Volume 1 - Number 1 May - September 1997

Volume 23 - Number 6 June 2019 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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Editor-in-Chief Jean-Loup Huret (Poitiers, France) Lymphomas Section Editor Antonino Carbone (Aviano, Italy) Myeloid Malignancies Section Editor Robert S. Ohgami (Stanford, California) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section 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) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren and Barnabas Nyesiga (Malmö, Sweden) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France)

Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Department of Health Sciences, University of Milan, Italy; [email protected] Beghini Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; Antonio Cuneo [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, François Desangles 91223 Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Kessel Nijmegen, The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Oskar A. Haas Research Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, 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] Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; Roberta Vanni [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 23, Number 6, June 2019 Table of contents

Gene Section

HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) 137 Murat Erdem, Ibrahim Özgül, Ayse Elif Erson-Bensan NOL4L (nucleolar protein 4 like) 143 Jean Loup Huret

Leukaemia Section

Extranodal NK/T-cell lymphoma, nasal type (ENKL) 146 Luis Miguel Juárez Salcedo, Diego Conde Royo, Samir Dalia Myeloid sarcoma 149 Karen M. Chisholm der(Y)t(Y;1)(q11-12;q12-21) 154 Adriana Zamecnikova t(8;14)(q24;q32) in BPDCN 157 Jean-Loup Huret

Cancer Prone Disease Section

Familial glioma 159 Riccardo Bazzoni, Angela Bentivegna Atlas of Genetics and Cytogenetics in Oncology and Haematology

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HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) Murat Erdem, Ibrahim Özgül, Ayse Elif Erson-Bensan Department of Biological Sciences, Middle East Technical University, Ankara, TURKEY, E-mail: [email protected]; [email protected]; [email protected]

Published in Atlas Database: October 2018 Online updated version : http://AtlasGeneticsOncology.org/Genes/HNRNPA1ID43803ch12q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70455/10-2018-HNRNPA1ID43803ch12q13.pdf DOI: 10.4267/2042/70455

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Identity Heterogeneous nuclear ribonucleoprotein Other names: HNRPA1, ALS20, hnRNP A1, (HNRNPA1) gene maps to chromosome 12, plus hnRNP-A1, IBMPFD3, UP 1, HNRPA1L3 strand and has 13 exons and 12 introns. There are HGNC (Hugo): HNRNPA1 three reported transcripts due to the alternative Location: 12q13.13 splicing. HNRNPA1 is one of the most abundant and Local order ubiquitously expressed nuclear proteins. HNRNPA1 From telomere to centromere: LOC105369777, is a member of RNA-binding protein family CBX5, ENSG00000257596, HNRNPA1, NFE2, comprising of 20 members in humans (Dreyfuss, ENSG00000258344, COPZ1, GPR84 1993; Pinol-Roma, Choi, Matunis, Dreyfuss, 1988). HNRNPA1 has diverse roles in RNA splicing, DNA/RNA telomere length maintenance, miRNA maturation Note and mRNA transport from nucleus to cytoplasm. HNRNPA1 gene consists of 13 exons and 12 introns. Keywords The gene maps to 12q13.13 and is 6399 bps long HNRNPA1; RNA-binding protein; RNA splicing; (NCBI Reference Sequence: NC_000012.12: telomere length maintenance; miRNA maturation; 54280690-54287088). Highlighted in red is the mRNA transport protein coding sequence from exons 1-10. (Figure 2)

Local order of HNRNPA1 together with neighboring upstream and downstream genes on chromosome 12. The direction of arrows indicates direction of transcription and arrow sizes approximate gene sizes.

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) 137 HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) Erdem M et al.

HNRNPA1 gene has 13 exons and 12 introns. Numbers indicate the exons. Red exons show protein-coding regions while blue color represents untranslated regions.

HNRNPA1 has three functional regions; two RNA-recognition motifs and one Glycine-rich Prion like domain. Numbers above the bars indicate amino acids harboring the domains. Description HNRNPA1P76, HNRNPA1P77, HNRNPA1P8, HNRNPA1P9, LOC100421349 and The HNRNPA1 gene is 6399 bases long and is on LOC100421402(NCBI,2018). the plus strand. HNRNPA1 gene has 13 exons (Jean- Philippe et al., 2013). Protein Transcription Note HNRNPA1 produces two coding transcripts (Exon HNRNPA1 gene encodes a 372 amino acid protein. 1-11). The difference between these coding The protein is a member of heterogeneous nuclear transcripts is the presence or absence of exon 8 (only ribonucleoproteins (hnRNPs) and has an estimated longer mRNA contains exon 8). A third one was molecular weight of 38-39 kDa (Jean-Philippe, Paz, reported as a potential non-coding transcript Caputi, 2013). (Mendell et al, 2004). This non-coding RNA transcript has exons 12 and 13, and it does not Description contain exon 8. HNRNPA1 has two RNA recognition motifs; RRM1 Pseudogene and RRM2. These domains are known for binding to single- There are 75 pseudogenes of HNRNPA1 which are: stranded RNAs (Dreyfuss, Swanson, Piñol-Roma, HNRNPA1P1, HNRNPA1P10, HNRNPA1P11, 1988). HNRNPA1P12, HNRNPA1P13, HNRNPA1P14, HNRNPA1 also possesses a prion-like domain HNRNPA1P15, HNRNPA1P16, HNRNPA1P17, (PLD). HNRNPA1P18, HNRNPA1P19, HNRNPA1P2, This domain is reported in RNA binding proteins HNRNPA1P20, HNRNPA1P21, HNRNPA1P22, that have been associated with neurodegenerative HNRNPA1P23, HNRNPA1P24, HNRNPA1P25, disorders such as Amyotrophic Lateral Sclerosis HNRNPA1P26, HNRNPA1P27, HNRNPA1P28, (Kim et al., 2013). HNRNPA1P29, HNRNPA1P3, HNRNPA1P30, In addition, glycine-rich region mediates subcellular HNRNPA1P31, HNRNPA1P32, HNRNPA1P33, localization and protein-protein interactions (Han, HNRNPA1P35, HNRNPA1P36, HNRNPA1P37, Tang, Smith, 2010). HNRNPA1P38, HNRNPA1P39, HNRNPA1P4, HNRNPA1P40, HNRNPA1P42, HNRNPA1P43, Expression HNRNPA1P44, HNRNPA1P45, HNRNPA1P46, HNRNPA1 mRNA is expressed in all human tissues HNRNPA1P47, HNRNPA1P48, HNRNPA1P49, including brain, skin, lung, breast and kidney (The HNRNPA1P5, HNRNPA1P50, HNRNPA1P51, Human Protein Atlas, 2018). HNRNPA1P52, HNRNPA1P53, HNRNPA1P54, HNRNPA1P55, HNRNPA1P56, HNRNPA1P58, Localisation HNRNPA1P59, HNRNPA1P6, HNRNPA1P60, HNRNPA1 protein is mainly nuclear; however, HNRNPA1P61, HNRNPA1P62, HNRNPA1P63, under certain conditions the protein is also present in HNRNPA1P64, HNRNPA1P65, HNRNPA1P66, the cytosol (Roy et al., 2014). HNRNPA1P67, HNRNPA1P68, HNRNPA1P69, In fact, HNRNPA1 may shuttle between nucleus and HNRNPA1P7, HNRNPA1P70, HNRNPA1P71, cytoplasm along with mRNAs (Jønson et al., 2007). HNRNPA1P72, HNRNPA1P74, HNRNPA1P75,

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) 138 HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) Erdem M et al.

Expression of HNRNPA1 in different types of tissues is shown (The Human Protein Atlas, 2018). Function APAF1, and XIAP mRNAs (Cammas et al. 2007). HNRNPA1 has a very broad range of reported In addition, the HIV-1 IRES is stimulated by functions including transcriptional regulation, hnRNPA1 (Martènez-Salas, Piñeiro, Fernández, alternative splicing, mRNA transport, translation 2012). and miRNA processing. Most surprisingly, In addition to mRNA processing and transport , HNRNPA1 can interact with certain promoters and HNRNPA1 interacts directly and specifically with induce transcriptional repression or activation of C-terminal region of NF-kB alpha inhibitory subunit target genes. VDR (Vitamin D receptor) (H. Chen, via its RNA-binding domain (between residues 95 Hewison, Hu, Adams, 2003), FGG (γ-fibrinogen) and 207) resulting in the activation of nuclear factor (Xia, 2005) and TK1 (thymidine kinase) (Lau et al., k B (Hay, Kemp, Dargemont, Hay, 2001). 2000) promoters are transcriptionally repressed The exact mechanism of HNRNPA1 and NF-kB while APOE promoter is activated by HNRNPA1 interaction is not completely understood. However, (Campillos et al., 2003). in cells lacking HNRNPA1, activation of NF-kB is HNRNPA1 has an important role in mRNA splicing. defected. When HNRNPA1 loss is rescued, an The protein modulates alternative splicing of various effective NF-kB response to signal induction is genes including INSR (Insulin Receptor) (Talukdar observed only upon ligand induction. et al., 2011), BRCA1 (Breast Cancer 1) (Goina, As for the microRNA processing, HNRNPA1 binds Skoko, Pagani, 2008), PKM (Pyruvate Kinase to the terminal loop of pri-miR-18a, and facilitates M1/2) (David, Chen, Assanah, Canoll, Manley, MIR18A production by creating favorable cleavage 2010) and its own HNRNPA1 mRNA (Hutchison, site for DROSHA (Guil Cáceres, 2007). In contrast, LeBel, Blanchette, Chabot, 2002). mRNA splicing HNRNPA1 negatively affects MIRNLET7A1 (let- is modulated by HNRNPA1 by exon skipping and 7a) biogenesis. HNRNPA1 binds to terminal loop of splice site repression (Jean-Philippe et al., 2013). pri-let-7a-1 and interferes with the binding of HNRNPA1 contributes to telomere regulation by KHSRP (component of both Drosha and Dicer promoting telomerase activity via binding to complexes, known to promote let-7a biogenesis); telomeric sequences, potentially as an auxiliary hence, inhibiting processing of pri-let-7a by Drosha factor for the telomerase enzyme (Zhang, Manche, (Michlewski Cáceres, 2010). Xu, Krainer, 2006). Homology HNRNPA1 has roles in mRNA transport between HNRNPA1 gene has homologs across Amniota nucleus and cytoplasm. Although the exact including P. troglodytes, M. mulatta, B. taurus, R. mechanism is unknown, HNRNPA1 binds to norvegicus, G. gallus, M. musculus and H. sapiens poly(A) tailed mRNAs both in the nucleus and (NCBI HomoloGene, 2018). cytoplasm (Mili, Shu, Zhao, Pinol-Roma, 2001), There is also a well-studied HNRNPA1 homolog in and possibly aid their transfer through nuclear pores D. melanogaster called Hrp36 (Singh Lakhotia, (Piñol-Roma Dreyfuss, 1992). 2012). Another function attributed to HNRNPA1 is during In total, there are 97 species including invertebrates translation. HNRNPA1 binds to internal ribosomal that have genes orthologous to A1 (NCBI Ensembl, entry sites (IRES) that initiates 5' cap-independent 2018). translation of certain cellular and viral mRNAs (such as, MYC), CSDE1 (Upstream of NRAS), Mutations CCND1 (Cyclin D1), VEGFA (Vascular Endothelial Growth Factor), FGF2 (Fibroblast Growth Factor), Note

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) 139 HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) Erdem M et al.

Up to 106 substitution mutations were reported in the shorter relapse-free survival than patients (309 HNRNPA1 gene in 42,067 cancer patients. samples) expressing low level of HNRNPA1 and Reported mutations are generally missense that patients (121 samples) showing high HNRNPA1 mutations (70 of 106). There are also 4 nonsense expression had a shorter overall survival than mutations, 30 synonymous substitutions and 2 patients (120 samples) with low level of HNRNPA1 frameshift deletions (COSMIC database, 2018). One expression. (Otsuka, Yamamoto, Ochiya, 2018). of the frameshift deletions found in cancer patients is discovered in the Sanger Institute Cancer Genome Cervical Carcinoma Project (study ID :COSU652) while the other is Note discovered in 619 incident colorectal cancer patients HNRNPA1 has higher expression in cervical in the study conducted by Giannakis et al(2016). carcinoma compared with normal tissue samples in Yu et al. (2018) also reported a recessive frameshift 32 patients with cervical cancer (Y. J. Kim et al., mutation in HNRNPA1 leading to deregulation of 2017). cardiac transcription network and multiple signaling HNRNPA1 expression is upregulated during pathways, including Bone Morphogenetic Protein, differentiation of virus-infected epithelial cells in Notch and Fibroblast growth factor signaling. monolayer and 3D cell cultures. HNRNPA1 interacts directly with the Human papillomavirus Implicated in type 16 (HPV16) late regulatory element (LRE) (which has an important role in temporally Top note controlling virus late gene expression during HNRNPA1 has been implicated in diverse diseases. epithelial differentiation) in the nucleus of Amyotrophic Lateral Sclerosis (ALS) differentiated W12 cells in vitro and may facilitate Note the alternative splicing of late transcripts of virus in differentiated epithelial cells (Cheunim, Zhang, Immunohistochemistry and immunofluorescence Milligan, McPhillips, Graham, 2008). results showed that HNRNPA1 protein was decreased in the nuclei of neurons and the significant Colon Cancer loss of HNRNPA1 in motor neurons with Note concomitant cytoplasmic aggregation in ALS cases while HNRNPA1 was mainly located in nucleus of HNRNPA1 mRNA is overexpressed in 40-78% of motor neurons in normal cases (Honda et al., 2015). colon cancer stages, compared with normal colon Mutations in prion-like domain (PrLD), enriched in (Ubagai, Fukuda, Tsuchiya, 2005). uncharged polar amino acids and glycine, promote A cell line based study showed HNRNPA1 to be excess incorporation of HNRNPA1 into stress suppressed by MIR18a in SW620 cells through granules and cause the formation of cytoplasmic autophagolysosomal degradation and thus, inclusions in animal models (H. J. Kim et al., 2013b). HNRNPA1 silencing resulted in the suppression of Whole-exome sequencing conducted by Liu et colon cancer cell progression (Fujiya et al., 2014). al.(2016) showed a missense mutation in HNRNPA1 Gastric Cancer (GC) in Flail-Arm ALS patients leading to cytoplasmic inclusions that co-localized with stress granules in Note Flail-Arm ALS. GC tissues have elevated levels of HNRNPA1 protein compared with normal tissues. HNRNPA1 Breast Cancer silencing significantly prevented anchorage- Note dependent growth in GC cells and HNRNPA1 was Invasive breast cancer cells (MDA-MB-231) express important to cell growth and progression of GC. the CD44v6 variants, which are regulated by HNRNPA1 knockdown caused reduction in cell HNRNPA1. Downregulation of HNRNPA1 induces growth, invasion, migration and reversal of EMT a significant change in the expression levels of CD44 (Epithelial to Mesenchymal Transition) in GC cells. isoforms through alternative splicing. Silencing of Collectively, these results pointed out that HNRNPA1 significantly induced cell death and HNRNPA1 may have a pivotal role in GC cell caused a decrease in cell invasion in the MDA-MB- invasion and metastasis (Chen et al., 2018). 231 cells (Loh et al., 2015). HNRNPA1 silencing Hepatocellular Carcinoma (HCC) through siRNAs significantly lowers the cell proliferation in MDA-MB-231 cells (Otsuka, Note Yamamoto, Ochiya, 2018). High expression of HNRNPA1 was reported in the highly metastatic HCC cell lines and in tumor tissues Prognosis of patients with recurrent HCC. HNRNPA1 In basal-like breast cancer, Kaplan-Meier survival silencing reduced cell invasion in highly metastatic analysis showed that patients (309 samples) showing HCC cells while overexpression of HNRNPA1 high HNRNPA1 expression, had an distinctively caused a significant increase in invasive behavior of

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) 140 HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) Erdem M et al.

poorly metastatic HCC cells HNRNPA1 was Sukawa Y, Stewart C, Rosenberg M, Mima K, Inamura K, reported to regulate the invasive capacity of HCC Nosho K, Nowak JA, Lawrence MS, Giovannucci EL, Chan AT, Ng K, Meyerhardt JA, Van Allen EM, Getz G, Gabriel cells through regulating the CD44v6 SB, Lander ES, Wu CJ, Fuchs CS, Ogino S, Garraway LA. expression(Zhou et al., 2013). Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma Cell Rep 2016 Apr 26;15(4):857-865 Lung Cancer Goina E, Skoko N, Pagani F. Binding of DAZAP1 and Note hnRNPA1/A2 to an exonic splicing silencer in a natural The HNRNPA1 protein expression was reported to BRCA1 exon 18 mutant Mol Cell Biol 2008 Jun;28(11):3850-60 be upregulated in most tissue samples from lung cancer patients by immunohistochemistry Guil S, Cáceres JF. The multifunctional RNA-binding protein (Boukakis, Patrinou-Georgoula, Lekarakou, hnRNP A1 is required for processing of miR-18a Nat Struct Mol Biol 2007 Jul;14(7):591-6 Valavanis, Guialis, 2010). HNRNPA1 knockdown inhibited cell viability and colony formation of lung Han SP, Tang YH, Smith R. Functional diversity of the hnRNPs: past, present and perspectives Biochem J 2010 cancer cells and arrested cells in the G0/G1 phase Sep 15;430(3):379-92 (Liu, Zhou, Lou, Zhong, 2016). Hay DC, Kemp GD, Dargemont C, Hay RT. Interaction between hnRNPA1 and IkappaBalpha is required for References maximal activation of NF-kappaB-dependent transcription Mol Cell Biol 2001 May;21(10):3482-90 Boukakis G, Patrinou-Georgoula M, Lekarakou M, Valavanis C, Guialis A. Deregulated expression of hnRNP Honda H, Hamasaki H, Wakamiya T, Koyama S, Suzuki A/B proteins in human non-small cell lung cancer: parallel SO, Fujii N, Iwaki T. Loss of hnRNPA1 in ALS spinal cord assessment of protein and mRNA levels in paired motor neurons with TDP-43-positive inclusions tumour/non-tumour tissues. BMC Cancer. 2010 Aug Neuropathology 2015 Feb;35(1):37-43 17;10:434 Hutchison S, LeBel C, Blanchette M, Chabot B. Distinct sets Cammas A, Pileur F, Bonnal S, Lewis SM, Lévêque N, of adjacent heterogeneous nuclear ribonucleoprotein Holcik M, Vagner S. Cytoplasmic relocalization of (hnRNP) A1/A2 binding sites control 5' splice site selection heterogeneous nuclear ribonucleoprotein A1 controls in the hnRNP A1 mRNA precursor J Biol Chem 2002 Aug translation initiation of specific mRNAs. Mol Biol Cell. 2007 16;277(33):29745-52 Dec;18(12):5048-59 Izumi R, Warita H, Niihori T, Takahashi T, Tateyama M, Campillos M, Lamas JR, García MA, Bullido MJ, Valdivieso Suzuki N, Nishiyama A, Shirota M, Funayama R, F, Vázquez J. Specific interaction of heterogeneous nuclear Nakayama K, Mitsuhashi S, Nishino I, Aoki Y, Aoki M. ribonucleoprotein A1 with the -219T allelic form modulates Isolated inclusion body myopathy caused by a multisystem APOE promoter activity. Nucleic Acids Res. 2003 Jun proteinopathy-linked hnRNPA1 mutation Neurol Genet 15;31(12):3063-70 2015 Sep 24;1(3):e23 Chen H, Hewison M, Hu B, Adams JS. Heterogeneous Jønson L, Vikesaa J, Krogh A, Nielsen LK, Hansen Tv, nuclear ribonucleoprotein (hnRNP) binding to hormone Borup R, Johnsen AH, Christiansen J, Nielsen FC. response elements: a cause of vitamin D resistance. Proc Molecular composition of IMP1 ribonucleoprotein granules Natl Acad Sci U S A. 2003 May 13;100(10):6109-14 Mol Cell Proteomics 2007 May;6(5):798-811 Chen Y, Liu J, Wang W, Xiang L, Wang J, Liu S, Zhou H, Jean-Philippe J, Paz S, Caputi M. hnRNP A1: the Swiss Guo Z. High expression of hnRNPA1 promotes cell army knife of gene expression Int J Mol Sci 2013 Sep invasion by inducing EMT in gastric cancer Oncol Rep 2018 16;14(9):18999-9024 Apr;39(4):1693-1701 Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Cheunim T, Zhang J, Milligan SG, McPhillips MG, Graham Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, SV. The alternative splicing factor hnRNP A1 is up- Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus regulated during virus-infected epithelial cell differentiation JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, and binds the human papillomavirus type 16 late regulatory Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner element Virus Res 2008 Feb;131(2):189-98 J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP. David CJ, Chen M, Assanah M, Canoll P, Manley JL. Mutations in prion-like domains in hnRNPA2B1 and HnRNP proteins controlled by c-Myc deregulate pyruvate hnRNPA1 cause multisystem proteinopathy and ALS kinase mRNA splicing in cancer Nature 2010 Jan Nature 2013 Mar 28;495(7442):467-73 21;463(7279):364-8 Kim YJ, Kim BR, Ryu JS, Lee GO, Kim HR, Choi KH, Ryu Dreyfuss G, Swanson MS, Piñol-Roma S. Heterogeneous JW, Na KS, Park MC, So HS, Cho JH, Park DS. HNRNPA1, nuclear ribonucleoprotein particles and the pathway of a Splicing Regulator, Is an Effective Target Protein for mRNA formation Trends Biochem Sci 1988 Mar;13(3):86- Cervical Cancer Detection: Comparison With Conventional 91 Tumor Markers Int J Gynecol Cancer 2017 Feb;27(2):326- Fujiya M, Konishi H, Mohamed Kamel MK, Ueno N, Inaba 331 Y, Moriichi K, Tanabe H, Ikuta K, Ohtake T, Kohgo Y. Lau JS, Baumeister P, Kim E, Roy B, Hsieh TY, Lai M, Lee microRNA-18a induces apoptosis in colon cancer cells via AS. Heterogeneous nuclear ribonucleoproteins as the autophagolysosomal degradation of oncogenic regulators of gene expression through interactions with the heterogeneous nuclear ribonucleoprotein A1 Oncogene human thymidine kinase promoter J Cell Biochem 2000 2014 Oct 2;33(40):4847-56 Sep 7;79(3):395-406 Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Liu Q, Shu S, Wang RR, Liu F, Cui B, Guo XN, Lu CX, Li Nishihara R, Bahl S, Cao Y, Amin-Mansour A, Yamauchi M, XG, Liu MS, Peng B, Cui LY, Zhang X. Whole-exome

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sequencing identifies a missense mutation in hnRNPA1 in Singh AK, Lakhotia SC. The hnRNP A1 homolog Hrp36 is a family with flail arm ALS Neurology 2016 Oct essential for normal development, female fecundity, omega 25;87(17):1763-1769 speckle formation and stress tolerance in Drosophila melanogaster J Biosci 2012 Sep;37(4):659-78 Liu X, Zhou Y, Lou Y, Zhong H. Knockdown of HNRNPA1 inhibits lung adenocarcinoma cell proliferation through cell Talukdar I, Sen S, Urbano R, Thompson J, Yates JR 3rd, cycle arrest at G0/G1 phase Gene 2016 Feb 1;576(2 Pt Webster NJ. hnRNP A1 and hnRNP F modulate the 2):791-7 alternative splicing of exon 11 of the insulin receptor gene PLoS One 2011;6(11):e27869 Loh TJ, Moon H, Cho S, Jang H, Liu YC, Tai H, Jung DW, Williams DR, Kim HR, Shin MG, Liao DJ, Zhou J, Shi W, Teng Y, Manavalan TT, Hu C, Medjakovic S, Jungbauer A, Zheng X, Shen H. CD44 alternative splicing and hnRNP A1 Klinge CM. Endocrine disruptors fludioxonil and fenhexamid expression are associated with the metastasis of breast stimulate miR-21 expression in breast cancer cells Toxicol cancer Oncol Rep 2015 Sep;34(3):1231-8 Sci 2013 Jan;131(1):71-83 Martínez-Salas E, Piñeiro D, Fernández N. Alternative Ushigome M, Ubagai T, Fukuda H, Tsuchiya N, Sugimura Mechanisms to Initiate Translation in Eukaryotic mRNAs T, Takatsuka J, Nakagama H. Up-regulation of hnRNP A1 Comp Funct Genomics 2012;2012:391546 gene in sporadic human colorectal cancers Int J Oncol 2005 Mar;26(3):635-40 Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC. Nonsense surveillance regulates expression of diverse Xia H. Regulation of gamma-fibrinogen chain expression by classes of mammalian transcripts and mutes genomic noise heterogeneous nuclear ribonucleoprotein A1 J Biol Chem Nat Genet 2004 Oct;36(10):1073-8 2005 Apr 1;280(13):13171-8 Michlewski G, Cáceres JF. Antagonistic role of hnRNP A1 Yu Z, Tang PL, Wang J, Bao S, Shieh JT, Leung AW, Zhang and KSRP in the regulation of let-7a biogenesis Nat Struct Z, Gao F, Wong SY, Hui AL, Gao Y, Dung N, Zhang ZG, Mol Biol 2010 Aug;17(8):1011-8 Fan Y, Zhou X, Zhang Y, Wong DS, Sham PC, Azhar A, Kwok PY, Tam PP, Lian Q, Cheah KS, Wang B, Song YQ. Mili S, Shu HJ, Zhao Y, Piñol-Roma S. Distinct RNP Mutations in Hnrnpa1 cause congenital heart defects JCI complexes of shuttling hnRNP proteins with pre-mRNA and Insight 2018 Jan 25;3(2) mRNA: candidate intermediates in formation and export of mRNA Mol Cell Biol 2001 Nov;21(21):7307-19 Zhang QS, Manche L, Xu RM, Krainer AR. hnRNP A1 associates with telomere ends and stimulates telomerase Otsuka K, Yamamoto Y, Ochiya T. Regulatory role of activity RNA 2006 Jun;12(6):1116-28 resveratrol, a microRNA-controlling compound, in HNRNPA1 expression, which is associated with poor Zhou ZJ, Dai Z, Zhou SL, Fu XT, Zhao YM, Shi YH, Zhou J, prognosis in breast cancer Oncotarget 2018 May Fan J. Overexpression of HnRNP A1 promotes tumor 15;9(37):24718-24730 invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma Int J Cancer 2013 Piñol-Roma S, Dreyfuss G. Shuttling of pre-mRNA binding Mar 1;132(5):1080-9 proteins between nucleus and cytoplasm Nature 1992 Feb 20;355(6362):730-2 This article should be referenced as such: Roy R, Durie D, Li H, Liu BQ, Skehel JM, Mauri F, Cuorvo Erdem M, Özgül I, Erson-Bensan AE. HNRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1). Atlas LV, Barbareschi M, Guo L, Holcik M, Seckl MJ, Pardo OE. Genet Cytogenet Oncol Haematol. 2019; 23(6):137-142. hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling Nucleic Acids Res 2014 Nov 10;42(20):12483-97

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Gene Section Short Communication

NOL4L (nucleolar protein 4 like) Jean Loup Huret [email protected]

Published in Atlas Database: October 2018 Online updated version : http://AtlasGeneticsOncology.org/Genes/NOL4LID51676ch20q11.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70456/10-2018-NOL4LID51676ch20q11.pdf DOI: 10.4267/2042/70456 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Transcription Review on NOL4L, with data on DNA, on the 8 potential splice forms coding for potential proteins protein encoded, and where the gene is implicated. with 76 amino acids (aa) to 680 aa. Keywords Protein NOL4L; C20orf112; C20orf113; Acute lymphoblastic leukemia; Acute myeloid leukemia: Note Breast adenocarcinoma; Skin melanoma; Uterus Nothing is known concerning the domains of the cancer; Bladder cancer. protein, nor it's function. Identity Description Two coding proteins: NOL4L-010, from: 11 exons; Other names: LOC140688 transcript length: 6,577 bps translation: 680 amino HGNC (Hugo): NOL4L acids; and NOL4L-001, from: 8 exons; transcript length: 5,991 bps translation: 436 amino acids. A Location: 20q11.2 Poly-Asp is found at aa 161 to 169 according to Vega Local order (http://vega.archive.ensembl.org/Homo_sapiens/Ge Cen --- PLAGL2, POFUT1, KIF3B, ASXL1, ne/Summary?db=core;g=OTTHUMG00000032219 NOL4L, NOL4L-DT, C20orf203, COMMD7, ;r=20:32443059-32585074) and UniProt DNMT3B ---Tel (https://www.uniprot.org/uniprot/Q96MY1#express Note ion). This gene and protein is very poorly known; a very Expression few data comes from the literature, and other data Expressed in all tissues; High expression in the from databases. testis, and, to a lesser extend, in the small DNA/RNA intestine,other digestive organs, brain and bone marrow. NOL4L orthologs are present in most Description vertebrates and are well conserved. 11 exons

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) 143 NOL4L (nucleolar protein 4 like) Huret JL

In zebrafish embryos, Znol4lb (the zebrafish nol4l - fusion/translocation t(17;20)(q22;q11) with the highest identity with human NOL4L) MMD/NOL4L in breast adenocarcinoma (Yoshihara mRNA is localized to the intermediate mesoderm. It et al. 2015). is expressed in the central nervous system, - fusion 20q11-20q11 NOL4L/ COMMD7 in breast pronephros, the gut and, at low levels, in the adenocarcinoma (Yoshihara et al. 2015). hematopoietic cells (Borah et al. 2016). - fusion 20q11-20q11 NOL4L/ EFCAB8 in Localisation malignant melanoma of the skin (Hu et al., 2018). - fusion 20q11-20q11 PDRG1/NOL4L in malignant Mainly localized to the nucleoplasm. epithelial tumor of the uterus corpus (Hu et al., Function 2018). Acccording to BioGRID Pediatric acute lymphoblastic (https://thebiogrid.org/12665), interacts with: leukemia (ALL) CTBP1 (C-terminal binding protein 1), corepressor Note targeting various transcription regulators. 5 cases of dic(9;20) (p13;q11) PAX5/NOL4L TEX9 (testis expressed 9). available to date (Nebral et al., 2007; An et al., 2008; SRPK1 (SRSF protein kinase 1), involved in the Kawamata et al., 2008; Kawamata et al. 2012). regulation of splicing via phosphorylation of splicing factors. Hybrid/Mutated gene CTBP2 (C-terminal binding protein 2), corepressor In one case, exon 5 of PAX5 was fused to exon 8 of targeting various transcription regulators. NOL4L, and in four cases, exon 8 of PAX5 was SKA3 (spindle and kinetochore associated complex fused to exon 3 of NOL4L, producing two proteins, subunit 3), component of a microtubule-binding a short (PAX5/C20ORF112S) and long complex essential for chromosome segregation. (PAX5/C20ORF112L) form, localizing in the TRIM25 (tripartite motif containing 25), ubiquitin nucleus, and/or in the cytoplasm and the nucleus E3 ligase. (Kawamata et al., 2008). MIR206 (microRNA 206). Oncogenesis Four downstream target genes of PAX5 ( ATP1B1, Implicated in BLK, SEPT2 and TCF7L2) were down-regulated by Top note induction of PAX5/NOL4L. Loss of the C-terminal end of PAX5 may play role in generation of a Expression level according to Entrez dominant negative form of mutated PAX5 (https://www.ncbi.nlm.nih.gov/gene/140688) and (Kawamata et al., 2008). The Human Protein Atlas (http://www.proteinatlas.org/ENSG00000197183- Acute myeloid leukemia (AML) NOL4L/pathology): Note High expression of NOL4L is an unfavourable A 62-year-old man was diagnosed with AML with prognostic factor in endometrial cancer. maturation (M2- AML), and presented with a High expression of NOL4L is a favourable t(20;21)(q11.2;q22.1) RUNX1/NOL4L prognostic factor in urothelial cancer. accompanied with monosomy 7 (Guastadisegni et al. Expression level of NOL4L has no prognostic 2010). significance in: Glioma, Thyroid cancer, Lung cancer, Liver cancer, Pancreatic cancer, Head and Hybrid/Mutated gene neck cancer, Stomach cancer, Colorectal cancer, RUNX1 exon 6 was fused to NOL4L exon 8. Renal cancer, Prostate cancer, Testis cancer, Breast Oncogenesis cancer, Cervical cancer, Ovarian cancer, Melanoma. Wild-type NOL4L was expressed at low levels in Main translocations: (detailed herein below) AML and normal bone marrow, whereas the - dic(9;20)(p13;q11) PAX5/NOL4L. RUNX1/NOL4L was expressed at high levels - t(20;21)(q11;q22) RUNX1/NOL4L. (Guastadisegni et al. 2010). Other fusion transcripts: (data extracted from the Atlas References http://atlasgeneticsoncology.org//Bands/20q11.html An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman ) AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, - fusion/translocation t(7;20)(p22;q11) Harrison CJ, Irving JA, Strefford JC. Variable breakpoints ACTB/NOL4L in triple-negative (TN) target PAX5 in patients with dicentric chromosomes: a adenocarcinoma. The triple-negative breast cancer model for the basis of unbalanced translocations in cancer. subtype is the most aggressive form of invasive Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17050-4 breast adenocarcinoma (Asmann et al. 2012). Asmann YW, Necela BM, Kalari KR, Hossain A, Baker TR, Carr JM, Davis C, Getz JE, Hostetter G, Li X, McLaughlin SA, Radisky DC, Schroth GP, Cunliffe HE, Perez EA,

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) 144

NOL4L (nucleolar protein 4 like) Huret JL

Thompson EA. Detection of redundant fusion transcripts as Y, Koehler R, Flohr T, Miller CW, Harbott J, Ludwig WD, biomarkers or disease-specific therapeutic targets in breast Stanulla M, Schrappe M, Bartram CR, Koeffler HP. Cloning cancer. Cancer Res. 2012 Apr 15;72(8):1921-8 of genes involved in chromosomal translocations by high- resolution single nucleotide polymorphism genomic Borah S, Barrodia P, Swain RK. Nucleolar protein 4-like has microarray Proc Natl Acad Sci U S A 2008 Aug a complex expression pattern in zebrafish embryos. Int J 19;105(33):11921-6 Dev Biol. 2016;60(1-3):53-6 Nebral K, König M, Harder L, Siebert R, Haas OA, Strehl S. Guastadisegni MC, Lonoce A, Impera L, Di Terlizzi F, Identification of PML as novel PAX5 fusion partner in Fugazza G, Aliano S, Grasso R, Cluzeau T, Raynaud S, childhood acute lymphoblastic leukaemia Br J Haematol Rocchi M, Storlazzi CT. CBFA2T2 and C20orf112: two 2007 Oct;139(2):269-74 novel fusion partners of RUNX1 in acute myeloid leukemia. Leukemia. 2010 Aug;24(8):1516-9 Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna R, Kim H, Verhaak RG. The landscape and therapeutic Hu X, Wang Q, Tang M, Barthel F, Amin S, Yoshihara K, relevance of cancer-associated transcript fusions Lang FM, Martinez-Ledesma E, Lee SH, Zheng S, Verhaak Oncogene 2015 Sep 10;34(37):4845-54 RGW. TumorFusions: an integrative resource for cancer- associated transcript fusions Nucleic Acids Res 2018 Jan This article should be referenced as such: 4;46(D1):D1144-D1149 Huret JL. NOL4L (nucleolar protein 4 like). Atlas Genet Kawamata N, Ogawa S, Zimmermann M, Niebuhr B, Cytogenet Oncol Haematol. 2019; 23(6):143-145. Stocking C, Sanada M, Hemminki K, Yamatomo G, Nannya

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Leukaemia Section Short Communication

Extranodal NK/T-cell lymphoma, nasal type (ENKL) Luis Miguel Juárez Salcedo, Diego Conde Royo, Samir Dalia Guadalajara University Hospital, Guadalajara, Spain [email protected] (LMJS); Principe de Asturias University Hospital, Madrid, Spain [email protected] (DCR); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA [email protected] (SD)

Published in Atlas Database: September 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/ExtranodalNKTLNHID1689.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70457/09-2018-ExtranodalNKTLNHID1689.pdf DOI: 10.4267/2042/70457 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

aggressive pathology, with predilection for Asian Abstract and South American populations (Barrionuevo C et al., 2007; Liang R et al., 2009). Neoplastic cells are Review on Extranodal NK/T-cell lymphoma and the surface CD3-, cytoplasmic CD3ε+, CD56+, genes involved. cytotoxic-molecule positive, Epstein-Barr virus Keywords (EBV) positive, with germline T-cell receptor gene Extranodal NK/T-cell lymphoma, nasal type; (Chan JK et al., 2008). This lymphoma is almost Angiocentric T-cell lymphoma; Malignant exclusively extranodal (Kwong YL et al., 2005). reticulosis Occur commonly in the nasal and upper aerodigestive region. Occasional cases present in the Identity skin, salivary gland, testis, and gastrointestinal tract. Quantification of circulating EBV DNA is an Other names accurate biomarker of tumor load (Au WY et al., Angiocentric T-cell lymphoma 2005). Concomitant sequential chemotherapy and Malignant reticulosis, NOS radiotherapy is standard treatment. Malignant midline reticulosis T/NK-cell lymphoma Etiology Polymorphic reticulosis Etiology is poorly understood, but is related in part Extranodal NK/T-cell lymphoma, nasal type to infection of the tumor cells with Epstein-Barr virus (EBV). Expression of EBV latent membrane Clinics and pathology protein-1 by immunohistochemistry has also been described (Kanavaros P et al., 1993). Disease Epidemiology Peripheral T cell lymphomas (PTCL) are a NK/T-cell lymphomas occur worldwide, with a heterogeneous group of aggressive neoplasm in strong geographic predilection for Asian population adults. Among these are: peripheral T cell (China, Japan, Korea and Southeast Asia) and for lymphoma, anaplastic large cell lymphoma, Central and South American population (Mexico, angioimmunoblastic T cell lymphoma, extranodal Peru, Argentina and Brazil) (Kwong YL et al., NK/T cell lymphoma (nasal type), enteropathy 2005). associated T cell lymphoma, hepatosplenic T cell Constituting 5-15% of lymphomas in these countries lymphoma. Extranodal natural killer/T-cell (Swerdlow SH et al., 2016). lymphoma, nasal type (ENKL), or nasal NK/T cell The median age at presentation is 52 years (Au WY lymphoma (angiocentric lymphoma), is an et al., 2009); however, rare cases have been reported

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) 146 Extranodal NK/T-cell lymphoma, nasal type (ENKL) Juárez Salcedo LM et al.

in childhood. There is a male predominance with an therapy is the frequent treatment option (i.e., approximately 2:1 male to female ratio. (Chim SC et radiotherapy with concurrent chemotherapy) (Tse E al., 2004; Li XY et al., 2009). et al., 2012). Radiation dose of 50 GY and Clinics concurrent therapy with reduced dose 2/3DeVIC (dexamethasone, etoposide, ifosfamide, carboplatin) The large majority of patients present with localized or VIDL (etoposide, ifosfamide, dexamethasone, L- disease resulting in symptoms of nasal obstruction, asparaginase). epistaxis, and/or a destructive mass involving the CHOP-based regimen (cyclophosphamide, nose, sinuses, or palate (Liu QF et al., 2014). Other doxorubicin, vincristine and prednisone) is not extranodal sites may be involved either primarily recommended for NK/T-cell lymphoma (Kim SJ et (extranasal NK/T cell lymphoma) or as a direct al., 2010). extension of the primary tumor. These sites include Other chemotherapy regimens like LVP (L- the upper airway, Waldeyer's ring, gastrointestinal asparaginase, vincristine and prednisolone) or tract, skin, testis, lung, eye, or soft tissue (Tse E et GELOX (gemcitabine, E. coli L-asparaginase, al., 2013). Lymph nodes may be involved oxaplatin) are been used in this pathology with high secondarily, but are only rarely the primary site of rates of remissions. involvement. Bone marrow involvement and B In disseminated disease cases, SMILE regimen symptoms are seen in approximately 10 and 35 (dexamethasone, methotrexate, ifosfomide, L- percent of patients, respectively (Li YX et al., 2009). asparaginase) achieves best results, but neutropenia Disease occurred in most of the patients with high rates of serious infections (Kwong YL et al., 2012). Diagnosis: The diagnosis of ENKL is made based The use of hematopoietic stem cell transplantation upon the evaluation of a biopsy specimen from the (HSCT) has been explored in NK/T-cell lymphomas, site of involvement, usually in the facial area. however most studies contained small number of Because the morphology of the tumor cells is so patients so the results are difficult to interpret. variable, it is important to consider this diagnosis in all cases of aggressive extranodal lymphoma Prognosis associated with vascular invasion and necrosis. ENKL is an aggressive lymphoma. Without The key diagnostic features are the demonstration of treatment survival is measured in months. The NK/T cell markers and Epstein Barr virus (EBV). prognosis with treatment is largely related to the Although CD56 is typically expressed, tumors that location and stage of disease at diagnosis. do not express CD56 may still be classified as ENKL Age over 60 years, stage III/IV disease, distant if both cytotoxic molecules and EBV are positive lymph node involvement, non-nasal type and (Chan JK et al., 2008). detectable Epstein-Barr virus viral DNA titer are Immunophenotype in this case can be useful; these consider the most important patient information for tumors express CD2, cytoplasmic CD3, CD56, and the prognosis determination. cytotoxic granule proteins (Chan JK et al., 2008). Cytology Genetics Immunephenotype is similar to that of a NK cell. The Note atypical cells in most cases express CD2, CD56, and A high percentage of these tumors overexpress the cytoplasmic CD3, but do not express surface CD3. p53 tumor suppressor protein, with about one- Most cases express cytotoxic granule protein such as quarter showing evidence of p53 mutation granzyme B, TIA-1, and perforin, and lack surface T (Quintanilla-Martinez L et al., 2001). In most other cell receptor (TCR). Uncommon cases may express tumor types, p21 overexpression is linked to wild- CD4, CD8, and/or CD7. (Lei KI et al., 2002). type p53 expression, but in this tumor it has been Pathology found even with mutant p53 or low p53 expression. Other tumor suppressor genes that have been The tumors cells can be of any size, but most implicated in the pathogenesis of ENKL include commonly are either medium-sized or a mixture of PRDM1 and FOXO3 (Karube et al., 2011). The gene small and large cells. They have a moderate amount PRDM1 (alias BLIMP1) is particularly interesting of pale/clear cytoplasm with irregularly folded because it regulates the amduration, homeostasis and nuclei typically containing granular chromatin and proliferation of NK cells (Kallies A et al., 2011). inconspicuous or small nucleoli. Azurophilic Several oncogenic pathways are activated, including granules may be seen on touch preps stained with Notch-1, Wnt, JAK/STAT, AKT, and nuclear factor giemsa (Swerdlow SH et al., 2008). kB. Recently, hole-exome sequencing has identified Treatment somatic-activating mutations of the JAK3 gene in Therapy and prognosis are based upon the stage of 35% of NK/T-cell lymphomas (Koo GC et al., 2012) the disease. In localized stages, combined modality

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resulting in cytokine-independent constitutive JAK- by genomic and functional analyses. Blood. 2011 Sep STAT activation. 22;118(12):3195-204 Koo GC, Tan SY, Tang T, Poon SL, Allen GE, Tan L, Chong Cytogenetics SC, Ong WS, Tay K, Tao M, Quek R, Loong S, Yeoh KW, Yap SP, Lee KA, Lim LC, Tan D, Goh C, Cutcutache I, Yu W, Ng CC, Rajasegaran V, Heng HL, Gan A, Ong CK, Cytogenetics morphological Rozen S, Tan P, Teh BT, Lim ST. Janus kinase 3-activating The TCR and immunoglobulin (Ig) genes are usually mutations identified in natural killer/T-cell lymphoma. germline, but a small fraction of cases demonstrate Cancer Discov. 2012 Jul;2(7):591-7 clonal rearrangement of TCR genes, suggesting Kwong YL. Natural killer-cell malignancies: diagnosis and derivation from a cytotoxic T lymphocyte (Lipford treatment. Leukemia. 2005 Dec;19(12):2186-94 et al., 1988). Clonal EBV genomes are virtually Lei KI, Chan LY, Chan WY, Johnson PJ, Lo YM. Diagnostic always present. In situ hybridization for EVB and prognostic implications of circulating cell-free Epstein- encoded small nuclear RNAs is the preferred method Barr virus DNA in natural killer/T-cell lymphoma. Clin Cancer Res. 2002 Jan;8(1):29-34 of demonstrating the presence of EBV (Lei KL et al, 2002). Liang R. Advances in the management and monitoring of extranodal NK/T-cell lymphoma, nasal type. Br J Haematol. References 2009 Oct;147(1):13-21 Lipford EH Jr, Margolick JB, Longo DL, Fauci AS, Jaffe ES. Au WY, Ma SY, Chim CS, Choy C, Loong F, Lie AK, Lam Angiocentric immunoproliferative lesions: a CC, Leung AY, Tse E, Yau CC, Liang R, Kwong YL. clinicopathologic spectrum of post-thymic T-cell Clinicopathologic features and treatment outcome of mature proliferations. Blood. 1988 Nov;72(5):1674-81 T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification Liu QF, Wang WH, Wang SL, Liu YP, Huang WT, Lu N, scheme: a single center experience of 10 years. Ann Oncol. Zhou LQ, Ouyang H, Jin J, Li YX. Immunophenotypic and 2005 Feb;16(2):206-14 clinical differences between the nasal and extranasal subtypes of upper aerodigestive tract natural killer/T-cell Barrionuevo C, Zaharia M, Martinez MT, Taxa L, Misad O, lymphoma Int J Radiat Oncol Biol Phys 2014 Mar Moscol A, Sarria G, Guerrero I, Casanova L, Flores C, 15;88(4):806-13 Zevallos-Giampietri EA. Extranodal NK/T-cell lymphoma, nasal type: study of clinicopathologic and prognosis factors Quintanilla-Martinez L, Kremer M, Keller G, Nathrath M, in a series of 78 cases from Peru. Appl Immunohistochem Gamboa-Dominguez A, Meneses A, Luna-Contreras L, Mol Morphol. 2007 Mar;15(1):38-44 Cabras A, Hoefler H, Mohar A, Fend F. p53 Mutations in nasal natural killer/T-cell lymphoma from Mexico: Kallies A, Carotta S, Huntington ND, Bernard NJ, Tarlinton association with large cell morphology and advanced DM, Smyth MJ, Nutt SL. A role for Blimp1 in the disease Am J Pathol 2001 Dec;159(6):2095-105 transcriptional network controlling natural killer cell maturation. Blood. 2011 Feb 10;117(6):1869-79 Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Kanavaros P, Lescs MC, Brière J, Divine M, Galateau F, Jaffe ES. The 2016 revision of the World Health Joab I, Bosq J, Farcet JP, Reyes F, Gaulard P. Nasal T-cell Organization classification of lymphoid neoplasms Blood lymphoma: a clinicopathologic entity associated with 2016 May 19;127(20):2375-90 peculiar phenotype and with Epstein-Barr virus. Blood. 1993 May 15;81(10):2688-95 Tse E, Kwong YL. How I treat NK/T-cell lymphomas Blood 2013 Jun 20;121(25):4997-5005 Karube K, Nakagawa M, Tsuzuki S, Takeuchi I, Honma K, This article should be referenced as such: Nakashima Y, Shimizu N, Ko YH, Morishima Y, Ohshima K, Nakamura S, Seto M. Identification of FOXO3 and PRDM1 Juárez Salcedo LM, Conde Royo D, Dalia S. Extranodal as tumor-suppressor gene candidates in NK-cell neoplasms NK/T-cell lymphoma, nasal type (ENKL). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6):146-148.

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Leukaemia Section Review Myeloid sarcoma Karen M. Chisholm Department of Laboratories, Seattle Childrens Hospital, Seattle, WA, USA; [email protected]

Published in Atlas Database: September 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/MyeloidSarcomaID1822.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70458/09-2018-MyeloidSarcomaID1822.pdf DOI: 10.4267/2042/70458 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Phenotype/cell stem origin The cells of origin are hematopoietic stem Review on myeloid sarcoma, with data on clinics, cells/progenitor cells. pathology, and involved genes. Etiology Keywords The etiology of myeloid sarcoma is similar to that of chloroma, extramedullary myeloid tumor, acute myeloid leukemia, but instead is present in an granulocytic sarcoma, myeloid sarcoma extramedullary site. Identity Epidemiology Myeloid sarcoma can occur at any age, but does Myeloid sarcoma appear more frequent in children and in older Other names patients. Some reports give a slightly increased male Granulocytic sarcoma predominance (Pileri et al., 2007; Kawamoto et al., Chloroma 2016). Myeloid sarcoma is thought to occur in 1.4- Extramedullary myeloid tumor 9% of patients with AML (Alexiev et al., 2007). In children, the rate of isolated myeloid sarcoma is Clinics and pathology approximately 1.3%, while the rate of isolated myeloid sarcoma preceding AML is approximately Disease 2.5% (Reinhardt and Creutzig, 2002). Myeloid Myeloid sarcoma is defined as a proliferation of sarcoma occurs in 6.7%-23.3% of children with a myeloblasts effacing tissue architecture and forming concurrent diagnosis of AML (Dusenbery et al., a mass in a site other than bone marrow. Originally 2003; Johnston et al., 2012; Stve et al., 2017). termed "chloroma" due to the greenish hue Clinics appreciated grossly owing to the production of myeloperoxidase, it has also been called Myeloid sarcoma is thought to occur in four different granulocytic sarcoma (due to immature to maturing scenarios: 1) de novo in the absence of any granulocytes, usually consistent with an acute underlying acute myeloid leukemia or other myeloid myeloid leukemia with maturation, French- neoplasm; 2) concurrently with acute myeloid American-British subtype M2), and extramedullary leukemia (sometimes the first sign of disease); 3) myeloid tumor. In skin, this entity has been referred representing blast crisis or blast transformation in to as leukemia cutis. However, the most recent and myeloproliferative disorders or myelodysplastic most encompassing term is myeloid sarcoma; while syndromes; 4) representing relapse AML (often this entity can consist of myeloblasts (with or post-transplant). The latter scenario occurs in 5-12% without maturation), it can also consist of of patients after allogeneic stem cell transplantation, monoblasts or myelomonocytes, and rarely erythroid accounting for 7-46% of post-transplant AML precursors or megakaryoblasts. relapses (Solh et al., 2016). Approximately 27% of

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patients present with de novo/isolated disease (Pileri et al., 2007). Some reports have identified myeloid sarcoma in patient with concurrent non-Hodgkin's lymphoma or with a history of a non-hematopoietic tumor (Pileri et al., 2007). Myeloid sarcoma can occur anywhere in the body (except for the bone marrow), but has been found to be most frequent in the skin, lymph nodes, bone, soft tissue, gastrointestinal tract, and mediastinum, with less frequent sites including the testes (Traweek et al., 1993; Pileri et al., 2007; Kawamoto et al., 2016). Multiple sites of involvement may occur in the same individual at the same time. In children, the orbit is an additional common site (Reinhardt and Creutzig, 2002; Dusenbery et al., 2003; Johnston et al., 2012; Støve et al., 2017). Symptoms of myeloid sarcoma depend on the site of involvement. Cytology As stated previously, the cells can be myeloblasts, differentiating granulocytes (ex. promyelocytes), a mixture of myeloblasts and monoblasts, pure monoblasts, or cells with monocytic differentiation. Rarely myeloid sarcomas consist of erythroblasts or megakaryoblasts. The cells are usually medium to large in size with high nuclear-to-cytoplasmic ratios, fine to vesicular chromatin, variably prominent nucleoli, and scant cytoplasm which may contain Figure 1: Leukemia cutis, or myeloid sarcoma of the skin. granules. Nuclei with irregular or indented contours Left panel is low power magnification and right panel is high may represent monocytic cells. power magnification demonstrating an infiltrate of atypical cells with round to irregular nuclear contours, fine Pathology chromatin, conspicuous nucleoli, and pale cytoplasm.

By definition, myeloid sarcoma consists of blasts forming a mass in extramedullary tissue. Depending Treatment on the tissue, the cells may be present in confluent The treatment for myeloid sarcoma is the same as sheets, nests, or in cords divided by fibrous septae. that for acute myeloid leukemia, which includes In lymph nodes, they can efface the architecture or induction systemic chemotherapy (Bakst et al., be present infiltrating the paracortex and sinuses. In 2011). Cytogenetic and molecular data are the spleen, the neoplasm usually infiltrates the red important for risk stratification, similar to AML. For pulp with persistent white pulp. In some cases, those with intermediate or high risk disease, eosinophilic myelocytes and a variety of granulocyte allogeneic transplant may be considered (Solh et al., precursors can be seen intermixed with the blasts. 2016). The blasts may accumulate around blood vessels and Local radiation has not been found to be beneficial may even invade blood vessel walls. Mitoses may in induction therapy, but has been useful in be readily identifiable and tingible body consolidation if a complete response has not been macrophages may be present. Of note, in those cases achieved with chemotherapy. Radiation may also be with isolated myeloid sarcoma, bone marrow blasts of use in situations where debulking or rapid may be present at symptom relief from compression are needed prior By morphology, the sarcoma can usually be to induction chemotherapy, or when there is classified as acute myeloid leukemia with recurrence after transplant. Surgery could also be maturation, acute myelomonocytic leukemia, or performed if rapid debulking is required. (Bakst et acute monoblastic/monocytic leukemia. The al., 2011) myeloid sarcomas of the skin are often myelomonocytic or monoblastic/monocytic (Reinhardt and Creutzig, 2002; Pileri et al., 2007). Those in the orbit in pediatrics are often acute myeloid leukemia with maturation.

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Figure 3: Biopsy of soft tissue near the left knee demonstrates an infiltrate of medium sized cells with irregular nuclear contours, open chromatin, variably prominent nucleoli, and eosinophilic cytoplasm. Immunohistochemical staining for lysozyme is positive (second panel). This myeloid sarcoma represented an extramedullary relapse after transplantation in a patient with AML with KMT2A gene rearrangement (MLL on chromosome 11q23). Treatment The treatment for myeloid sarcoma is the same as that for acute myeloid leukemia, which includes induction systemic chemotherapy (Bakst et al., 2011). Cytogenetic and molecular data are important for risk stratification, similar to AML. For those Figure 2: Soft tissue mass demonstrating a proliferation of with intermediate or high risk disease, allogeneic immature myeloid cells into adipose tissue. Scattered transplant may be considered (Solh et al., 2016). eosinophilic myelocytes are also present in this myeloid Local radiation has not been found to be beneficial sarcoma with t(8;21). The middle panel demonstrates in induction therapy, but has been useful in immunohistochemical staining for myeloperoxidase which is positive. The right panel demonstrates positivity for CD117 consolidation if a complete response has not been immunohistochemical staining. achieved with chemotherapy. Radiation may also be of use in situations where debulking or rapid symptom relief from compression are needed prior to induction chemotherapy, or when there is recurrence after transplant. Surgery could also be performed if rapid debulking is required. (Bakst et al., 2011)

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Evolution with chronic myelogenous leukemia in blast phase, and most commonly occur in lymph nodes (Wilson If isolate myeloid sarcoma is not treated, it will and Medeiros, 2015). usually evolve into acute myeloid leukemia within 5 to 12 months. References Prognosis Alexiev BA, Wang W, Ning Y, Chumsri S, Gojo I, Rodgers In patients with concurrent AML, the additional WH, Stass SA, Zhao XF. Myeloid sarcomas: a histologic, clinical finding of myeloid sarcoma has not been immunohistochemical, and cytogenetic study Diagn Pathol found to have clinical significance (Traweek et al., 2007 Oct 31;2:42 1993; Kawamoto et al., 2016). A possible exception Audouin J, Comperat E, Le Tourneau A, Camilleri-Brot S, is in adult patients with the t(8;21) translocation in Adida C, Molina T, Diebold J. Myeloid sarcoma: clinical and which myeloid sarcoma associated with leukemia morphologic criteria useful for diagnosis Int J Surg Pathol has a worse prognosis than the leukemia alone (Byrd 2003 Oct;11(4):271-82 et al., 1997). However, in children, isolated myeloid Bakst RL, Tallman MS, Douer D, Yahalom J. How I treat sarcoma has been found to have better prognosis extramedullary acute myeloid leukemia Blood 2011 Oct than similarly aged children with acute myeloid 6;118(14):3785-93 leukemia (Dusenbery et al., 2003). Additionally, Byrd JC, Weiss RB, Arthur DC, Lawrence D, Baer MR, children with orbital myeloid sarcoma have a higher Davey F, Trikha ES, Carroll AJ, Tantravahi R, Qumsiyeh M, Patil SR, Moore JO, Mayer RJ, Schiffer CA, Bloomfield CD. overall survival compared to myeloid sarcoma from Extramedullary leukemia adversely affects hematologic other sites, even after adjustment for cytogenetics complete remission rate and overall survival in patients with (Johnston et al., 2012). t(8;21)(q22;q22): results from Cancer and Leukemia Group In adults, studies have varied, with some B 8461 J Clin Oncol 1997 Feb;15(2):466-75 demonstrated increased survival, others worse Dusenbery KE, Howells WB, Arthur DC, Alonzo T, Lee JW, survival, and others no change in outcomes of Kobrinsky N, Barnard DR, Wells RJ, Buckley JD, Lange BJ, isolated myeloid sarcoma cases compared to acute Woods WG. Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the myeloid leukemia not associated with myeloid Children's Cancer Group J Pediatr Hematol Oncol 2003 sarcoma (Wilson and Medeiros, 2015); however, Oct;25(10):760-8 two studies did show increased overall survival for Falini B, Lenze D, Hasserjian R, Coupland S, Jaehne D, those with isolated myeloid sarcoma (Tsimberidou et Soupir C, Liso A, Martelli MP, Bolli N, Bacci F, Pettirossi V, al., 2008; Movassaghian et al., 2015). Kawamoto et Santucci A, Martelli MF, Pileri S, Stein H. Cytoplasmic al. (2016) found that those with myeloid sarcoma mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas Leukemia representing blast crisis or blast transformation in 2007 Jul;21(7):1566-70 myeloproliferative disorders or myelodysplastic syndromes have a worse prognosis than myeloid Johnston DL, Alonzo TA, Gerbing RB, Lange BJ, Woods WG. Superior outcome of pediatric acute myeloid leukemia sarcoma with or without concurrent AML. patients with orbital and CNS myeloid sarcoma: a report from the Children's Oncology Group Pediatr Blood Cancer Cytogenetics 2012 Apr;58(4):519-24 Kawamoto K, Miyoshi H, Yoshida N, Takizawa J, Sone H, Cytogenetics morphological Ohshima K. Clinicopathological, Cytogenetic, and Studies have shown that approximately 55% of cases Prognostic Analysis of 131 Myeloid Sarcoma Patients Am have karyotypic abnormalities (Pileri et al., 2007). J Surg Pathol 2016 Nov;40(11):1473-1483 Similar to acute myeloid leukemia, myeloid sarcoma Movassaghian M, Brunner AM, Blonquist TM, Sadrzadeh H, can have recurrent genetic abnormalities, including Bhatia A, Perry AM, Attar EC, Amrein PC, Ballen KK, Neuberg DS, Fathi AT. Presentation and outcomes among t(8;21)(q22;q22.1) ( RUNX1 / RUNX1T1), patients with isolated myeloid sarcoma: a Surveillance, inv(16)(p13.1q22) ( CBFB / MYH11), and KMT2A Epidemiology, and End Results database analysis Leuk (11q23) gene rearrangements. Other karyotypic Lymphoma 2015 Jun;56(6):1698-703 abnormalities include monosomy 7 and trisomy 8. Pileri SA, Ascani S, Cox MC, Campidelli C, Bacci F, Piccioli Those with t(8;21) are more often located in the orbit M, Piccaluga PP, Agostinelli C, Asioli S, Novero D, and associated with pediatric cases; these cases Bisceglia M, Ponzoni M, Gentile A, Rinaldi P, Franco V, Vincelli D, Pileri A Jr, Gasbarra R, Falini B, Zinzani PL, represent acute myeloid leukemia with maturation Baccarani M. Myeloid sarcoma: clinico-pathologic, (Reinhardt and Creutzig, 2002). Cases with inv(16) phenotypic and cytogenetic analysis of 92 adult patients tend to involve the intestine, breast, or uterus and are Leukemia 2007 Feb;21(2):340-50 also associated with foci of plasmacytoid dendritic Reinhardt D, Creutzig U. Isolated myelosarcoma in children- cells (Pileri et al., 2007). Cases with KMT2A -update and review Leuk Lymphoma 2002 translocations more often involve the skin or breast, Mar;43(3):565-74 and are usually myelomonocytic or monoblastic/monocytic in morphology. Those with Seifert RP, Bulkeley W 3rd, Zhang L, Menes M, Bui MM. A t(9;22)(q34.1;q11.2) ( BCR / ABL1) are associated practical approach to diagnose soft tissue myeloid sarcoma

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preceding or coinciding with acute myeloid leukemia Ann Tsimberidou AM, Kantarjian HM, Wen S, Keating MJ, Diagn Pathol 2014 Aug;18(4):253-60 O'Brien S, Brandt M, Pierce S, Freireich EJ, Medeiros LJ, Estey E. Myeloid sarcoma is associated with superior event- Solh M, Solomon S, Morris L, Holland K, Bashey A. free survival and overall survival compared with acute Extramedullary acute myelogenous leukemia Blood Rev myeloid leukemia Cancer 2008 Sep 15;113(6):1370-8 2016 Sep;30(5):333-9 Wilson CS, Medeiros LJ. Extramedullary Manifestations of Stve HK, Sandahl JD, Abrahamsson J, Asdahl PH, Forestier Myeloid Neoplasms Am J Clin Pathol 2015 Aug;144(2):219- E, Ha SY, Jahnukainen K, Jnsson G, Lausen B, Palle J, 39 Zeller B, Hasle H. Extramedullary leukemia in children with acute myeloid leukemia: A population-based cohort study This article should be referenced as such: from the Nordic Society of Pediatric Hematology and Oncology (NOPHO) Pediatr Blood Cancer 2017 Dec;64(12) Chisholm KM. Myeloid Sarcoma. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6):149-153. Traweek ST, Arber DA, Rappaport H, Brynes RK. Extramedullary myeloid cell tumors An immunohistochemical and morphologic study of 28 cases Am J Surg Pathol

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Leukaemia Section Short Communication der(Y)t(Y;1)(q11-12;q12-21) Adriana Zamecnikova Kuwait Cancer Control Center, Kuwait [email protected]

Published in Atlas Database: March 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0Yq01qID1818.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70459/03-2018-t0Yq01qID1818.pdf DOI: 10.4267/2042/70459 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

2002). Abstract Acute myeloid leukemia in 5 (aged 0 to 86 years, Structural abnormalities involving sex chromosomes median 63 years): 2 acute myeloblastic leukemia are uncommon in hematological malignancies. The with maturation (AML-M2) (Haupt et al., 1991; unbalanced translocation between the long arm of Singh et al., 1993), 2 acute myelomonocytic chromosomes 1 and Y results in a partial trisomy of leukemia (AML- M4) (Bao et al., 2006; Brown et al., the 1q region and has been described mainly in 2012) and 1 acute monoblastic leukemia (AML-M5) chronic myeloproliferative disorders. (Tuborgh et al., 2013). ). Keywords Acute lymphoblastic leukemia in 2 pediatric patients aged 0 and 10 years (Dayton et al.,1994; Chronic myeloproliferative disorders; unbalanced Heerema et al., 1999). ). translocation; genomic gains; disease evolution. Multiple myeloma in 3 (1 aged 73 years, 2 unknown age) (Mugneret et al., 1995; Wang et al., Clinics and pathology 2010; Sawyer et al., 2014) and). Disease Mature B-cell neoplasm in 4 (aged 10,11,36 and 60 years) (Tanaka et al., 1990; Dayton et al., 1994; Myeloid disorders mainly, rarely B-cell lymphoid Lones et al., 2004; Havelange et al., 2013). malignancies. Epidemiology Note About 28 male patients harboring der(Y)t(Y;1)(q11- Chronic myeloid neoplasm in 15 patients (15 12;q12-21) have been reported (aged 1 to 86 years, males aged 15 to 75 years; median 63 years). Among median 60 years). Among them, there were 7 them, there were 7 cases of myelodysplastic pediatric patients aged 0 to 15 years (median 10 syndrome (MDS) (Hollings et al., 1988; Thompsonet years). al., 1991; Wei et al., 1993; Raymakersetal et al.,1996; Djordjevicet al., 2008; Wan et al., 2001; Prognosis Sanford et al., 2015), 1 polycythemia vera (Testa et The acquisition of an unbalanced 1q rearrangement al., 1981), 1 idiopathic myelofibrosis (Michaux et a., in patients with myeloid malignancies appears to be l 1996), 1 post-polycythemic myelofibrosis a late event associated with disease transition and (Manabe et al., 2013), 1 essential thrombocythemia poor response to treatment. der(Y)t(Y;1) in multiple (Lim et al.,2016), 3 chronic myelomonocytic myeloma and lymphoid malignancies is part of leukemia (Hollings et al., 1988; Michaux et al., complex karyotypes with coexisting other high-risk 1996; Chen et al., 2010) and 1 atypical chronic genetic abnormalities such as 11q23 and 8q24 myeloid leukemia (Ohsaka Hisa rearrangements that have an additional impact leading to shorter survival in these patients.

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Figure 1. Partial karyotypes showing the unbalanced rearrangement between chromosome Y and 1. Fluorescence hybridization with LSI X/Y probe (Abott molecular/Vysis, US) showing the der(Y) chromosome (A) and 2 copies of the derivative chromosome (B) on metaphase and interphase cell.

1q trisomy results in deregulation of several genes Cytogenetics implicated in leukemogenesis. Cytogenetics morphological References Unbalanced translocation; a trisomic 1q juxtaposed to Yq12-21 replacing the terminal segment of Bao L, Wang X, Ryder J, Ji M, Chen Y, Chen H, Sun H, Yang Y, Du X, Kerzic P, Gross SA, Yao L, Lv L, Fu H, Lin chromosome Y. G, Irons RD. Prospective study of 174 de novo acute myelogenous leukemias according to the WHO Additional anomalies classification: subtypes, cytogenetic features and FLT3 Sole karyotype aberration in 10 patients, while it was mutations. Eur J Haematol. 2006 Jul;77(1):35-45 accompanied by a limited number of additional Brown T, Swansbury J, Taj MM. Prognosis of patients with chromosomal changes in 5 myeloid malignancies: t(8;16)(p11;p13) acute myeloid leukemia. Leuk Lymphoma. +9 in 2 and +8, del(20q), del(11)(q13) sole cases. 2012 Feb;53(2):338-41 Found with 11q23 rearrangements as part of Chen B, Ma Y, Xu X, Wang X, Qin W, Ji M, Lin G. Analyses complex karyotypes in 2 AML patients. Association on clinical characteristic and prognoses of 41 patients with with t(8;14)(q24;q32)/8q24 rearrangement in 1 ALL chronic myelomonocytic leukemia in China. Leuk Res. 2010 in all the 4 patients with mature B-cell neoplasm; Apr;34(4):458-62 highly complex rearrangements in MM. Dayton VD, Arthur DC, Gajl-Peczalska KJ, Brunning R. L3 acute lymphoblastic leukemia. Comparison with small noncleaved cell lymphoma involving the bone marrow. Am Result of the chromosomal J Clin Pathol. 1994 Feb;101(2):130-9 anomaly Djordjević V, Dencić-Fekete M, Jovanović J, Drakulić D, Stevanović M, Janković G, Gotić M. Pattern of trisomy 1q in Fusion protein hematological malignancies: a single institution experience. Cancer Genet Cytogenet. 2008 Oct;186(1):12-8 Oncogenesis Haupt R, Comelli A, Garré ML, Defferrari R, Fugazza G, Complete or partial trisomies of 1q are well-known Basso G, Rosanda C, Sessarego M, Sansone R. in hematological malignancies, but involvements of Cytogenetics of infantile leukemias and its correlations with sex chromosomes are uncommon. Among them, bio-clinical features. The "G. Gaslini" Children's Hospital der(Y)t(Y;1)(q11-12;q12-21) is most common in experience over a 9-year period. Haematologica. 1991 Mar- chronic myeloproliferative disorders, but cases of Apr;76(2):109-12 other diseases, such as AML or Burkitt's lymphoma Havelange V, Ameye G, Théate I, Callet-Bauchu E, have also been reported. While it is unknown which Mugneret F, Michaux L, Dastugue N, Penther D, Barin C, Collonge-Rame MA, Baranger L, Terré C, Nadal N, Lippert genes on 1q are responsible for the development E, Laï JL, Cabrol C, Tigaud I, Herens C, Hagemeijer A, and/or progression of these diseases, it is likely that Raphael M, Libouton JM, Poirel HA. Patterns of genomic aberrations suggest that Burkitt lymphomas with complex

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karyotype are distinct from other aggressive B-cell Cytogenet 1996 May;88(1):83-5 lymphomas with MYC rearrangement. Genes Chromosomes Cancer. 2013 Jan;52(1):81-92 Sanford D, DiNardo CD, Tang G, Cortes JE, Verstovsek S, Jabbour E, Ravandi F, Kantarjian H, Garcia-Manero G. Heerema NA, Sather HN, Ge J, Arthur DC, Hilden JM, Trigg Jumping Translocations in Myeloid Malignancies ME, Reaman GH. Cytogenetic studies of infant acute Associated With Treatment Resistance and Poor Survival lymphoblastic leukemia: poor prognosis of infants with Clin Lymphoma Myeloma Leuk 2015 Sep;15(9):556-62 t(4;11) - a report of the Children's Cancer Group. Leukemia. 1999 May;13(5):679-86 Sawyer JR, Tian E, Heuck CJ, Epstein J, Johann DJ, Swanson CM, Lukacs JL, Johnson M, Binz R, Boast A, Hollings PE, Giles LM, Rosman I, Fitzgerald PH. An Sammartino G, Usmani S, Zangari M, Waheed S, van Rhee identical t(Y;1)(q12;q21) in two patients with F, Barlogie B. Jumping translocations of 1q12 in multiple myelodysplastic syndromes. Cancer Genet Cytogenet. myeloma: a novel mechanism for deletion of 17p in 1988 Sep;34(2):285-93 cytogenetically defined high-risk disease Blood 2014 Apr 17;123(16):2504-12 Lim HH, Choi JM, Kim BR, Woo KS, Kim KH, Kim JM, Kim SH, Han JY.. A Rare der(Y)t(Y;1)(q12;q12) in a Patient with Singh S, Wass J, Devaraj J, Young G, Vincent P. Essential Thrombocythemia. Lab Med Online 2016 July 6, Translocation (Y;1)(q12;q21) in acute leukemia Cancer 3: 183-186. Genet Cytogenet 1993 Oct 15;70(2):136-9 Lones MA, Sanger WG, Le Beau MM, Heerema NA, Sposto Tanaka S, Nishigaki H, Nakagawa H, Okuda T, Nishida K, R, Perkins SL, Buckley J, Kadin ME, Kjeldsberg CR, Tsuda S, Taniwaki M, Imanishi H, Misawa S, Kashima K, et Meadows A, Siegel S, Finlay J, Bergeron S, Cairo MS; al. Reciprocal t(14;19)(q32 3;q13 1) in a patient with B-cell Children's Cancer Group Study CCG-E08. Chromosome lymphoma abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: Testa JR, Kanofsky JR, Rowley JD, Baron JM, Vardiman a report from Children's Cancer Group Study CCG-E08 J JW. Karyotypic patterns and their clinical significance in Pediatr Hematol Oncol 2004 Mar;26(3):169-78 polycythemia vera Am J Hematol 1981;11(1):29-45 Manabe M, Takeda O, Okita J, Takakuwa T, Harada N, Thompson PW, Standen GR, Geddes AD. Transient Nakano H, Okamoto S, Aoyama Y, Kumura T, Ohta T, t(Y;1)(q12;q21) in a patient with Fanconi anemia and Furukawa Y, Mugitani A. A rare der(Y)t(Y;1)(q12;q12) in a myelodysplastic syndrome Cancer Genet Cytogenet 1991 patient with post-polycythemic myelofibrosis: a case report Apr;52(2):201-2 Am J Blood Res 2013 May 5;3(2):186-90 Tuborgh A, Meyer C, Marschalek R, Preiss B, Hasle H, Michaux L, Wlodarska I, Vellosa ER, Verhoef G, Van Kjeldsen E. Complex three-way translocation involving Orshoven A, Michaux JL, Scheiff JM, Mecucci C, Van den MLL, ELL, RREB1, and CMAHP genes in an infant with Berghe H. Translocation (Y;1)(q12;q12) in hematologic acute myeloid leukemia and t(6;19;11)(p22 2;p13 1;q23 malignancies Report on two new cases, FISH Wan TSK, Ma SK, Chan LC, Au WY.. Association between characterization, and review of the literature Cancer Genet der(Y)t(Y;1)(q12;q12) and myelodysplastic syndrome. Cytogenet Cancer Genet Cytogenet 2001; 124 : 84-85. Mugneret F, Sidaner I, Favre B, Manone L, Maynadié M, Wang T, Qiu JY, Ma XL, Jia XP, Wang YP, Yu HJ, Li H, Caillot D, Solary E. Der(16)t(1;16)(q10;p10) in multiple Tong CR.. cThe clinical and experimental analyses of a myeloma: a new non-random abnormality that is frequently multiple myeloma patient with derivative der(Y;1). Chinese associated with Burkitt's-type translocations Leukemia journal of medical genetics 2010 Apr;27(2):214-6. 1995 Feb;9(2):277-81 Wei DC, Wan TS, Chan LC, Cheng PN. der(Y)t(Y;1) is a Ohsaka A, Hisa T. Spectral karyotyping refined the nonrandom abnormality in myelodysplastic syndrome identification of a der(Y)t(Y;1)(q11 1 or 2;q12) in the blast Cancer Genet Cytogenet 1993 Oct 15;70(2):155-6 cells of a patient with atypical chronic myeloid leukemia Raymakers R, Stellink F, Geurts van Kessel A. Derivative This article should be referenced as such: (y)t(Y;1)(q12;q12),+9 in a patient with polycythemia vera Zamecnikova A. der(Y)t(Y;1)(q11-12;q12-21). Atlas during transition into myelodysplasia Cancer Genet Genet Cytogenet Oncol Haematol. 2019; 23(6):154-156.

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Leukaemia Section Short Communication t(8;14)(q24;q32) in BPDCN Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France Published in Atlas Database: August 2018 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0814q24q32BPDCNID1828.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70460/08-2018-t0814q24q32BPDCNID1828.pdf DOI: 10.4267/2042/70460

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Cytogenetics The t(8;14)(q24;q32) was the sole anomaly. Review on t(8;14)(q24;q32) in BPDCN, with data on clinics Genes involved and Keywords proteins Chromosome 8; chromosome 14; Blastic plasmacytoid dendritic cell neoplasm Note The partner gene of MYC is unknown. Clinics and pathology MYC Disease Location Blastic plasmacytoid dendritic cell neoplasm 8q24.21 (BPDCN) DNA/RNA Note MYC is composed of three exons spanning over 4 BPDCN has been known with various names, kb. including agranular CD4+ natural killer (NK) Protein leukemia, CD4+/CD56+ hematodermic neoplasm, MYC is expressed in almost all proliferating cells. It and blastic NK lymphoma. BPDCN malignant cells is located predominantly in the nucleus. MYC is a are derived from the precursors of plasmacytoid transcriptional regulator, capable to induce or dendritic cells. It most commonly involves the skin. repress the expression of thousands genes. MYC is BPDCN is an aggressive neoplasm. BPDCN is often deregulated in cancer by several different associated with a complex karyotype (review in mechanisms: chromosomal translocations, Meloni-Ehrig 2017). amplifications, point mutations, epigenetic Epidemiology reprogramming, enhanced translation and increased protein stability (review in Mohamed, 2017). In a series of 41 patients with BPDCN, five had a MYC rearrangement confirmed by FISH, one had a References t(X;8)(q24;q24), one had a t(3;8)(p25;q24), two had a t(6;8)(p21;q24) MYC/SUPT3H, and one had a Boddu PC, Wang SA, Pemmaraju N, Tang Z, Hu S, Li S, Xu t(8;14)(q24;q32) (Boddu et al., 2018). J, Medeiros LJ, Tang G. 8q24/MYC rearrangement is a recurrent cytogenetic abnormality in blastic plasmacytoid Clinics dendritic cell neoplasms. Leuk Res. 2018 Mar;66:73-78 The patient with a t(8;14)(q24;q32) was a 55 year- Meloni-Ehrig A. Blastic Plasmacytoid Dendritic Cell old male patient with skin involvement. He did not Neoplasm (BPDCN) Atlas Genet Cytogenet Oncol Haematol. in press respond to treatment and died 12 months after http://AtlasGeneticsOncology.org/Anomalies/BPDCNID214 diagnosis. 6.html

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(6) 157 t(8;14)(q24;q32) in BPDCN Huret JL

Mohamed AN. MYC (MYC proto-oncogene, bHLH This article should be referenced as such: transcription factor); Atlas Genet Cytogenet Oncol Haematol. in press Huret JL. t(8;14)(q24;q32) in BPDCN. Atlas Genet http://AtlasGeneticsOncology.org/Genes/MYCID27.html Cytogenet Oncol Haematol. 2019; 23(6):157-158.

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Cancer Prone Disease Section Review

Familial glioma Riccardo Bazzoni, Angela Bentivegna School of Medicine and Surgery, University of Milan-Bicocca, via Cadore, Monza, Italy (RB,AB); 2 NeuroMI, Milan center of Neuroscience, University of Milan-Bicocca, Dept. of Neurology and Neuroscience, San Gerardo Hospital, via Pergolesi, Monza, Italy (AB)[email protected]; [email protected]

Published in Atlas Database: September 2018 Online updated version : http://AtlasGeneticsOncology.org/Kprones/FamilialGliomaID10123.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70461/09-2018-FamilialGliomaID10123.pdf DOI: 10.4267/2042/70461 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Identity Abstract Note Glioma is the most common brain tumor, Primary central nervous system (CNS) tumors can characterized by several histological and malignancy be divided into gliomas and non-gliomas. For the grade. The majority of gliomas are sporadic, but more recent classification of gliomas (2016 WHO some familial cases have been reported (<5%). classification), see Table 1. Despite hereditary predisposition to gliomas has been associated to rare inherited cancer syndromes, Clinics such as Li-Fraumeni and Turcot's syndromes, neurofibromatosis and tuberous sclerosis, not all Note familial gliomas can be explained by these Gliomas represent 30% of all brain and central syndromes. Most familial gliomas seem to be nervous system (CNS) tumors and 80% of all characterized by cluster of two cases, suggesting the malignant brain tumors. The most common and involvment of low penetrance factor risks. malignant glioma is glioblastoma multiforme Moreover, no sex-linked disorders or SNPs on the X (GBM) (Goodenberger and Jenkins, 2012). chromosome have been associated with increased Although there are several histologic types of glioma risk, except for ATRX gene, whose loss-of- gliomas, the incidence rates for all sporadic gliomas function has been observed in 20 % of adult range from 4.67 to 5.73 per 100,000 persons oligodendrogliomas and in 80 % of grade 2 and 3 (Barbagallo et al., 2016). Gliomas are more common astrocytomas. Finally, the risk to inherit tumors such in men than in women and in white rather than in as glioma could also be related to combinations of black population (Ostrom et al., 2013). Anyway, multiple risk variants: besides GWAS analysis familial glioma cases are similar to sporadic ones in identified many SNPs involved in familial gliomas terms of gender distribution, age, morphology and at 5p15.33 (TERT), 7p11.2 (EGFR), 8q24.21 grade as shown in Table 2 (results from Gliogene (CCDC26), 9p21.3 (CDKN2A/CDKN2B), 11q23.3 Consortium https://www.bcm.edu/centers/cancer- (PHLDB1) and 20q13.33 (RTEL1), mutatio could be center/research/gliogene/) (Sadetzki et al., 2013). associated with the risk of glioma ns in POT1 gene Neoplastic risk and rare variants in SPAG9 and RUNDC1 genes ENVIRONMENTAL: Some epidemiologic risk could be associated with the risk of glioma. factors might lead to development of glioma such as Keywords therapeutic ionizing radiation, pesticides, smoking, Familial glioma, glioma petroleum refining or production work and employment in synthetic rubber manufacturing

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(Alifieris and Trafalis, 2015). An inverse association gliomas (Sadetzki et al., 2013). It is currently between glioma incidence and allergies, atopic thought that approximately 5-10% of patients have a diseases and systemic infections has been reported family history of glioma (Lindor et al., 2008, by multiple groups (Goodenberger and Jenkins, Robertson et al., 2010). An increased risk of 2012). developing primary brain tumors among first-degree FAMILIARITY: Excluding those gliomas known relatives of patients with gliomas has been shown to be due to rare hereditary cancer syndromes such (Robertson et al., 2010), and there is a greater risk as Turcot's and Li-Fraumeni syndromes as well as for first-degree relatives of probands with a younger neurofibromatosis ( NF1, NF2) or tuberous sclerosis age of onset than for first-degree relatives of (Melin et al., 2017), there is evidence that gliomas probands with later onset (Malmer et al., 2003, cluster in families. Most familial gliomas appear to Blumenthal and Cannon-Albright, 2008), as shown comprise clusters of two cases, suggesting low in Table 3. penetrance and a low risk of developing additional

Table 1.

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Table 2 - Distribution of glioma cases by date of diagnosis* and selected demographic and clinical characteristics. *When the glioma in the proband was diagnosed from 2007 all gliomas in the family were included in the incident cases column; when the glioma in the proband was diagnosed before 2007 all gliomas in the family were included in the prevalent cases column; **Excluding three cases with unknown age at diagnosis; comparison between mean age at diagnosis of incident and prevalent p = 0.003; ***p-value = 0.00009 (total incidents versus prevalent); ****For 92 cases of the 831 verified tumours, tumour histological behavior was unknown, and for 58 cases of the 481 verified tumours from the total incident cases, tumour histological behavior was unknown; *****For grades I-II p-value = 0.3 (total incident versus total prevalent). [Modified from Sadetzki et al., 2013]

Clinics Neoplastic risk Gliomas represent 30% of all brain and central ENVIRONMENTAL: Some epidemiologic risk nervous system (CNS) tumors and 80% of all factors might lead to development of glioma such as malignant brain tumors. The most common and therapeutic ionizing radiation, pesticides, smoking, malignant glioma is glioblastoma multiforme petroleum refining or production work and (GBM) (Goodenberger and Jenkins, 2012). employment in synthetic rubber manufacturing Although there are several histologic types of (Alifieris and Trafalis, 2015). An inverse association gliomas, the incidence rates for all sporadic gliomas between glioma incidence and allergies, atopic range from 4.67 to 5.73 per 100,000 persons diseases and systemic infections has been reported (Barbagallo et al., 2016). Gliomas are more common by multiple groups (Goodenberger and Jenkins, in men than in women and in white rather than in 2012). black population (Ostrom et al., 2013). Anyway, FAMILIARITY: Excluding those gliomas known familial glioma cases are similar to sporadic ones in to be due to rare hereditary cancer syndromes such terms of gender distribution, age, morphology and as Turcot's and Li-Fraumeni syndromes as well as grade as shown in Table 2 (results from Gliogene Consortium https://www.bcm.edu/centers/cancer- neurofibromatosis ( NF1, NF2) or tuberous sclerosis center/research/gliogene/) (Sadetzki et al., 2013). (Melin et al., 2017), there is evidence that gliomas cluster in families. Most familial gliomas appear to

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comprise clusters of two cases, suggesting low Anyway, the third-degree relative risks were not penetrance and a low risk of developing additional significantly elevated for astrocytoma, GBM or for gliomas (Sadetzki et al., 2013). It is currently the two types combined (Blumenthal and Cannon- thought that approximately 5-10% of patients have a Albright, 2008). However, familial aggregation of family history of glioma (Lindor et al., 2008, cancer can indicate a genetic etiology but may also Robertson et al., 2010). An increased risk of indicate shared familial environmental exposures. developing primary brain tumors among first-degree Unfortunately, a multifactorial inheritance model relatives of patients with gliomas has been shown could not be clearly rejected (Table 4) (de Andrade (Robertson et al., 2010), and there is a greater risk et al., 2001, Malmer et al., 2001, Shete et al., 2011). for first-degree relatives of probands with a younger The variation in inherited risk of glioma could be age of onset than for first-degree relatives of related to combinations of multiple risk variants. probands with later onset (Malmer et al., 2003, Here, we reported the most significant variants Blumenthal and Cannon-Albright, 2008), as shown (SNPs) figured out from GWASs (Table 5 and 6) in Table 3.

Table 3 - Relative risks (RR) for brain tumor among: first-degree relatives of patients (A), second-degree relatives of patients (B), first-degree relatives of patients with early onset brain tumor (C). [Modified from Blumenthal and Cannon- Albright, 2008].

Table 4 - Epidemologic studies in families with gliomas and other tumors. *Utah Population Data Base; RR=risk relative; CI=confidential interval; SIR=standardized incidence ratio; FDR=first-relative degree [Modified from Kyritsis et al., 2010]

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Table 5 - Heritable variants associated with glioma risk from GWASs. Data from Kinnersley et al., 2015, Kinnersley et al., 2015, Melin et al., 2017, Ostrom et al., 2014.

Table 6 - Representative recent studies describing genetic polymorphism linked to glioma risk. OD= odd ratio [Modified from Kyritsis et al., 2010]

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A particular attention goes to POT1 gene, which association studies. belongs to the telomere-shelterin complex. Indeed, However, somatic loss of-function mutations in the Bainbridge et al. found two different mutations in X chromosome gene Alpha thalassemia/mental POT1 in two families (A and B) (Bainbridge et al., retardation syndrome X-linked (ATRX) have been 2015). In family A, six individuals had POT1 observed in 20 % of adult oligodendroglioma tumors mutation (NM_015450:p.G95C, and in 80 % of grade 2 and 3 astrocytomas (Osorio HG19:chr7:g.124503667C>A), of whom three et al., 2015). developed glioma. In family B, also six individuals Treatment had POT1 mutation (NM_015450:p.E450X, HG19:chr7:g.124481048C>A) and two developed Multimodal therapies including surgical resection, glioma. Moreover, they identified, in a third family radio- and chemotherapy (Bush et al., 2017). (C), a third protein-changing mutation Evolution (NM_015450:p.D617Efs*8, The lower-grade gliomas can evolve towards higher- HG19:chr7:g.124464068TTA>T). In families with grade ones. POT1 mutations, they reported that the affected members suffered from oligodendroglioma, which is Prognosis substantially sensitive to irradiation. Anyway, the Except for pilocytic astrocytomas ID: 5773>, the association between familial glioma and POT1 median survival of glioma patients is still poor (12- mutations still needs to be validated. 14 months). The 5-years survival of GBM patients is Jalali et al. figured out that MYO19 and KIF18B <10%, with a final mortality rate of close to 100% genes and rare variants in SPAG9 and RUNDC1 are (Roy et al., 2015). potentially involved in familial gliomas (Jalali et al., 2015). Cytogenetics MENDELIAN CANCER SYNDROMES: A heritable genetic contribution to gliomagenesis was Note initially suggested by the increased incidence of Here, we reported the most karyotype abnormalities these tumors in families with Mendelian cancer associated with familial gliomas found in literature syndromes (Table 7). Although numerous familial (Table 8) cancer syndromes are associated with increased glioma risk, monogenic Mendelian disorders Genes involved and account for only a small proportion of adult glioma incidence at the population level (Ostrom et al., proteins 2014). However, germline mutations of PTEN, Note TP53, CDKN2A p16(INK4A)/p14(ARF), and Many SNPs could be associated with the risk of CDK4 are not common events in familial glioma, but glioma at 5p15.33 ( TERT), 7p11.2 ( EGFR), occasionally they may account for a subset of 8q24.21 ( CCDC26), 9p21.3 (CDKN2A/ CDKN2B), familial glioma cases (Tachibana et al., 2000). 11q23.3 (PHLDB1) and 20q13.33 (RTEL1), Several syndromes are associated to pediatric mutations in POT1 gene, MYO19 and KIF18B genes To date, no sex-linked disorders have been and rare variants in SPAG9 and RUNDC1 genes associated with increased glioma risk, nor has any could be associated with the risk of glioma. PTEN, SNP on the X chromosome been identified as a TP53, CDKN2A, and CDK4 are not common events glioma risk factor in previous genome-wide in familial glioma.

Table 7 -| Known germline gene mutations associated with increased risk of glioma. Data from Ostrom et al., 2014, Kyritsis et al., 2010.

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