausanne). 2017;8:361 cycle, differentiation, metabolism, immune JAK2 (janus kinase 2). Strehl, S Atlas Genet Cytogenet regulation, Golgi assembly, cell polarity, cell Oncol Haematol. 2006;10(1):3-6. migration, etc. STRN3 protects cells from oxidative JAK2 mutations in myeloproliferative neoplasms. Gangat N, stress. SG2NA is involved in maintaining ER Tefferi A Atlas Genet Cytogenet Oncol Haematol. homeostasis. Downregulation of SG2NA reduces the 2009;13(8):612-617. level of CCND1 (cyclin D1) and retains a population Pandey S, Talukdar I, Jain BP, Tanti GK, Goswami SK. of cells in the G1 phase, and its overexpression GSK3beta and ERK regulate the expression of 78kDa extends G2 (Jain et al., 2017; Pandey et al., 2018). SG2NA and ectopic modulation of its level affects phases of cell cycle Sci Rep 2017 Aug 8;7(1):7555 Result of the chromosomal Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, Chen SC, Payne-Turner D, Churchman ML, Harvey RC, anomaly Chen X, Kasap C, Yan C, Becksfort J, Finney RP, Teachey DT, Maude SL, Tse K, Moore R, Jones S, Mungall K, Birol Hybrid gene I, Edmonson MN, Hu Y, Buetow KE, Chen IM, Carroll WL, Wei L, Ma J, Kleppe M, Levine RL, Garcia-Manero G, Description Larsen E, Shah NP, Devidas M, Reaman G, Smith M, STRN3 exon 9 was fused to JAK2 exon 17. Paugh SW, Evans WE, Grupp SA, Jeha S, Pui CH, Gerhard DS, Downing JR, Willman CL, Loh M, Hunger SP, Marra Fusion protein MA, Mullighan CG. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute Description lymphoblastic leukemia Cancer Cell 2012 Aug 835 amino acids. The N-term striatin domain was 14;22(2):153-66 fused to the pseudo kinase domain and C-term Tyr kinase domain). Sequence junction: This article should be referenced as such: .ARAEEV_LQER.... Huret JL. t(9;14)(p24;q12) STRN3/JAK2. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8):321-321. References

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Leukaemia Section Short Communication Primary Cutaneous CD8 Aggressive Epidermotropic Cytotoxic T Cell Lymphoma Ana Marèa Corazón-Monzón, Luis Miguel Juárez-Salcedo, Samir Dalia Adelfas Health Center, Madrid; [email protected] (AMCM), Gregorio Marañon University Hospital, Madrid; [email protected] (LMJS), Spain; Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA; [email protected] (SD).

Published in Atlas Database: November 2019

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/AggrEpidCytotoxTLymphomaID1753.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70779/11-2019-AggrEpidCytotoxTLymphomaID1753.pdf DOI: 10.4267/2042/70779

Abstract Clinics The clinical course usually begins with a prodrome Review on Primary Cutaneous CD8 Aggressive of localized or disseminated eruptive papules, Epidermotropic Cytotoxic T Cell Lymphoma, with nodules, and tumors with a central data on clinics, and the genes involved. ulceration/necrosis or hyperkeratotic Keywords patches/plaques in the skin and cutaneous adnexa. Primary Cutaneous CD8+ Epidermotropic Cytotoxic The disease rapidly disseminates to organs such as T Cell Lymphoma. lungs, testis, CNS and oral mucosa in just weeks or months (Willemze R et al, 2008). Lymph nodes are Other names not infiltrated by the disease. B symptoms (fever, CD8+ AECTCL night sweats, and weight loss) are seen in most patients. Some cases may be associated with Clinics and pathology hemophagocytic syndrome (Toro JR et al, 2003). Disease Pathology Primary cutaneous CD8+ aggressive epidermotropic Histologically the disease shows infiltrates of T cells cytotoxic T cell lymphoma (AECTCL) had been in full epidermal thickness with a different degree of considered a provisional disease until the 2016 spongiosis, intraepidermal blistering and necrosis. In World Health Organization Classification of the early stages a lichenoid pattern with pagetoid Cutaneous lymphomas (Guitart J et al, 2017). It is a epidermotropism and subepidermal edema is seen. rare cutaneous lymphoma, representing less than 1% In advances stages, diffuse dermal infiltrates in of all cutaneous lymphomas and it has aggressive nodular and tumor-like lesions are characteristic. behavior and a poor prognosis (Willemze R et al, Epidermal necrosis and ulceration or destruction of 2005). skin structures are commonly found (Berti E et al, Etiology 1999; Santucci M et al, 2003; Robson A e tal, 2015). AECTCL is a proliferation of epidermotropic CD8+ The neoplastic cells showed a high Ki-67 cytotoxic T cells with the expression oh TIA-1 proliferation index. marker. Immunophenotype AECTCL express a peripheral T cell phenotype with CD3+, CD8+, CD7+/-, Epidemiology CD45RA+, beta-F1+, Granzyme B+ (g-B), perforin AECTCL is rare, but most patients are adult with a (PF), T-intracytoplasmic antigen (TIA-1) and median survival among 12 months (Berti E et al, CD45RO-. CD2, CD4 and CD5 are frequently lost 1999). and CD30 is rarely expressed but they have a high

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 322 Nervous system: Embryonal tumors: Neuroblastoma Pudela C et al.

proliferation, expressed with Mib-1 marker. Epstein- Apr;139(4):491-514 Barr virus is negative (Robson A et al, 2015; Guitart Robson A, Assaf C, Bagot M, Burg G, Calonje E, Castillo C, J et al, 2017; Quintanilla-Martinez L et al, 2013). Cerroni L, Chimenti N, Dechelotte P, Franck F, Geerts M, AECTCL express clonal T cell receptor gene Gellrich S, Goodlad J, Kempf W, Knobler R, Massone C, Meijer C, Ortiz P, Petrella T, Pimpinelli N, Roewert J, rearrangements. Russell-Jones R, Santucci M, Steinhoff M, Sterry W, Genes Wechsler J, Whittaker S, Willemze R, Berti E. Aggressive epidermotropic cutaneous CD8+ lymphoma: a cutaneous The neoplastic T cells that are representative of this lymphoma with distinct clinical and pathological features. disease show clonal T cell receptor gene Report of an EORTC Cutaneous Lymphoma Task Force rearrangements. Specific genes abnormalities have Workshop. Histopathology. 2015 Oct;67(4):425-41 not been described. Santucci M, Pimpinelli N, Massi D, Kadin ME, Meijer CJ, Müller-Hermelink HK, Paulli M, Wechsler J, Willemze R, Treatment Audring H, Bernengo MG, Cerroni L, Chimenti S, Chott A, Treatment remains unclear since no randomized Díaz-Pérez JL, Dippel E, Duncan LM, Feller AC, Geerts ML, Hallermann C, Kempf W, Russell-Jones R, Sander C, Berti trials are available. Peripheral T Cell lymphoma E. Cytotoxic/natural killer cell cutaneous lymphomas. combination chemotherapy is usually tried but Report of EORTC Cutaneous Lymphoma Task Force response rates remain poor (Berti E et al, 1999). Workshop. Cancer. 2003 Feb 1;97(3):610-27 Toro JR, Liewehr DJ, Pabby N, Sorbara L, Raffeld M, References Steinberg SM, Jaffe ES. Gamma-delta T-cell phenotype is associated with significantly decreased survival in Berti E, Tomasini D, Vermeer MH, Meijer CJ, Alessi E, cutaneous T-cell lymphoma. Blood. 2003 May Willemze R. Primary cutaneous CD8-positive 1;101(9):3407-12 epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical Willemze R, Jansen PM, Cerroni L, Berti E, Santucci M, behavior. Am J Pathol. 1999 Aug;155(2):483-92 Assaf C, Canninga-van Dijk MR, Carlotti A, Geerts ML, Hahtola S, Hummel M, Jeskanen L, Kempf W, Massone C, Guitart J, Martinez-Escala ME, Subtil A, Duvic M, Pulitzer Ortiz-Romero PL, Paulli M, Petrella T, Ranki A, Peralto JL, MP, Olsen EA, Kim E, Rook AH, Samimi SS, Wood GS, Robson A, Senff NJ, Vermeer MH, Wechsler J, Whittaker S, Girardi M, Junkins-Hopkins J, Ivan DS, Selim MA, Sable KA, Meijer CJ. Subcutaneous panniculitis-like T-cell lymphoma: Virmani P, Pincus LB, Tetzlaff MT, Kim J, Kim YH. Primary definition, classification, and prognostic factors: an EORTC cutaneous aggressive epidermotropic cytotoxic T-cell Cutaneous Lymphoma Group Study of 83 cases. Blood. lymphomas: reappraisal of a provisional entity in the 2016 2008 Jan 15;111(2):838-45 WHO classification of cutaneous lymphomas. Mod Pathol. 2017 May;30(5):761-772 This article should be referenced as such: Quintanilla-Martinez L, Jansen PM, Kinney MC, Swerdlow Corazón-Monzón A, Juárez-Salcedo LM, Dalia S. SH, Willemze R. Non-mycosis fungoides cutaneous T-cell Primary Cutaneous CD8 Aggressive Epidermotropic lymphomas: report of the 2011 Society for Cytotoxic T Cell Lymphoma. Atlas Genet Cytogenet Hematopathology/European Association for Oncol Haematol. 2020; 24(8):323-323. Haematopathology workshop. Am J Clin Pathol. 2013

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