EEF1E1-BLOC1S5 366 Luigi Cristiano

Volume 1 - Number 1 May - September 1997

Volume 24 - Number 10 October 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

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

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

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

Editorial correspondance

Jean-Loup Huret, MD, PhD, [email protected]

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

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

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Editors-in-Chief Jesús María Hernández Rivas (Salamanca, Spain) Paola Dal Cin (Boston, Massachusetts) Jean-Loup Huret (Poitiers, France) Hematology Section Editor Ana E. Rodríguez, Teresa Gonzalez (Salamanca, Spain) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editor Cécile Badoual (Paris, France) Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts) Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland) Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy) Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil) DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands) Epigenetics Section Editor Roberto Piergentili (Rome, Italy) Hematopoeisis Section Editor Olga Weinberg (Boston, Massachusetts) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren, Barnabas Nyesiga (Malmö, Sweden) Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223 François Desangles Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, Kessel The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Research Oskar A. Haas Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Roderick Mc Leod Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(10) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 24, Number 10, October 2020

Table of contents

Gene Section

CDC7 (cell division cycle 7) 358 Hugo Passos Vicari, João Agostinho Machado-Neto EEF1E1-BLOC1S5 366 Luigi Cristiano

Leukaemia Section

Langerhans cell sarcoma 369 Ding-Bao Chen

Solid Tumour Section

Malignant pleural mesothelioma subtypes 373 Benjamin Wadowski, Yin P. Hung; Assunta De Rienzo

Deep Insight Section

Y RNA in cell cycle progression and cancer 379 Roberto Piergentili

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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CDC7 (cell division cycle 7) Hugo Passos Vicari, João Agostinho Machado-Neto Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil; [email protected]; [email protected]

Published in Atlas Database: February 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/CDC7ID40015ch1p22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70816/02-2020-CDC7ID40015ch1p22.pdf DOI: 10.4267/2042/70816

acids [aa]): the transcript variant 1 represents the Abstract most commonly occurring transcript (transcript CDC7 is a serine-threonine kinase that participates length: 3215 bp); the transcript variant 2 presents a in multiple cellular processes, including DNA different splice site in the 5' UTR (transcript length: replication, chromosomal segregation, S phase cell 3188 bp), while the transcript variant 3 has different cycle progression, and DNA damage checkpoint. segment for part of its 5' UTR (transcript length: CDC7 is frequently highly expressed in several types 3316 bp). of neoplasm, and it has been associated with cancer On the Ensembl database development and poor clinical outcomes. In different (http://www.ensembl.org/), there are 3 additional cancer models, functional studies indicated that transcript variants for CDC7: one transcript variant CDC7 may be an attractive target for antineoplastic has 6 exons (5 coding exons), length of 701 bp, and therapy, and CDC7 inhibitors have been developed. encode a 157 aa protein, and two transcript variant The present review on CDC7 contains data on that encodes no protein (one with 4 exons and length DNA/RNA, the protein encoded, and the implication of 729 bp, and other with 4 exons and length of 594 of this gene in cancer cell biology and clinical bp). outcomes. Keywords Protein CDC7; DDK; DNA replication; Chromosome segregation; DNA damage checkpoint Identity Other names: Hsk1, CDC7L1, HsCDC7, huCDC7 HGNC (Hugo): CDC7 Location: 1p22.1 DNA/RNA

Description Figure 1. Schematic structure of CDC7 protein. (A) The The entire CDC7 gene is approximately 24.9 Kb CDC7 protein presents 574 aa and contains a protein (start: 91500851 and end: 91525764 bp; orientation: kinase domain that is responsible for its activity. The position of amino acids is indicated in the Figure. The 3D Plus strand). On the NCBI database reconstitution of CDC7 protein was constructed using (https://www.ncbi.nlm.nih.gov/gene), there are 3 Swiss-model platform (https://swissmodel.expasy.org/), and transcript variants (exons: 12, coding exons: 11) for cartoon (B) and surface (C) versions of the protein are CDC7 that encode for the same protein (574 amino illustrated.

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(10) 358 CDC7 (cell division cycle 7) Passos Vicari H, Machado-Neto JA

Figure 2. CDC7-mediated cell signaling and cellular processes. (A) CDC7 binds to DBF4 (activated complex), which acts in initiation of DNA replication at origins by phosphorylation of MCM (mini-chromosome maintenance) proteins. (B) Upon DNA damage or stress, CDC7 phosphorylates claspin and activates ATR/CHK1 pathway. (C) CDC7 phosphorylates HP1 that promotes cohesion of sister chromatids in mitosis.

Description phosphorylation of CLSPN (claspin) (Kim et al., 2008; Rainey et al., 2013; Tenca et al., 2007), which CDC7 protein consists of 574 aminoacids (aa) with leads to inactivation of the anaphase-promoting a molecular weight of 64 kDa and has a conserved complex (Yamada et al., 2013). It has been protein kinase domain (58-574 aa) in the C-terminal demonstrated that DBF4 are upstream targets of region. The schematic representation of the CDC7 ATM or ATR, and once phosphorylated activates protein is illustrated in Figure 1. intra-S phase checkpoint, which suppresses DNA Expression replication under stress (Lee et al., 2012). Under high Ubiquitous. replication stress, CDC7 may trigger apoptosis by CHK1-dependent pathway (Costanzo et al., 2003; Localisation Tsuji et al., 2008). The main cellular and molecular Nucleoplasm, cytokinetic bridge, and mitotic functions of CDC7 are illustrated in Figure 2. spindle. Homology Function The CDC7 gene and protein are highly homologous CDC7 is a serine-threonine kinase that participates among different species, as shown in Table 1. in chromosomal DNA replication promoting % Identity for: Homo Symbol Protein DNA progression of S phase of the cell cycle, normal sapiens CDC7 chromosomal segregation during mitosis, and vs. P.troglodytes CDC7 97.7 98.6 checkpoint response to DNA damage (Bousset and vs. M.mulatta CDC7 96.9 97.8 Diffley, 1998; Sawa and Masai, 2009; Takahashi et al., 2008). During DNA synthesis, CDC7 forms a vs. C.lupus CDC7 90.6 92.9 complex with DBF4 (CDC7/DBF4 complex, also vs. B.taurus CDC7 89.4 90.8 known as DDK), which acts in initiation of DNA vs. M.musculus Cdc7 81.4 83.2 replication at origins by phosphorylation of MCM vs. R.norvegicus Cdc7 81.5 81.9 (mini-chromosome maintenance) proteins vs. G.gallus CDC7 69.8 74.1 (important components of replicative helicase), and allowing replisome activity (Kim et al., 2003b; vs. X.tropicalis cdc7 66.9 68.3 Labib, 2010; Matsumoto and Masai, 2013; Sclafani vs. D.rerio cdc7 63.7 60.6 and Hesselberth, 2018). Regarding chromosomal vs. A.gambiae AgaP_AGAP002110 40.0 43.8 segregation, CDC7 regulates multiple proteins that Table 1. Comparative identity of human CDC7 with other enable cohesin deposition on DNA (Takahashi et al., species (Source: http://www.ncbi.nlm.nih.gov/homologene) 2008) and phosphorylates HP1 that promotes cohesion of sister chromatids in mitosis (Bailis et al., Mutations 2003). In addition, it has been described as a relevant role for CDC7 in the monopolar attachment to Somatic kinetochores during meiosis (Matos et al., 2008). In A total of 272 unique samples presenting CDC7 checkpoint response to DNA damage, CDC7 is mutations were found among the 36154 tested important for ATR - CHK1 activation by samples reported in COSMIC (Catalogue of Somatic

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Mutations in Cancer; amplification of HER2, MYC, MDM2, CCND1, and http://cancer.sanger.ac.uk/cancergenome/projects/c ESR1, unfavorable tumor phenotype, and poor osmic). The mutations p.N31Tfs*51 ([c.92del] large prognosis (Choschzick et al., 2010). intestine, n=16; stomach, n=4; lung, n=1; and biliary In triple negative breast cancer cellular models, the tract, n=1) and p.L28* ([c.83T>A], liver, n=4; dual CDC7/CDK9 inhibitor (PHA-767491) prostate, n=3; skin, n=3; lung, n=2; soft tissue, n=1; synergizes with tyrosine kinase inhibitors to and glioma, n=1) were the most frequent. In overcome resistance to EGFR -targeted therapy agreement, 315 out of 46651 (0.7%) tested samples (McLaughlin et al., 2019): combined inhibition of presented CDC7 genetic alterations (mutations, EGFR and CDC7/CDK9 reduced cell proliferation amplifications, deep deletions, and multiple accompanied by apoptosis induction, G2/M cell alterations), as reported in cBioPortal cycle arrest, and DNA replication inhibition. (http://www.cbioportal.org). The distribution of Due to the rarity of male breast cancer (MBC), serum somatic mutations was 122 missense substitutions, protein alterations have not been extensively studied. 51 truncating, 1 inframe, and 2 other mutations (a Using two-dimensional gel electrophoresis (2-DE) total of 176 mutated samples [0.4%]). Interestingly, and matrix-assisted laser desorption/ionization time p.N31Tfs*51 mutation was observed in 15 out of mass spectrometry (MALDI-TOF MS), a panel of 176 mutations in stomach adenocarcinoma, uterine differentially expressed serum proteins were endometrioid carcinoma, colon cancer, and others. identified, which included the high CDC7 Indeed, somatic mutations in CDC7 have been expression in MBC patients (Zografos et al., 2019). reported in colorectal and gastric cancer, but its Clear cell renal cell carcinoma biological relevance is still poorly elucidated (Greenman et al., 2007). Ghatalia et al. (Ghatalia et al., 2016) analyzed the gene expression of kinases paired samples from Implicated in primary and metastatic tumor tissues and found that CDC7 is more expressed in metastatic tumors. Using Adrenocortical carcinoma the Cancer Genome Atlas (TCGA) data, the authors Data mining of gene expression revealed positive also observed an association between high CDC7 regulation of genes involved in DNA damage and expression and reduced metastasis-free survival cell cycle pathways in samples from adrenocortical (Ghatalia et al., 2016). DISEASE carcinoma patients, including CDC7, their higher Cervical intraepithelial neoplasia levels were associated with worse overall survival Using microarray analysis, CDC7 was found among (Subramanian and Cohen, 2019). highly expressed genes in high-grade squamous Bladder cancer cervical intraepithelial lesions (Suman and Mishra, In order to identify candidate genes associated with 2018). cisplatin-resistant bladder cancer cells, sensitive and Colorectal cancer cisplatin-resistant cell lines were used for microarray analysis to determine the differential expression of Bonte et al. (Bonte et al., 2008) reported a high significant genes in resistance. A total of 18 genes, CDC7 expression in 8 of out 10 cases of colorectal including CDC7, were significantly upregulated in cancer. In agreement, Chen et al. (Chen et al., 2013) cisplatin-resistant cell lines (Kim et al., 2016). reported a significantly higher CDC7 mRNA and protein expression in samples from 39 colorectal Breast Cancer patients compared to their tumor-adjacent normal In breast cancer, high CDC7 expression had been colorectal tissues. Analysis of 1800 colorectal reported (Bonte et al., 2008; Zografos et al., 2019), carcinomas, by immunohistochemistry and tissue and associated with the development of aggressive microarray, showed that CDC7 was highly disease, including ERBB2 (HER2) overexpression, expressed. Of note, CDC7 expression was triple-negative subtypes, accelerated cell cycle significantly associated with TP53, suggesting that progression, disrupted tumor differentiation, CDC7 may be a potential target in a subset of tumors genomic instability, increased NPI score, and with high TP53 expression (Melling et al., 2015). In reduced disease-free survival (Rodriguez-Acebes et contrast, loss of CDC7 expression was significantly al., 2010). Using tissue microarray of a cohort of associated with high tumor stage and grade, but was 2197 highly characterized breast carcinomas, CDC7 not related to nodal status. In multivariate survival expression was found in 1088 samples (57%), of analysis, strong CDC7 expression was an which 228 samples exhibited moderate or strong independent marker of improved patient survival expression. High CDC7 levels were also related to (Melling et al., 2015). medullary histotype, high tumor grade, estrogen receptor-negative status, high Ki67 expression; overexpression of TP53 and CDKN2A; and

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Esophageal squamous cell The dual CDC7/ CDK9 inhibitor, PHA-767491, also carcinoma induced cell death on a panel of multiple myeloma cell lines and primary patient samples alone or in CDC7 is highly expressed in esophageal squamous combination with drugs currently used in the clinics, cell carcinoma (ESCC) tissues, and that CDC7 including the TP53 mutant cells that developed knockdown inhibits cell proliferation, migration, and resistance to dexamethasone, melphalan, and invasion, and induces apoptosis in ESCC cells. In doxorubicin. PHA-767491 had the same effect on addition, downregulation of CDC7 also partially primary myeloma cells from patients who relapsed enhances the chemosensitivity of ESCC cells to with progressive refractory disease. These data cisplatin and 5-fluorouracil, indicating that CDC7 suggested that the mechanisms leading to may serve as a potential therapeutic target in ESCC chemoresistance in myeloma may not affect the (Cao and Lu, 2019). activity of a dual CDC7/CDK9 inhibitor, thus Glioblastoma supporting further evaluation of CDC7 and CDK9 targeting in multiple myeloma (Natoni et al., 2013). Inhibition of CDC7 by inhibitor PHA-767491 In acute myeloid leukemia (AML), the dual significantly reduced cell viability, proliferation, CDC7/CDK9 inhibitor, PHA-767491, migration, invasion, and tumorigenesis, and induced downregulated MCL1 and sensitized AML cell lines apoptosis in glioblastoma models (Erbayraktar et al., and primary AML blasts to BCL2 inhibitors, ABT- 2016; Li et al., 2018). 737 and ABT-199 (O' Reilly et al., 2018). Li et al. (Li et al., 2018) identified that CDC7 expression was enhanced and functionally necessary Hepatocellular carcinoma for proliferation in glioblastomas, and its high Using gene expression data sets, Zhuang et al. expression was associated with poor prognosis. (Zhuang et al., 2018) detected that expression of Head and neck squamous cell various genes, including CDC7, was increased in hepatocellular carcinoma tissues compared to carcinoma adjacent normal tissues. CDC7 overexpression was Human papillomavirus (HPV) is associated with a correlated with advanced histological grade and/or subset of head and neck squamous cell carcinoma vascular invasion, and predicted worse overall and (HNSCC) that can harbor HPV DNA and it was disease-free survival in hepatocellular carcinoma suggestive that there are biological and clinical patients (Zhuang et al., 2018). It is important to differences between HPV positive (HPV +) and highlight that the CDC7 inhibitor (PHA-767491) had negative (HPV -) HNSCC. Slebos et al. (Slebos et a synergistic antitumor effect with 5-FU, exhibiting al., 2006), comparing gene expression profiles of stronger cytotoxicity and inducing significant HPV+ and HPV- tumors, found 91 genes apoptosis in hepatocellular carcinoma cell lines and differentially expressed, including high CDC7 xenograft models (Li et al., 2015). expression in HPV+ HNSCC. Lung cancer Hematological neoplasms In non-small lung cancer (NSCLC) cell lines and Hess and colleagues (Hess et al., 1998) identified the tissue samples, CDC7 expression was highly sequence of encoding human gene CDC7 and expressed (Bonte et al., 2008). In agreement, CDC7 reported its overexpression in several types of was significantly increased in lung adenocarcinoma cancers, including hematological neoplasms. tissues, as observed by immunohistochemistry and Latterly, it was confirmed by Bont et al. (Bonte et gene expression analysis in lung adenocarcinoma al., 2008) in additional leukemia cellular models. (Cao, 2019). In another study, high CDC7 In chronic lymphocytic leukemia (CLL), CDC7 was expression significantly correlates with TP53 expressed and activated in lymph node biopsies. mutational status and predicts poor clinical outcomes A similar finding was also observed in an in vitro in lung adenocarcinoma patients. In an experimental model that partially recapitulates lymph node lung cancer model, CDC7 was also upregulated by proliferation centers of CLL. gain-of-function mutant TP53, which induced cell These data suggested a potential role for CDC7 in cycle progression and tumorigenesis (Datta et al., the aberrant lymph node microenvironment (Natoni 2017). et al., 2011). In addition, high CDC7 expression was associated Melanoma with poor prognosis in patients with diffuse large B- CDC7 gene is located at chromosome 1p22 band, cell lymphoma (DLBCL) (Hou et al., 2012b; Hou et which was identified as a melanoma susceptibility al., 2011; Krawczyk et al., 2009). In DLBCL cell locus with the high frequency of loss of lines, CDC7 silencing combined with rituximab heterozygosity (Walker et al., 2004). synergistically increased apoptosis (Hou et al., In a series of benign and dysplastic nevi, primary 2012a). cutaneous melanomas and melanoma cutaneous

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metastasis samples, CDC7 regulatory subunits, Ovarian carcinoma DBF4, were found to be upregulated in malignant CDC7 was a strong independent prognostic marker tissues (Nambiar et al., 2007), which was associated in epithelial ovarian carcinoma and CDC7 targeted with shorter relapse-free survival. inhibition leads to specific tumor cell death. In a In the same study, DBF4 depletion reduced cohort of 143 cases of ovarian cancer, increased melanoma cell survival and proliferation (Nambiar levels of CDC7 protein were significantly associated et al., 2007). with reduced tumor differentiation, advanced Clarke and colleagues (Clarke et al., 2009), using a clinical stage, genomic instability, and accelerated tissue microarray containing 40 melanomas, 40 Spitz cell cycle progression (Kulkarni et al., 2009). tumors, and 30 nevi reported that invasive Moreover, CDC7 predicted disease-free survival, melanomas and atypical Spitz nevi exhibited the regardless of age, tumor grade and stage. CDC7 highest CDC7 expression. downregulation by siRNA in ovarian cancer cells In order to better understand the transcriptional (SKOV-3 and Caov-3) resulted in high levels of regulation cell cycle checkpoints in melanocytes and apoptosis (Kulkarni et al., 2009). melanoma cell lines, Kaufmann et al. (Kaufmann et al., 2008) analyzed global gene expression patterns Pancreatic cancer upon DNA damage induced by ionizing radiation, In a cohort of 73 pancreatic adenocarcinoma and most melanoma cell lines (11 of out 16) showed patients, including 24 controls, CDC7 was highly significant defects in checkpoints, which included expressed in pancreatic adenocarcinoma compared reduced expression of TP53 transcriptional targets, to benign pancreatic tissue, as observed by and enhanced expression of proliferation-associated immunohistochemistry (Huggett et al., 2016). CDC7 genes. Of note, defective melanomas at checkpoint depletion using siRNA and PHA-76749, a CDC7 G1 exhibited higher levels of DNA synthesis-related small molecule inhibitor, in pancreatic cancer genes, including CDC7 and CKS1B. cellular models (Capan-1 and PANC-1), resulted in Using a VSV-cDNA library and B16 melanoma marked apoptotic cell death. Using human tumors, CDC7 was identified (among others) as a pancreatic cell lines (Capan-1, BxPC3, and PANC- potential immunogenic antigen for chemotherapy or 1), the preclinical efficacy of another CDC7 immunotherapy (Zaidi et al., 2015). inhibitor, MSK-777, was reported (induction of cell Oral squamous cell carcinoma cycle arrest in G1/S and apoptosis) (Skoura et al., 2013). Taken together, these results indicated that Evaluating CDC7 protein expression, by CDC7 is a potential target and may be used as a immunohistochemistry, in a cohort of 105 oral complementary diagnosis marker to predict squamous cell carcinoma (OSCC) tumors and 30 responses in pancreatic adenocarcinoma. benign oral tissues, CDC7 overexpression was found in 91% of tumor cases and 1% benign cases (Cheng Papillary thyroid carcinoma et al., 2013). In multivariate analysis, CDC7 was an Fluge et al. (Fluge et al., 2006) studied gene independent marker for overall survival in a cohort expression profile using cDNA microarray in of 80 OSCC patients. papillary thyroid carcinoma samples, including 7 In OSCC cell lines, overexpression of CDC7 clinically aggressive carcinomas, 10 differentiated inhibited genotoxin-induced apoptosis, suggesting thyroid papillary carcinomas, and normal thyroid that high CDC7 expression increases chemotherapy tissues, which were confirmed by RT-PCR, in situ resistance (Cheng et al., 2013). hybridization and immunohistochemistry. Patients Yong-Deok and colleagues (Yong-Deok et al., 2015) with aggressive and poorly differentiated thyroid investigated the expression of inflammation- carcinoma were specifically characterized by the associated genes in samples from tumor and normal marked positive regulation of several genes related tissue from OSCC patients, in which genetic analysis to cell proliferation, including CDC7 (Fluge et al., of functional networks and ontologies identified 2006). CDC7 as one of the relevant genes. Pharmacological CDC7 inhibition with XL413 markedly reduced cell Salivary gland tumor viability and proliferation by induction of apoptosis Jaafari-Ashkavandi et al. (Jaafari-Ashkavandi et al., in OSCC cell lines (Jin et al., 2018). 2019) reported high CDC7 expression in malignant Osteosarcoma salivary gland tumors compared to pleomorphic In order to screen for key osteosarcoma biomarkers, adenomas, and its positive correlation with tumor Liu et al. (Liu et al., 2016) systematically screened differentiation in samples from 15 cystic adenoid mRNA and proteins differently expressed, and carcinomas, 12 mucoepidermoid carcinomas, 14 CDC7 was found as part of a gene signature for pleomorphic adenomas, and 5 normal salivary osteosarcoma. glands (total 46 patients and donors).

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Uterine leiomyosarcoma References Barlin and colleagues (Barlin et al., 2015) compared Bailis JM, Bernard P, Antonelli R, Allshire RC, Forsburg SL. the molecular profiles of 23 samples of uterine Hsk1-Dfp1 is required for heterochromatin-mediated leiomyosarcoma (ULMS) and 29 samples of normal cohesion at centromeres. Nat Cell Biol. 2003 myometrium (NL) to identify clinically relevant Dec;5(12):1111-6 molecular subtypes. Pathway analyses of genes Barlin JN, Zhou QC, Leitao MM, Bisogna M, Olvera N, Shih differentially expressed between ULMS and NL KK, Jacobsen A, Schultz N, Tap WD, Hensley ML, Schwartz samples identified over-representation of cell cycle GK, Boyd J, Qin LX, Levine DA. Molecular subtypes of regulation, DNA repair, and genomic integrity. uterine leiomyosarcoma and correlation with clinical outcome. Neoplasia. 2015 Feb;17(2):183-9 External validation confirmed differential expression in 31 genes, with 84% overexpressed Bonte D, Lindvall C, Liu H, Dykema K, Furge K, Weinreich M. Cdc7-Dbf4 kinase overexpression in multiple cancers genes, including CDC7 and other cell cycle and tumor cell lines is correlated with p53 inactivation. regulators (Barlin et al., 2015). Neoplasia. 2008 Sep;10(9):920-31 Bousset K, Diffley JF. The Cdc7 protein kinase is required To be noted for origin firing during S phase Genes Dev 1998 Feb 15;12(4):480-90 Cdc7-deficient mice present embryonic lethality at day 3.5 (Kim et al., 2002). Mice carrying Cdc7 Cao JX. miR888 regulates cancer progression by targeting -/- multiple targets in lung adenocarcinoma Oncol Rep 2019 hypomorphic allele (Cdc7 tg) were born apparently Jun;41(6):3367-3376 normal, but smaller than their littermates. However, the rate of mortality during postnatal development Cao JX, Lu Y. Targeting CDC7 improves sensitivity to - chemotherapy of esophageal squamous cell carcinoma was 75% within 3 days postpartum. Surviving Cdc7 Onco Targets Ther 2018 Dec 20;12:63-74 /tg mice presented a normal life span and body Chen HJ, Zhu Z, Wang XL, Feng QL, Wu Q, Xu ZP, Wu J, growth retardation compared to their littermates. In Yu XF, Qian HL, Lu Q. Expression of huCdc7 in colorectal -/ addition, male and female Cdc7 tg mice had cancer World J Gastroenterol 2013 May 28;19(20):3130-3 impaired spermatogenesis and abnormal oogenesis, Cheng AN, Jiang SS, Fan CC, Lo YK, Kuo CY, Chen CH, respectively (Kim et al., 2003a). Liu YL, Lee CC, Chen WS, Huang TS, Wang TY, Lee AY. Promising results of CDC7 inhibition in cancer Increased Cdc7 expression is a marker of oral squamous models drawn attention for the development of cell carcinoma and overexpression of Cdc7 contributes to selective pharmacological inhibitors, among which the resistance to DNA-damaging agents Cancer Lett 2013 Sep 1;337(2):218-25 can be mentioned 89S (Menichincheri et al., 2009), PHA-767491 (Natoni et al., 2011), 1H-pyrrolo[2,3- Choschzick M, Lebeau A, Marx AH, Tharun L, Terracciano b]pyridine derivatives (Ermoli et al., 2009), 3- L, Heilenkötter U, Jaenicke F, Bokemeyer C, Simon R, Sauter G, Schwarz J. Overexpression of cell division cycle aminopyrimidine analog, pyrrolopyridinone analog, 7 homolog is associated with gene amplification frequency tricyclic CDC7 inhibitor, indazolylpyrimidin-2(1H)- in breast cancer Hum Pathol 2010 Mar;41(3):358-65 one inhibitor, thienopyrazole-base inhibitor, 2- Clarke LE, Fountaine TJ, Hennessy J, Bruggeman RD, pyrimidyl-5-amidothiophene, imidazolone-based Clarke JT, Mauger DT, Helm KF. Cdc7 expression in inhibitor (Sawa and Masai, 2009), NMS-1116354 melanomas, Spitz tumors and melanocytic nevi J Cutan (Colotta et al., 2010), TAK-931 (Iwai et al., 2019; Pathol 2009 Apr;36(4):433-8 Kurasawa et al., 2020), and XL413 (Koltun et al., Costanzo V, Shechter D, Lupardus PJ, Cimprich KA, 2012). The main cellular effects triggered by CDC7 Gottesman M, Gautier J. An ATR- and Cdc7-dependent inhibitors in the neoplasm models are: the late S- DNA damage checkpoint that inhibits initiation of DNA replication Mol Cell 2003 Jan;11(1):203-13 phase progression, reduced cell proliferation, DNA damage checkpoint activation, and apoptosis (Iwai et Datta A, Ghatak D, Das S, Banerjee T, Paul A, Butti R, al., 2019; Kurasawa et al., 2020; Sawa and Masai, Gorain M, Ghuwalewala S, Roychowdhury A, Alam SK, Das P, Chatterjee R, Dasgupta M, Panda CK, Kundu GC, 2009). Clinical studies using CDC7 inhibitors, Roychoudhury S. p53 gain-of-function mutations increase NMS-1116354 and TAK-931, in patients with solid Cdc7-dependent replication initiation EMBO Rep 2017 tumors have been conducted, but the results of the Nov;18(11):2030-2050 clinical outcomes have not yet been published Erbayraktar Z, Alural B, Erbayraktar RS, Erkan EP. Cell (https://clinicaltrials.gov/). division cycle 7-kinase inhibitor PHA-767491 hydrochloride Acknowledgments: The authors thank Fernanda T. suppresses glioblastoma growth and invasiveness Cancer Cell Int 2016 Nov 18;16:88 Udinal, from the Hemocentro Foundation of Ribeirão Preto, São Paulo, Brazil, for the English Ermoli A, Bargiotti A, Brasca MG, Ciavolella A, Colombo N, language review. This work was supported by the Fachin G, Isacchi A, Menichincheri M, Molinari A, grant #2017/24993-0 and #2019/01700-2, São Paulo Montagnoli A, Pillan A, Rainoldi S, Sirtori FR, Sola F, Research Foundation (FAPESP), and grant Thieffine S, Tibolla M, Valsasina B, Volpi D, Santocanale C, Vanotti E. Cell division cycle 7 kinase inhibitors: 1H- #402587/2016-2, Conselho Nacional de pyrrolo[2,3-b]pyridines, synthesis and structure-activity Desenvolvimento Cientèfico e Tecnológico (CNPq). relationships J Med Chem 2009 Jul 23;52(14):4380-90

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Fluge Ø, Bruland O, Akslen LA, Lillehaug JR, Varhaug JE. Kim JM, Takemoto N, Arai K, Masai H. Hypomorphic Gene expression in poorly differentiated papillary thyroid mutation in an essential cell-cycle kinase causes growth carcinomas Thyroid 2006 Feb;16(2):161-75 retardation and impaired spermatogenesis EMBO J 2003 Oct 1;22(19):5260-72 Ghatalia P, Yang ES, Lasseigne BN, Ramaker RC, Cooper SJ, Chen D, Sudarshan S, Wei S, Guru AS, Zhao A, Cooper Kim JM, Yamada M, Masai H. Functions of mammalian T, Della Manna DL, Naik G, Myers RM, Sonpavde G. Kinase Cdc7 kinase in initiation/monitoring of DNA replication and Gene Expression Profiling of Metastatic Clear Cell Renal development Mutat Res 2003 Nov 27;532(1-2):29-40 Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets PLoS One 2016 Aug 30;11(8):e0160924 Kim SH, Ho JN, Jin H, Lee SC, Lee SE, Hong SK, Lee JW, Lee ES, Byun SS. 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to sensitise triple-negative breast cancer to EGFR-targeted Yarbrough WG, Chung CH. Gene expression differences therapy Breast Cancer Res 2019 Jul 1;21(1):77 associated with human papillomavirus status in head and neck squamous cell carcinoma Clin Cancer Res 2006 Feb Melling N, Muth J, Simon R, Bokemeyer C, Terracciano L, 1;12(3 Pt 1):701-9 Sauter G, Izbicki JR, Marx AH. Cdc7 overexpression is an independent prognostic marker and a potential therapeutic Subramanian C, Cohen MS. Over expression of DNA target in colorectal cancer Diagn Pathol 2015 Jul 25;10:125 damage and cell cycle dependent proteins are associated with poor survival in patients with adrenocortical carcinoma Menichincheri M, Bargiotti A, Berthelsen J, Bertrand JA, Surgery 2019 Jan;165(1):202-210 Bossi R, Ciavolella A, Cirla A, Cristiani C, Croci V, D'Alessio R, Fasolini M, Fiorentini F, Forte B, Isacchi A, Martina K, Suman S, Mishra A. 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Targeting DNA replication before it starts: CCNB1, CDC7, CDC20, and MCM3 in Tumor Tissues Cdc7 as a therapeutic target in p53-mutant breast cancers Predicted Worse Overall Survival and Disease-Free Am J Pathol 2010 Oct;177(4):2034-45 Survival in Hepatocellular Carcinoma Patients Biomed Res Sawa M, Masai H. Drug design with Cdc7 kinase: a potential Int 2018 Sep 30;2018:7897346 novel cancer therapy target Drug Des Devel Ther 2009 Feb Zografos E, Anagnostopoulos AK, Papadopoulou A, Legaki 6;2:255-64 E, Zagouri F, Marinos E, Tsangaris GT, Gazouli M. Serum Sclafani RA, Hesselberth JR. O Cdc7 kinase where art Proteomic Signatures of Male Breast Cancer Cancer thou? Curr Genet 2018 Jun;64(3):677-680 doi: 10 Genomics Proteomics 2019 Mar-Apr;16(2):129-137 Skoura E, Syrigos KN, Saif MW. Preclinical research in This article should be referenced as such: treatment of pancreatic cancer JOP 2013 Jul 10;14(4):384- 7 Passos Vicari H, Machado-Neto JA. CDC7 (cell division cycle 7). Atlas Genet Cytogenet Oncol Haematol. 2020; Slebos RJ, Yi Y, Ely K, Carter J, Evjen A, Zhang X, Shyr Y, 24(10):358-365. Murphy BM, Cmelak AJ, Burkey BB, Netterville JL, Levy S,

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Gene Section Short Communication

EEF1E1-BLOC1S5 Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy; [email protected] - [email protected]

Published in Atlas Database: March 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/EEF1E1-BLOC1S5ID62733ch6p24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70817/03-2020-EEF1E1-BLOC1S5ID62733ch6p24.pdf DOI: 10.4267/2042/70817

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Location: 6p24.3 EEF1E1-BLOC1S5 is a long non-coding RNA that DNA/RNA derives from the read-through transcription between the neighboring EEF1E1 and BLOC1S5 genes. This Description review collects the data on DNA/RNA and the EEF1E1-BLOC1S5 was identified for the first time diseases where it is involved. by Prakash and colleagues in 2010 (Prakash et al, Keywords 2010). It starts at 8,013,567 nt and ends at 8,102,595 EEF1E1-BLOC1S5; EEF1E1-MUTED; EEF1E1- nt from pter with a length of 89,029 bp. It counts 7 BLOC1S5 readthrough; lncRNA exons and the current reference sequence is NC_000006.12. Identity Near to the genomic sequence of EEF1E1- BLOC1S5 there is a strong promoter transcriptional Other names: EEF1E1-BLOC1S5 readthrough, element that is located at +1.0 kb. Enhancer EEF1E1-MUTED, lnc-EEF1E1-2 transcriptional elements are located at +38.2 Kb and HGNC (Hugo): EEF1E1-BLOC1S5 at +18.1 Kb respectively.

Figure. 1. EEF1E1-BLOC1S5 lncRNA. The figure shows the locus on chromosome 6 for EEF1E1-BLOC1S5 (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org)

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(10) 366 EEF1E1-BLOC1S5 Cristiano L

Transcription Implicated in EEF1E1-BLOC1S5 counts 2,992 bp and it is a long Top note non-coding RNA with reference sequence LncRNAs are nowadays considered as emerging key NR_037618.1. It derives from the read-through regulators of cellular processes and they are often transcription between the neighboring EEF1E1 aberrantly expressed in various diseases (Kumar et (eukaryotic translation elongation factor 1 epsilon 1) al, 2019). and MUTED (muted homolog) genes on EEF1E1-BLOC1S5 is not been still well- chromosome 6. MUTED gene, alias BLOC1S5 characterized, i.e. it is still unclear its physiologic (biogenesis of lysosomal organelles complex 1 role in the cell and its involvement in diseases when subunit 5), is a component of BLOC-1 (biogenesis of its expression is altered, however it is involved in lysosome-related organelles complex 1) complex some genomic translocations with the creation of that is involved in the biogenesis of organelles like several fusion genes (Table.1). melanosomes and platelet-dense granules. It is a chimeric RNA, i.e. an RNA with a sequence Prostate cancer derived from two genes and its transcriptional and Two genomic translocations were found in prostate post-transcriptional regulations could be the same as cancer samples derived from patients, i.e. the those of the other known-genes (He et al, 2018). t(6;17)(p24;p12) EEF1E1-BLOC1S5/NCOR1 and It was not possible to find experimentally a protein the t(6;12)(p24;p13) EEF1E1-BLOC1S5/ZNF384 product for this chimeric RNA (Fagerberg et al, (Robinson et al., 2015). 2014), although in some databases is reported a The t(6;17)(p24;p12) EEF1E1-BLOC1S5/NCOR1 theoretical protein product of 151 amino acids, with is originated by the fusion of EEF1E1-BLOC1S5 a predicted weight of 17,02 kDa and isoelectric point gene at 5'-end with "nuclear receptor corepressor 1" of 7.39 (https://www.uniprot.org/uniprot/C9J1V9; (NCOR1) gene at 3' end while the t(6;12)(p24;p13) http://www.ensembl.org/Homo_sapiens/Transcript/ EEF1E1-BLOC1S5/ZNF384 NCOR1 is originated ProteinSummary?g=ENSG00000265818;r=6:80157 by the fusion of EEF1E1-BLOC1S5 gene at 5'-end 26-8102530;t=ENST00000397456). Therefore with "zinc finger protein 384" ( ZNF384) gene at 3'. EEF1E1-BLOC1S5 is a candidate for nonsense- There are no data about the respective chimeric mediated mRNA decay (NMD) because it is unlikely transcripts or proteins and the role of these genomic to produce a protein product. alterations is still unknown. Protein Cystic fibrosis EEF1E1-BLOC1S5 is found to be over-expressed in Expression cystic fibrosis (CF) airway tissues respect control EEF1E1-BLOC1S5 ncRNA is transcribed (but not tissues and it may play an important role in the translated) widely in human tissues and normal cells. pathophysiology of CF lung disease. However, In memory B cells, it was found that the EEF1E1- further studies are needed to understanding its exact BLOC1S5 is downregulated in the early gene role in this disease (Kumar et al, 2019). expression (Day3-Day 0) following seasonal trivalent influenza vaccination in older individuals (Haralambieva et al, 2016) Name 5' end 3' end Loc1 Loc2 Description Type Disease Organ Code Ref. CDYL/EEF1E1- EEF1E1- CDYL 6p25.1 6p24.3 t(6;6)(p24;p25) Translocation Cancer (?) - 1 BLOC1S5 BLOC1S5 Readthrough EEF1E1-BLOC1S5 EEF1E1 BLOC1S5 6p24.3 6p24.3 Fusion gene (?) (?) - - transcription EEF1E1- EEF1E1- Normal NSMCE4A 6p24.3 10q26.13 t(6;10)(p24;q26) Translocation (?) - - BLOC1S5/NSMCE4A BLOC1S5 cells EEF1E1- EEF1E1- NCOR1 6p24.3 17p12 t(6;17)(p24;p12) Translocation Cancer Prostate - 2 BLOC1S5/NCOR1 BLOC1S5 EEF1E1- EEF1E1- ZNF384 6p24.3 12p13.31 t(6;12)(p24;p13) Translocation Cancer Prostate - 2 BLOC1S5/ZNF384 BLOC1S5

Table.1 EEF1E1-BLOC1S5 rearrangements: translocations and fusion genes (reworked from: http://www.tumorfusions.org; https://mitelmandatabase.isb-cgc.org/; http://quiver.archerdx.com; http://atlasgeneticsoncology.org//Bands/6p24.html#references: https://fusionhub.persistent.co.in/home.html). [ (?) ] unknown; [ 1 ] Campbell et al, 2020; [ 2 ] Robinson et al, 2015; [ - ] no reference

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EEF1E1-BLOC1S5 Cristiano L

Feb;578(7793):82-93 References Kumar P, Sen C, Peters K, Frizzell RA, Biswas R. Comparative analyses of long non-coding RNA profiles in Fagerberg L, Hallström BM, Oksvold P, Kampf C, vivo in cystic fibrosis lung airway and parenchyma tissues. Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Respir Res. 2019 Dec 16;20(1):284 Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, F, Uhlén M. Analysis of the human tissue-specific Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, expression by genome-wide integration of transcriptomics Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, and antibody-based proteomics. Mol Cell Proteomics. 2014 Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Feb;13(2):397-406 Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate Haralambieva IH, Ovsyannikova IG, Kennedy RB, SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Zimmermann MT, Grill DE, Oberg AL, Poland GA. Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Transcriptional signatures of influenza A/H1N1-specific IgG Robinson BD, Sboner A, Schiffman M, Nanus DM, Tagawa memory-like B cell response in older individuals. Vaccine. ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, 2016 Jul 25;34(34):3993-4002 Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, He Y, Yuan C, Chen L, Lei M, Zellmer L, Huang H, Liao DJ. Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM. Transcriptional-Readthrough RNAs Reflect the Integrative Clinical Genomics of Advanced Prostate Phenomenon of "A Gene Contains Gene(s)" or "Gene(s) Cancer. Cell. 2015 Jul 16;162(2):454 within a Gene" in the Human Genome, and Thus Are Not Chimeric RNAs. Genes (Basel). 2018 Jan 16;9(1) This article should be referenced as such: Pan-cancer analysis of whole genomes. Nature. 2020 Cristiano L. EEF1E1-BLOC1S5. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(10): 366-368.

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Leukaemia Section Short Communication Langerhans cell sarcoma Ding-Bao Chen Department of Pathology, Peking University People's Hospital, Beijing 100044, People's Republic of China; [email protected]

Published in Atlas Database: November 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/LangerhansCellSarcomaID1731.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70818/11-2019-LangerhansCellSarcomaID1731.pdf DOI: 10.4267/2042/70818

(Swerdlow, et al, 2008. Swerdlow, et al, 2017. Abstract Nakamine, 2016). It is reported that LCS can arise Tumours derived from Langerhans cells (LCs) are from LCH (Yi, 2019). divided into two main subgroups, according to the Phenotype/cell stem origin degree of cytological atypia and clinical aggressiveness: LC histiocytosis (LCH) and LC The neoplastic cells of LCS may expresses CD1a, sarcoma (LCS). LCS is a high-grade neoplasm with langerin, and S100 protein. obviously malignant cytologic features and the However, the staining of individual markers may be Langerhans cell phenotype, which is rare. Here the focal and patchy. clinic-pathological of LCS will be discussed based The Langerhans cells are derived from mononuclear on reported cases in the literature. phagocytes macrophages and dendritic cells) or histiocytes. (Swerdlow, et al, 2008. Swerdlow, et al, Keywords 2017) Langerhans cell sarcoma; CD1a; immunophenotype; LCS may arise de novo or be observed in other Cytogenetics disorders. Several cases have been reported in myeloproliferative syndromes, other histiocytic Identity disorders, B-lineage leukemia, follicular lymphoma, Other names dermal lentigines, and after liver transplantation. (Zwerdling 2014). Dendritic/histiocytic sarcoma, Langerhans cell type Malignat histiocytosis X Epidemiology LCS is rare, and the reported cases are mainly in Clinics and pathology adults. The median age is 39 years (range, 10-72 years). There is a male predilection, with a male-to- Disease female ratio of 2:1. Rare cases may be associated Tumours derived from Langerhans cells (LCs) are with follicular lymphoma (West, 2013. Swerdlow, et divided into two main subgroups, according to the al, 2008. Swerdlow, et al, 2017). degree of cytological atypia and clinical aggressiveness: LC histiocytosis (LCH) and LC Clinics sarcoma (LCS). Both subgroups maintain the Most cases involve skin, bone and multifoci, and phenotypic profile and ultrastructural features of LC. lymph node in 22%. Other sites include soft tissue, LCS is a high-grade neoplasm with obviously lung, liver and spleen. 44% of disease is high-grade malignant cytologic features and the Langerhans cell (stage III-IV), Hepatosplenomegly is seen in 22% phenotype. Birbeck granules are present, but and pancytopenia in 11% masses (Swerdlow, et al, desmosomes/junctional specializations are absent 2008. Swerdlow, et al, 2017).

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Figure 1. Langerhans cell sarcoma involving the mediastinum of a female. Hypercellular proliferation of cells with oval-shaped nuclei and overt atypia can be seen. Scattered eosinophils are in the background.

Figure 2. Langerhans cell sarcoma. Hypercellularity, nuclear atypia, and mitotic cells are noted. The proliferating cells are rather uniform in size having fairly abundant, weakly eosinophilic cytoplasm.

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Figure 3. The tumor cells are positive for CD1a in the membrane.

Figure 4. The proliferation index of tumor cells is high shown by Ki67.

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Pathology References The most prominent feature is the obviously Bohn OL, Ruiz-Argüelles G, Navarro L, Saldivar J, malignant cytology of a pleomorphic tumour, and Sanchez-Sosa S. Cutaneous Langerhans cell sarcoma: a only the phenotype and/or chromatin is clumped and case report and review of the literature. Int J Hematol. 2007 nucleoli are conspicuous. Some cells may have the Feb;85(2):116-20 complex grooves of the LCH cell, which is an Chen W, Jaffe R, Zhang L, Hill C, Block AM, Sait S, Song important clue to the diagnosis. The mitotic rate is B, Liu Y, Cai D. Langerhans Cell Sarcoma Arising from high, usually > 50 mitoses/10 HPF. Scattered Chronic Lymphocytic Lymphoma/Small Lymphocytic eosinophils can be seen. Birbeck granules are Leukemia: Lineage Analysis and BRAF V600E Mutation Study. N Am J Med Sci. 2013 Jun;5(6):386-91 present, whereas desmosomes/junctional specializations are absent. Karai LJ, Sanik E, Ricotti CA, Susa J, Sinkre P, Aleodor AA. Langerhans cell sarcoma with lineage infidelity/plasticity: a Treatment diagnostic challenge and insight into the pathobiology of the disease. Am J Dermatopathol. 2015 Nov;37(11):854-61 An optimal treatment strategy for LCS has not been established, owing to its rarity; however, aggressive Keklik M, Sivgin S, Kontas O, Abdulrezzak U, Kaynar L, Cetin M. Langerhans cell sarcoma of the nasopharynx: a surgery, chemotherapy, and additional local control rare case Scott Med J 2013 Nov;58(4):e17-20 with radiation appear to be good option for localized lesions or confined nodal disease (Call, 2013. Matsukawa T, Suto K, Miyoshi H, Oshimi K, Ohshima K, Miyagishima T. Successful treatment of an elderly Zwerdling, 2014). Radiotherapy may be Langerhans cell sarcoma patient by EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and effective in treating minimally invasive LCS lesions doxorubicin) chemotherapy J Clin Exp Hematop 2018 Dec (Nakayama, 2010). The successful treatment of 13;58(4):184-187 advanced LCS with multipleorgan involvement is Nakamine H, Yamakawa M, Yoshino T, Fukumoto T, feasible with a variety of chemotherapeutic Enomoto Y, Matsumura I. Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma: Current Understanding and regimens. Systemic combination chemotherapy, Differential Diagnosis J Clin Exp Hematop 2016;56(2):109- such as the CHOP or CHOP-like regimens, may be 118 helpful in some cases (Bohn, 2007). Current data Nakayama M, Takahashi K, Hori M, Okumura T, Saito M, indicate that the ESHAP regimen may be partially Yamakawa M, Tabuchi K, Hara A. Langerhans cell sarcoma effective in treating relapsed patients (Keklik, 2013). of the cervical lymph node: a case report and literature Etoposide-containing chemotherapy, EPOCH, may review Auris Nasus Larynx 2010 Dec;37(6):750-3 be efficacious for LCS due in part to the similar Ropponen A, Silventoinen K, Hublin C, Svedberg P, pathogenic mechanisms of LCS with MCC and Koskenvuo M, Kaprio J. Sleep patterns as predictors for MCPyV infection, and it may be safe for elderly disability pension due to low back diagnoses: a 23-year patients (Matsukawa, 2018). longitudinal study of Finnish twins Sleep 2013 Jun 1;36(6):891-7 Prognosis Swerdlow SH,Campo E,Harris NL,et al,eds.. WHO LCS is an aggressive, high-grade malignancy, with Classification of Tumours of Haematopoietic and Lymphoid > 50% mortality from progressive disease (Chen, Tissues. Lyon :IARC:;2017:470-473. ISBN:978-92-832- 4494-3 2013). Patients presenting with multisite/multiorgan disease fared very poorly with 64% dead (Zwerdling, Yi W, Chen WY, Yang TX, Lan JP, Liang WN. Langerhans cell sarcoma arising from antecedent langerhans cell 2014). histiocytosis: A case report Medicine (Baltimore) 2019 Mar;98(10):e14531 Cytogenetics Zwerdling T, Won E, Shane L, Javahara R, Jaffe R. One reported case has been found to harbor the Langerhans cell sarcoma: case report and review of world literature J Pediatr Hematol Oncol 2014 Aug;36(6):419-25 BRAF V600E mutation. (Chen, et al., 2013; Swerdlow et al ,2016). Whole genome analysis for alli AO, Morgül Y, Alacaciolu , Bener S, Payzin B. Langerhans Cell Sarcoma of the Axillary Lymph Node: A copy number changes and loss of heterozygosity Case Report and Review of the Literature Turk J Haematol showed a complex karyotype with variable 2013 Jun 5;30(2):198-203 hyperdiploidy and numerous allelic imbalances. Significant findings included a homozygous deletion This article should be referenced as such: at 9p21 involving the CDKN2A and loss of Chen DB. Langerhans cell sarcoma. Atlas Genet heterozygosity at 17p involving TP53 gene, coupled Cytogenet Oncol Haematol. 2020; 24(10):369-372. with a TP53 missense mutation. (Karai, 2015)

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Solid Tumour Section Review

Malignant pleural mesothelioma subtypes Benjamin Wadowski, Yin P. Hung; Assunta De Rienzo Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, [email protected]; [email protected] (BW, ADR); Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA, [email protected] (YPH) Published in Atlas Database: December 2019 Online updated version : http://AtlasGeneticsOncology.org/Tumors/MesotheliomaSubtypesID6054.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70819/12-2019-MesotheliomaSubtypesID6054.pdf DOI: 10.4267/2042/70819

underlying asbestos-induced mutagenesis and Abstract alterations in gene expression are varied, and include generation of reactive oxidants, induction of chronic Review of histologic subtypes of mesothelioma, inflammation, and direct physical interference with with associated clinical, pathologic, and molecular mitotic structures (Huang et al., 2011). Beyond data. asbestos exposure, known causative factors of MPM Keywords include exposure to other non-asbestos fibres, Mesothelioma, pleura, histology, epithelioid, radiation exposure (such as therapeutic radiation and sarcomatoid, biphasic, BAP1 Thorotrast), other chronic mesothelial inflammatory conditions, and certain germline mutations Identity particularly in BRCA1-associated protein 1 (BAP1) (Attanoos et al., 2018). However, these constitute a Malignant pleural mesothelioma (MPM) is a rare but small percentage of cases. The majority of non- aggressive cancer associated with median survival of asbestos associated MPM are considered idiopathic 7-13 months from diagnosis and limited effective (Attanoos et al., 2018). treatment options (Beebe-Dimmer et al., 2016). MPM is classified by the World Health Organization Epidemiology into three major histologic subtypes: epithelioid, Approximately 3000 new patients in the United mixed/biphasic, and sarcomatoid (Galateau-Salle et States are diagnosed with MPM every year (Beebe- al., 2016). The precise incidence of each type varies Dimmer et al., 2016). The latency period between by study and sampling technique (biopsy versus asbestos exposure and diagnosis of MPM ranges surgical resection), but epithelioid is the most from 20-40 years. As a result, over 2/3 of MPM is common, followed by biphasic and sarcomatoid diagnosed in patients over age 65. Males are affected respectively. Histologic subtype has significant approximately four times as commonly as females implications for prognosis, with the poorest corresponding to patterns in occupational exposure. outcomes observed for sarcomatoid tumors. Use of asbestos has been banned in the United States since the 1970s, when the EPA's Clean Air Act Clinics and pathology (1973) banned most spray-applied asbestos products for insulation. In 1989, the EPA enacted the Etiology Asbestos Ban and Phase Out Rule which aimed to Over 80% of MPM cases are associated with impose a complete ban on the importation, asbestos exposure, and therefore asbestos is the production, and sale of asbestos-containing major factor implicated in MPM tumorigenesis products. However, due to the long latency period (Broeckx and Pauwels, 2018). The mechanisms and ongoing use in the developing world, the

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incidence of MPM is estimated to increase over the 44%), tubulopapillary (29%), micropapillary (13%), next several decades (Tolani et al., 2018, Cinausero tubular (7%), and trabecular (2%). Most epithelioid et al., 2019). MPM contains more than one growth pattern. The Clinics solid type in particular is associated with high-grade nuclear features as well as shorter median overall MPM does not become symptomatic until it is survival, while tubulopapillary and micropapillary advanced. Symptoms include dyspnoea, chest pain, have the longest overall survival (Krasinskas et al., and cough. MPM has a median overall survival of 7- 2016). 13 months from the time of diagnosis with 5-year In addition to growth pattern, nuclear grade, mitotic survival of less than 10%, although patients who are count, and necrosis have been found to predict treated with multimodality therapy have shown survival in epithelioid MPM (Rosen et al., 2018). median survival of 13-23.9 months (Beebe-Dimmer Higher Ki67 corresponds with shorter median et al., 2016, Zhuo et al., 2019, Cao et al. 2010). overall survival in epithelioid, but not in non- Longer survival is associated with female sex, epithelioid MPM. Ki67 level also decreases younger age at diagnosis, earlier clinical stage, following chemotherapy, which is consistent with absent lymph node involvement, and lower the prognostic effect of treatment in this group comorbidity score (Van Gerwen et al., 2019). (Ghanim et al., 2015). Beyond the TNM staging system, clinical factors Patients with epithelioid MPM were found to benefit associated with shorter survival include increased independently from both surgery and chemotherapy tumor volume and maximal interlobar thickness as (Verma et al., 2018). Poor surgical candidates with measured on computed tomography, elevated serum epithelioid histology and minimal pleural disease lactate dehydrogenase, neutrophil-to-lymphocyte can in rare cases be observed prior to resorting to ratio >5, anemia, and malnutrition (Gill et al., 2018; chemotherapy (Kindler et al., 2018). Doi et al., 2019; Harris et al., 2019). Histologic Biphasic - Current WHO criteria for defining subtype is one of the most significant prognostic biphasic tumors require a mixture of epithelial and factors, and non-epithelioid MPM is associated with spindle-shaped cells, with at least 10% of cells shorter survival than epithelioid MPM (hazard Ratio matching each type. However, the relative (HR) 1.3; p<0.001; Flores et al., 2008). proportion of each cell type within biphasic tumors Pathology has implications for clinical behaviour. An analysis by Vigneswaran and colleagues (2017) Histologic subtype is defined by tumor cell demonstrated that the amount of epithelioid morphology. Epithelioid tumors are ≥ 90% differentiation in biphasic MPM is a significant epithelioid-shaped cells, sarcomatoid tumors are ≥ predictor of survival. Similarly, Harling and 90% spindle-shaped cells, and biphasic tumors are a colleagues (2019) demonstrated shorter survival combination of the two in varying proportions. associated with increased sarcomatoid component in While epithelioid is consistently the most prevalent biphasic tumors. histologic subtype of MPM, the relative incidence of Diagnosing biphasic MPM can be challenging on the each subtype varies by study population and by basis of morphology alone. In one review series, specimen type. An estimate by Suzuki et al (2001) 17% of cases originally diagnosed as biphasic were identified an overall prevalence of 61.5%, 22%, and reclassified as pure epithelioid and 12% as pure 16.4% for epithelioid, biphasic, and sarcomatoid, sarcomatoid. Only 23% of biphasic diagnoses were respectively. More recently, Chirieac and colleagues made with morphology or immunohistochemistry (2019) compared subtypes as identified by biopsy (IHC) alone, with the remaining 77% requiring versus surgical resection and found 80.6% additional IHC assessment to confirm diagnosis concordance. Sarcomatoid histology on biopsy was (Galateau-Salle et al., 2018). found to have the highest correlation with resection Biphasic tumors are sometimes grouped with histology, followed by biphasic and epithelioid. sarcomatoid as 'non-epithelioid' based on their Histologic subtype is a significant independent clinical behaviour. For example, atypical mitoses are prognostic factor, and each subtype carries unique associated with decreased survival in non-epithelioid features. For all three subtypes, the degree of mesothelioma, but, unlike in epithelioid MPM, differentiation correlates with survival. Poorly mitotic count, necrosis, and nuclear atypia are not differentiated tumors have a HR of 2.5 compared associated with survival (Habougit et al., 2017). On with well or moderately differentiated tumors (Zhuo imaging, non-epithelioid MPM is more frequently et al., 2019). associated with calcified plaques (Escalon et al., Epithelioid - This subtype is the most common and 2018). Galateau-Salle and colleagues (2018) associated with most favourable prognosis (median demonstrated the presence of a transitional survival 14.4 months, Verma et al., 2018). The phenotype was associated with significantly shorter epithelioid subtype can exhibit a range of survival compared to biphasic tumors without morphologies, including solid (the most prevalent, transitional elements and behave in a manner

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prognostically similar to pure sarcomatoid tumors. fibrous pleuritis; Kinoshita and colleagues (2018) PD-L1 expression has also been found to be higher demonstrated that the incorporation of IHC is highly in both biphasic and sarcomatoid than in epithelioid specific in distinguishing these conditions. MPM (Brosseau et al., 2019). Sarcomatoid histology is associated with larger However, there are meaningful distinctions between tumor size at diagnosis and more advanced TNM biphasic and pure sarcomatoid MPM. Patients with stage (Paajanen et al., 2018). Patients with biphasic tumors have an intermediate overall sarcomatoid tumors have the lowest median overall survival compared to epithelioid and sarcomatoid survival of the three subtypes (median 5.3 months, (median 9.5 months, Verma et al., 2018). Treatment Verma et al., 2018). Gross macroscopic resection with pleurectomy/decortication, radiotherapy, or does not significantly prolong survival in chemotherapy improves survival compared with sarcomatoid tumors, in contrast to epithelioid and supportive care in this group but not sarcomatoid biphasic tumors (Verma et al., 2018). These patients tumors, with selective benefit of radiotherapy in have a diminished response to systemic tumors with higher sarcomatoid proportion (Verma chemotherapy (Kindler et al., 2018, Mansfield et al., et al., 2018, Harling et al., 2019). 2014). Sarcomatoid - Additional characteristics for Recent guidelines have recommended that diagnosis of the sarcomatoid subtype, in addition to sarcomatoid tumors (along with biphasic) should be the presence of ≥ 90% spindle-shaped cells, include considered candidates for systemic therapy and high nuclear/cytoplasmic ratio and frank should not be excluded from first-line clinical trials sarcomatoid features (Dacic et al., 2019). It can on the basis of histology alone (Nicholson et al., sometimes be histologically difficult to distinguish 2019). sarcomatoid MPM from benign conditions such as

Figure 1 Malignant pleural mesothelioma, epithelioid type.

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Figure 2 Malignant pleural mesothelioma, biphasic type.

Figure 3 Malignant pleural mesothelioma, sarcomatoid type.

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Treatment diffuse malignant pleural mesothelioma. Cancer. 2019 Dec 1;125(23):4164-4171 Multimodal therapy is the standard approach to Cinausero M, Rihawi K, Sperandi F, Melotti B, Ardizzoni A. MPM. The majority of patients are not candidates for Chemotherapy treatment in malignant pleural surgery at presentation due to advanced disease, age, mesothelioma: a difficult history. J Thorac Dis. 2018 or comorbidities (Sugarbaker et al., 2014). For these Jan;10(Suppl 2):S304-S310 patients, platinum-based chemotherapy Dacic S, Le Stang N, Husain A, Weynand B, Beasley MB, (cisplatin plus pemetrexed) is first line treatment Butnor K, Chapel D, Gibbs A, Klebe S, Lantuejoul S, Roden (Cinausero et al., 2018). In patients with resectable AC, Roggli V, Tazelaar H, Vignaud JM, Galateau-Sallé F. disease, the goal of surgery is macroscopic complete Interobserver variation in the assessment of the sarcomatoid and transitional components in biphasic resection. This can be accomplished via lung-sparing mesotheliomas Mod Pathol 2019 Jul 4 surgery (extended pleurectomy and decortication) or Doi H, Kuribayashi K, Kitajima K, Yamakado K, Kijima T. extrapleural pneumonectomy (Friedberg et al., Development of a Novel Prognostic Risk Classification 2019). Lung-sparing techniques have increased in System for Malignant Pleural Mesothelioma Clin Lung favour due to lower morbidity and comparable Cancer 2020 Jan;21(1):66-74 outcomes. However, five-year survival following Escalon JG, Harrington KA, Plodkowski AJ, Zheng J, radical surgery remains low at approximately 15% Capanu M, Zauderer MG, Rusch VW, Ginsberg MS. (Cinausero et al., 2019). Radiation therapy also plays Malignant Pleural Mesothelioma: Are There Imaging a role in select patients. There is some evidence that Characteristics Associated With Different Histologic Subtypes on Computed Tomography? J Comput Assist the addition of antiangiogenic agents such as Tomogr 2018 Jul/Aug;42(4):601-606 doi: 10 bevacizumab can improve outcomes in combination with chemotherapy (Zalcman et al., 2016). Given Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, Bains MS, Rusch VW. Extrapleural their success in other solid tumors, targeted therapies pneumonectomy versus pleurectomy/decortication in the and immunotherapeutics are being actively explored surgical management of malignant pleural mesothelioma: in MPM with mixed results (Cinausero et al., 2019). results in 663 patients J Thorac Cardiovasc Surg 2008 Overall, a review of 20,561 MPM patients in the Mar;135(3):620-6, 626 National Cancer Database by Nelson and colleagues Friedberg JS, Culligan MJ, Tsao AS, Rusch V, Sepesi B, (2017) identified significant improvement in patient Pass HI, Bueno R, Burt B, Sugarbaker DJ, de Perrot M, Adjei AA, Adusumilli PS, Hirsch FR, Malik SM, Harpole DJ survival with surgery-based multimodality therapy Jr. A Proposed System Toward Standardizing Surgical- compared with surgery alone, with the strongest Based Treatments for Malignant Pleural Mesothelioma, effect seen using a combination of cancer-directed From the Joint National Cancer Institute-International surgery, chemotherapy, and radiation therapy (HR Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Taskforce J Thorac Oncol 0.52). 2019 Aug;14(8):1343-1353 Galateau Salle F, Le Stang N, Nicholson AG, Pissaloux D, References Churg A, Klebe S, Roggli VL, Tazelaar HD, Vignaud JM, Attanoos RL, Churg A, Galateau-Salle F, Gibbs AR, Roggli Attanoos R, Beasley MB, Begueret H, Capron F, Chirieac L, VL. 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Extrapleural Feb;14(2):288-293 pneumonectomy in the treatment of epithelioid malignant Huang SX, Jaurand MC, Kamp DW, Whysner J, Hei TK. pleural mesothelioma: novel prognostic implications of Role of mutagenicity in asbestos fiber-induced combined N1 and N2 nodal involvement based on carcinogenicity and other diseases J Toxicol Environ Health experience in 529 patients Ann Surg 2014 Oct;260(4):577- B Crit Rev 2011;14(1-4):179-245 80; discussion 580-2 Kindler HL, Ismaila N, Armato SG 3rd, Bueno R, Hesdorffer Suzuki Y. Pathology of human malignant mesothelioma-- M, Jahan T, Jones CM, Miettinen M, Pass H, Rimner A, preliminary analysis of 1,517 mesothelioma cases Ind Rusch V, Sterman D, Thomas A, Hassan R. Treatment of Health 2001 Apr;39(2):183-5 Malignant Pleural Mesothelioma: American Society of Tolani B, Acevedo LA, Hoang NT, He B. Heterogeneous Clinical Oncology Clinical Practice Guideline J Clin Oncol Contributing Factors in MPM Disease Development and 2018 May 1;36(13):1343-1373 Progression: Biological Advances and Clinical Implications Kinoshita Y, Hamasaki M, Yoshimura M, Matsumoto S, Sato Int J Mol Sci 2018 Jan 13;19(1) A, Tsujimura T, Ueda H, Makihata S, Kato F, Iwasaki A, Van Gerwen M, Alpert N, Wolf A, Ohri N, Lewis E, Nabeshima K. A combination of MTAP and BAP1 Rosenzweig KE, Flores R, Taioli E. Prognostic factors of immunohistochemistry is effective for distinguishing survival in patients with malignant pleural mesothelioma: an sarcomatoid mesothelioma from fibrous pleuritis Lung analysis of the National Cancer Database Carcinogenesis Cancer 2018 Nov;125:198-204 2019 Jun 10;40(4):529-536 Krasinskas AM, Borczuk AC, Hartman DJ, Chabot JA, Taub Verma V, Ahern CA, Berlind CG, Lindsay WD, Shabason J, RN, Mogal A, Pingpank J, Bartlett D, Dacic S. Prognostic Sharma S, Culligan MJ, Grover S, Friedberg JS, Simone significance of morphological growth patterns and mitotic CB 2nd. Survival by Histologic Subtype of Malignant Pleural index of epithelioid malignant peritoneal mesothelioma Mesothelioma and the Impact of Surgical Resection on Histopathology 2016 Apr;68(5):729-37 Overall Survival Clin Lung Cancer 2018 Nov;19(6):e901- Mansfield AS, Symanowski JT, Peikert T. Systematic review e912 of response rates of sarcomatoid malignant pleural Vigneswaran WT, Kircheva DY, Ananthanarayanan V, mesotheliomas in clinical trials Lung Cancer 2014 Watson S, Arif Q, Celauro AD, Kindler HL, Husain AN. Nov;86(2):133-6 Amount of Epithelioid Differentiation Is a Predictor of Nelson DB, Rice DC, Niu J, Atay S, Vaporciyan AA, Survival in Malignant Pleural Mesothelioma Ann Thorac Antonoff M, Hofstetter WL, Walsh GL, Swisher SG, Roth JA, Surg 2017 Mar;103(3):962-966 Tsao A, Gomez D, Giordano SH, Mehran R, Sepesi B. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for Long-Term Survival Outcomes of Cancer-Directed Surgery newly diagnosed pleural mesothelioma in the Mesothelioma for Malignant Pleural Mesothelioma: Propensity Score Avastin Cisplatin Pemetrexed Study (MAPS): a Matching Analysis J Clin Oncol 2017 Oct 10;35(29):3354- randomised, controlled, open-label, phase 3 trial Lancet 3362 2016 Apr 2;387(10026):1405-1414 Nicholson AG, Sauter JL, Nowak AK, Kindler HL, Gill RR, Zhuo M, Zheng Q, Chi Y, Jia B, Zhao J, Wu M, An T, Wang Remy-Jardin M, Armato SG 3rd, Fernandez-Cuesta L, Y, Li J, Zhao X, Yang X, Zhong J, Chen H, Dong Z, Wang Bueno R, Alcala N, Foll M, Pass H, Attanoos R, Baas P, J, Zhai X, Wang Z. Survival analysis via nomogram of Beasley MB, Brcic L, Butnor KJ, Chirieac LR, Churg A, surgical patients with malignant pleural mesothelioma in the Courtiol P, Dacic S, De Perrot M, Frauenfelder T, Gibbs A, Surveillance, Epidemiology, and End Results database Hirsch FR, Hiroshima K, Husain A, Klebe S, Lantuejoul S, Thorac Cancer 2019 May;10(5):1193-1202 Moreira A, Opitz I, Perol M, Roden A, Roggli V, Scherpereel A, Tirode F, Tazelaar H, Travis WD, Tsao MS, van Schil P, This article should be referenced as such: Vignaud JM, Weynand B, Lang-Lazdunski L, Cree I, Rusch VW, Girard N, Galateau-Salle F. EURACAN/IASLC Wadowski B, Hung YP, De Rienzo A. Malignant pleural Proposals for Updating the Histologic Classification of mesothelioma subtypes. Atlas Genet Cytogenet Oncol Pleural Mesothelioma: Towards a More Multidisciplinary Haematol. 2020; 24(10):373-378. Approach J Thorac Oncol 2020 Jan;15(1):29-49

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS

Deep Insight Section

Y RNA in cell cycle progression and cancer Roberto Piergentili Department of Biology and Biotecnology - Charles Darwin, Sapienza University of Rome - Istituto Genetica, room 1-07 - P.Le A.Moro 5 00185 Roma, Italy [email protected]

Published in Atlas Database: February 2020 Online updated version : http://AtlasGeneticsOncology.org/Deep/YRNAID20152.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70820/02-2020-YRNAID20152.pdf DOI: 10.4267/2042/70820 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

erythematosus, (iii) neonatal lupus erythematosus, Abstract (iv) ANA-negative lupus erythematosus, and (v) systemic lupus erythematosus-like disease. These A growing amount of evidence demonstrates the role diseases are characterized by having as autoantigen of non-coding RNAs (ncRNA) in the targets, among the others, the soluble etiopathogenesis of cancer. ncRNA are the product ribonucleoproteins (RNP) (also known as SSA or of the transcription of genes which are not further TROVE2 - TROVE domain family, member 2) translated into proteins, thus they exert their (Deutscher et al. 1988; Ben-Chetrit et al. 1989) and functions as they are or more frequently after post- (small RNA-binding exonuclease protection factor - transcriptional modifications. In the last decades, also known as La) (Chambers et al. 1988). Y RNA several different classes of ncRNA had been are small non-coding RNAs that were originally described, both long (lncRNA) and short (sncRNA). identified as the RNA component of RO60 and SSB The former are molecules usually longer than 200 in these patients (Lerner et al. 1981; Hendrick et al. nucleotides (nt), while the latter usually include 1981). Y RNA, like other small RNAs, are species of a few tens of nucleotides in length, transcribed by RNA Polymerase III (Pol III) although exceptions are present (for example, (Hendrick et al. 1981; Wolin and Steitz 1983). After circRNA span a length of 100-1600nt; snoRNA are transcription, they may either remain inside the 60-300nt). Y RNA belong to the sncRNA family and nucleus or be exported in the cytoplasm (Kowalski are in the range of ca. 80-120nt. Here we summarize and Krude 2015). They were originally termed as 'Y' the current knowledge about Y RNA biology, their RNA to distinguish their cytoplasmic localization role in normal cellular homeostasis, and their from that of the nuclear 'U' RNA (Lerner et al. 1981). expression variations in human cancers. There are four known Y RNA members in humans, Keywords named hY1 (length: 112 nucleotides, nt), hY3 hY1; hY3; hY4; hY5; RNY1; RNY3, RNY4; RNY5; (101nt), hY4 (93nt) and hY5 (83nt) RNA; the cell cycle; DNA replication; RO60; presence of hY2 RNA was later confuted, as it was ribonucleoprotein particle found that it is a degradation product of hY1. Discovery, evolutionary According to ENSEMBL 75, there are also an additional 52 transcripts which are pseudogenes conservation and structure based on the 4 human Y RNA, and a further 966 The first discovery of Y RNA (Lerner et al. 1981) hYRNA pseudogenes (Perreault et al. 2005), with has been made by immunopurification with auto- 878 predicted transcripts, that make up the Y RNA antibodies in patients affected by the autoimmune category. In the most common use, hY1-5 are the diseases systemic lupus erythematosus (SLE) and names of the RNAs, while the HGNC approved gene subsequently confirmed in (i) primary Sjogren symbol for the four genes are RNY1-5, respectively syndrome, (ii) subacute cutaneous lupus (i.e. , , and ).

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(10) 379 Y RNA in cell cycle progression and cancer Piergentili R

Figure 1: structure of a generic human Y RNA. For the structure of specific genes, please see for example (Köhn et al. 2013); note that the loop domain is the less conserved both in length and structure, among all studied organisms and among the four human RNAs. Image taken from the Rfam database release 9.1 (http://rfam.xfam.org/family/RF00019) and partially modified (picture rotation; indication of domains). Nucleotide coloring indicates sequence conservation between the members of this family.

Y RNA have two recognized functions: repressors of significantly among the four hY RNA: it is likely RO60 and other Ro proteins, and initiation factors very flexible (Teunissen 2000) and fulfills different for DNA replication (Christov et al. 2006; Zhang et tasks such as modulation of chromatin association, al. 2011; Hall et al. 2013). Y RNA are conserved protein binding site (such as those reported in Table molecules, and confirmed (true Y RNA) or putative 1) (Fabini et al. 2001; Fouraux et al. 2002; Belisova (stem-bulge RNAs, sbRNA (Boria et al. 2010)) et al. 2005; Hogg and Collins 2007; Gallois- members of this family are found in mammals, birds, Montbrun et al. 2008; Sim et al. 2012; Köhn et al. amphibians, fishes, worms, insects, tunicates and 2013, 2015; Shukla and Parker 2017; Donovan et al. even bacteria (Mosig et al. 2007; Perreault et al. 2017) and site of cleavage for the formation of 2007; Boria et al. 2010; Duarte Junior et al. 2015, YsRNA (Y RNA-derived small RNAs, stretches of 2019). However, in some lower organisms such as 22-36 nucleotides that are produced in apoptotic Caenorhabditis elegans (CeY RNA), Branchiostoma cells - see the specific section below) (van Gelder et floridae (BfY RNA) and Deinococcus radiodurans al. 1994; Teunissen 2000; Kowalski and Krude (DrY RNA) the sequence similarity to vertebrate Y 2015). It is expected that Y RNA contemporarily RNA is only partial and does not include the upper bind at least two proteins, one of which is a core stem domain (Gardiner et al. 2009); moreover, their protein bound on the stem domain (such as RO60) function is not essential in them, since mutant and another on the loop domain; indeed, experiments organisms with missing Y RNA are viable. To date, using gel filtration show that Y RNP range in size only plants and fungi do not have any candidate Y from 150 to 550 kDa (see (Köhn et al. 2013) and RNA or sbRNA, thus the evolution of these references therein). All human Y RNA genes map molecules is still a debated topic in eukaryotes. inside the region 7q36.1 (Maraia et al. 1994; Maraia The stem-loop organization of Y RNA is conserved 1996) and, in particular, RNY3 is on the opposing as well, and it is schematically reported in Figure 1. DNA strand from the gene RNY1 (Wolin and Steitz Four specific regions can be identified. (i) A poly- 1983); interestingly, despite their high homology, uridine tail that is important for SSB binding and for these two RNAs do not cross-hybridize (Wolin and Y RNA stabilization (target of exonucleases); Steitz 1983). This clustering of Y RNA coding genes moreover, some authors suggest that, at least hY1 on chromosomes has been described also in other and hY3, potentially contain a variety of 3' ends, vertebrates (O'Brien et al. 1993; Farris et al. 1996; with the most abundant species being at positions -5 Mosig et al. 2007). and -4 relative to the previously mapped 3' ends Role of Y RNA in RO60 function (Shukla and Parker 2017). (ii) A lower stem domain, which is the binding site of RO60 and is important Ro ribonucleoproteins (Ro RNP) are implicated in for nuclear export; this region is frequently flanked RNA processing and quality control (Hogg and by a bulged region that is essential for RO60 binding Collins 2007; Sim and Wolin 2011), as well as in and separates the lower stem from (iii) an upper stem intracellular transport, bringing other Y RNA domain, which is important for the initiation of DNA binding proteins to their specific targets (Belisova et replication. Finally, (iv) a loop domain, which is the al. 2005). It has been recently proposed that an most variable portion of the Y RNA. In particular, evolutionarily conserved function of non-coding the loop domain length and sequence are the most RNAs (ncRNA), including Y RNA, might be the discriminating parameters among the four human Y assembly and function of RNP complexes; in this RNA, the longest loop being that of hY1 (65 nt) and case, these molecules could act as scaffolding factors the shortest that of hY5 (31 nt). Also the three- necessary to form functional RNP (Täuber et al. dimensional folded structure of the loops differ 2019).

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Protein (HGNC) Synonyms Interacting Y RNA Domain involved Function CEM15 1, 3, 4, 5 unknown unknown NEB1 1, 3 loop histone pre-mRNA processing EXOSC11 (1), (3) polyU tail Y RNA stabilization DIS3L1 1, 3 polyU tail Y RNA degradation and turnover PMSCL2 1, 3, 4, 5 polyU tail Y RNA trimming, stabilization HNRPK 1, 3 loop unknown C20ORF183 (1), 3 loop nuclear Export of RO60 and Y3 nucleolin, C23 1, 3 loop unknown DAN 1, 3, 4, 5 polyU tail Y RNA trimming, stabilization hnRNP I, PTB 1, 3 loop unknown RoBP1, FIR (1), (3), 5 unknown unknown PRCA1, RNS4 1, (3), 4, 5 loop cell cycle arrest and apoptosis La, LARP3 1, 3, 4, 5 polyU tail nuclear localization, protection of Y RNA 3' ends PAPD5 1, 3, 4, 5 polyU tail Y RNA oligoadenylation, degradation PCH7 1, (3) polyU tail Y RNA degradation and turnover TROVE2, Ro60, SSA 1, 3, 4, 5 lower stem stabilization, nuclear export, RNA quality control Table 1 - Y RNA binding proteins. Numbers inside parentheses indicate unconfirmed data or minor effects. Protein names (column 1) are those approved by the HUGO (Human Genome Organisation) Gene Nomenclature Committee (HGNC). Proteins are listed in alphabetical order according to data in column 1.

RO60 is a 60kDa ring-shaped RNA-binding protein binding proteins could complex Y RNA in a similar (Stein et al. 2005) important in the response to fashion, to fulfill additional tasks, such as mRNA environmental stress, such as exposure to UV regulation (Köhn et al. 2013). radiation or heat, in both animal cells and bacteria. It is highly conserved (Sim and Wolin 2011; Wolin et Role of Y RNA in DNA replication al. 2013), able to bind aberrant non-coding RNAs Y RNA functions during DNA replication seem such as mis-folded 5S rRNA or U2 snRNA (O'Brien quite distinct from those related to RO60 functions and Wolin 1994; Chen et al. 2003) and possibly (Langley et al. 2010). Indeed, Langley and acting as a cellular stress sensors (reviewed in collaborators showed that immunodepletion of (Kowalski and Krude 2015; Boccitto and Wolin RO60 and SSB RNP from human cytosolic extracts 2019)). does not inhibit DNA replication in human cell Structural and biochemical studies have shown that nuclei (Langley et al. 2010). Similarly, deletion of the binding affinity of Y RNA for RO60 is higher RO60 and SSB binding sites on the lower stem than that of mis-folded RNA, suggesting that Y RNA domain of vertebrate Y RNA does not inhibit the might act as a RO60 repressor (Stein et al. 2005; DNA replication activity of the mutant Y RNA Fuchs et al. 2006), although some evidence support (Christov et al. 2006; Gardiner et al. 2009) indicating the hypothesis that these molecules (or, at least, hY5) that the role of Y RNA in DNA replication is might also enhance the recognition of mis-folded uncoupled from Ro RNP binding. Instead, RNA ncRNA (Hogg and Collins 2007). interference (RNAi)-mediated depletion of either It has been suggested that the interaction of Y RNA hY1, hY3, or hY4 RNA in cell cultures eliminates or with nucleolin (NCL), polypyrimidine tract-binding reduces DNA replication in these cells (Christov et proteins (PTB) and Z-DNA binding protein 1 al. 2006, 2008; Krude et al. 2009; Collart et al. 2011), (ZBP1) (Köhn et al. 2013) might modulate the and DNA replication is restored back by artificial subcellular localisation of RO60 (Sim and Wolin reintroduction of any of them; the only exception 2011). being for hY5, which is consequently thought to be Indeed, RO60 can move between nucleus and refractory to RNAi. Similarly, functional cytoplasm, in a Y RNA-dependent way (Sim et al. inactivation of Y RNA (sbRNA in worms (Boria et 2009; Sim and Wolin 2011) and, in turn, RO60 al. 2010)) via microinjection of antisense protects them from degradation and allows their morpholino oligonucleotides (MOs) in embryos, is accumulation in several species (Chen and Wolin sufficient to impair DNA replication in Xenopus 2004). Consequently, some authors suggest a model laevis, Danio rerio and Caenorhabditis elegans, where Y RNA and bound RO60 can dissociate under where this treatment impairs DNA replication and certain conditions, so that RO60 can act in cellular causes cell cycle arrest and embryonic lethality recovery by salvaging mis-folded RNAs. In this (Collart et al. 2011; Kowalski et al. 2015). In this context, it is possible to hypothesize that other RNA- context, it is not surprising that Y RNA are over-

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expressed in some human solid tumors (Christov et that the rapid degradation of these molecules might al. 2008) (see also the specific sections below). occur at an early step during the systemic Y RNA function in DNA replication is fulfilled by deactivation of the dying cell. Despite the role of the upper stem domain (Gardiner et al. 2009; Wang these molecules is currently unknown, YsRNA have et al. 2014; Kowalski et al. 2015) which is important been identified both in healthy tissues (Nicolas et al. also for the recognition of specific chromatin 2012; Yamazaki et al. 2014) and in precursor B cells domains and DNA replication initiation proteins of acute lymphoblastic leukaemia patients (Schotte (Zhang et al. 2011; Collart et al. 2011). Interestingly, et al. 2009) as well as in solid tumors (Meiri et al. however, this interaction does not include replication 2010); for these reasons, they are under investigation fork proteins (Zhang et al. 2011) suggesting that the as possible biomarkers in cancer and/or other interaction is restricted to the DNA replication conditions (Meiri et al. 2010; Nicolas et al. 2012; initiation complex (Kheir and Krude 2017). Indeed, Dhahbi 2014; Vojtech et al. 2014; Ikoma et al. 2018). Y RNA localize inside nuclei in G1, before DNA Indeed, these fragments - especially those derived replication, and they are displaced upon DNA from hY4 - are particularly abundant in plasma, replication initiation (Zhang et al. 2011). To date, serum (Dhahbi et al. 2013; Yeri et al. 2017; Umu et there is no certainty about their role in this process, al. 2018) and other biofluids (Vojtech et al. 2014; and only hypotheses may be drawn (Kowalski and Godoy et al. 2018), where they circulate as part of a Krude 2015). Interestingly, although all Y RNA complex with a mass between 100 and 300 kDa but localize inside the nucleus, only hY1, hY3 and hY4 not included in exosomes or microvesicles (Dhahbi co-localize with each other on early-replicating et al. 2013). Some authors suggest that, beyond what euchromatin; instead, hY5 is prevalently localized in described before, Y RNA and their derivatives might nucleoli (Zhang et al. 2011). This different behavior also fulfill a signaling (Dhahbi et al. 2013) or a gene of hY5 is recurrent also in some of the tumors regulation (Van Balkom et al. 2015) function; described below. This localization is controlled, in actually, a role in gene regulation has also been all Y RNA, by the loop domain. Differently, the described for the maturation of histone mRNA nuclear export of Y RNA is controlled by the lower through hY3 and its derivative, hY3** (a smaller stem domain and is dependent on the small GTPase 60nt-long Y RNA) (Köhn et al. 2015; Köhn and Ran (Rutjes et al. 2001). Hüttelmaier 2016). Noteworthy, these fragments are Y RNA derivatives not confined inside cells, but can be found also in blood circulation, with a specific enrichment of hY4 Intracellular localization of Y RNA is dependent on derivatives (Dhahbi et al. 2013), and inside cellular stress (Chen and Wolin 2004); specifically, extracellular vesicles (EV) for hY5 derivatives both RO60 and Y RNA are up-regulated and (Chakrabortty et al. 2015). More detailed accumulate inside the nucleus following UV descriptions of these fragments can be found in the irradiation, starvation, heat stress, γ-irradiation, and following specific sections on human tumors. desiccation (Sim et al. 2009, 2012; Boccitto and Wolin 2019). However, it has been noted that this Y RNA and human cancer phenomenon could also be just a byproduct of the The role of Y RNA in DNA replication (and, inhibition of RanGTP gradient under stress consequently, in the regulation of cell cycle) sets the conditions (Köhn et al. 2013). The RNA component basis to hypothesize their possible role in cancer of Ro RNP is partly degraded during apoptosis and etiology. Indeed, there are reports showing that Y generates the so called Y RNA-derived small RNAs RNA are significantly up-regulated (4- to 13-fold for (YsRNA), such as miR-1975 and miR-1979. hY4 and hY1, respectively) in human cancer tissues However, is not required for the production of these (carcinomas and adenocarcinomas of the lung, YsRNA (Nicolas et al. 2012; Langenberger et al. kidney, bladder, prostate, , and ) compared to normal 2013) and indeed, after their identification as tissues (Christov et al. 2008), and are also required byproducts of Y RNA degradation, miR-1975 and for the proliferation of cancer cells, since their RNA miR-1979 were removed from miRBase interference (RNAi)-mediated degradation results in (http://www.mirbase.org/), the primary database for a significant cytostatic (but not cytotoxic) effect in micro RNAs. These shorter fragments are cell lines, probably by inducing a significant specifically, abundantly and rapidly generated from inhibition of chromosomal DNA replication in all four Y RNA during apoptosis, in a caspase- cultured human cells (Christov et al. 2008). dependent manner (Rutjes et al. 1999), but it is not Interestingly, hY5 seems under control of an yet clear if they have any causal role in these independent mechanism since its cellular amount is phenomena, or are just a product of apoptosis- frequently different from that of the other three Y mediated cellular changes (Rutjes et al. 1999; Meiri RNA, although over-expressed as well in at least et al. 2010). These Y RNA degradation products some tumors (Christov et al. 2008). remain bound to the RO60 protein and, in part, also As said, it has been reported in 2008 that hY1 and to the SSB protein (Rutjes et al. 1999). This suggests hY3 are highly over-expressed in (Christov et al.

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2008). Instead, in 2017 Tolkach and collaborators particular, are substantially increased in patients reported that all Y RNA are down-regulated in BC affected by systemic lupus erythematosus (Tolkach et al. 2017), with the low abundance of (Bernatsky et al. 2013). Chakrabortty and coworkers hY1, hY3 and hY4 typical of muscle-invasive (Chakrabortty et al. 2015) demonstrated that primary bladder cancer (MIBC) compared to non-muscle- cell cultures are sensitive to apoptosis induction invasive bladder cancer (NMIBC) and that low either by treatment with K562 cells EV, or by the amount of hY1, hY3 and hY4 also correlates with ectopic over-expression of 31nt-processed fragments lymph node metastases and advanced grade. No of hY5. Instead, this treatment is inefficient on correlation was found with age or gender. Further cancer cells, suggesting that this might be a way for studies are needed to assess with certainty if, in cancer cells to create a favorable microenvironment bladder cancer, Y RNA are indeed down-regulated. (Chakrabortty et al. 2015). More recently, a study on Dhabi and collaborators detected inside the serum (CLL) (Haderk et al. 2017) revealed that (i) hY4 is and plasma the presence of RNA fragments, highly enriched in exosomes; (ii) it is sufficient to including YsRNA (Dhahbi et al. 2013). Using this activate cytokine release in monocytes and trigger in approach, they later verified if their abundance can these cells the activation of Toll-like receptor 7 ( ), be related to (Dhahbi et al. 2014). They found a (iii) the pharmacologic inhibition of endosomal TLR major population of 30-33nt long fragments mostly attenuates CLL development in vivo; (iv) in CLL derived from Y RNA 5' end, and a minor population patients, the PD-L1 pathway is activated, allowing of 25-29nt long fragments almost exclusively the tumor cells to escape the immune response. derived from their 3' end. Interestingly, some It has been shown (Nientiedt et al. 2018) that in fragments increase while other decrease their (ccRCC) patients, the expression of RNY3 and amount, in a specific pattern. This result is in good RNY4 is significantly increased and that the agreement with a previous study describing an expression levels of RNY4 alone is inversely enrichment of 3'-end fragments - derived from correlated with ccRCC stage and the presence of human hY5 - detected in MCF 7 (mammary lymph node metastases. adenocarcinoma) cells (Nicolas et al. 2012). More In (ADC) and (SQCC) patients, Li and collaborators recently (Guo et al. 2018), another study on (TNBC) (Li et al. 2018) showed that 5' hY4-derived showed similar results for RNY1, RNY5 and, above fragments have a significantly higher expression in all, RNY4 expression, while another group (Tosar et plasma EV compared to controls, while they are al. 2015) found fragments of 31-33nt greatly and down-regulated inside cancer; moreover, over- significantly enriched in the extracellular space of expressing hY4 inhibits the proliferation of lung cultured breast cancer cells, suggesting that this cancer cell line A549, suggesting for hY4 fragments fragments are specifically excreted by these cells. a role of tumor suppressors in this pathology. These As for (the most common tumor of the brain), to results show evident differences from those reported date, only one manuscript was published, dealing before (Christov et al. 2008), thus a further with Y RNA (Wei et al. 2017). In glioma cells, all validation of either data is advisable. extracellular fractions, especially non-vesicular The analysis of ncRNA content of EV of the cell line RNPs, are highly enriched in specific Y RNA MML-1 (Lunavat et al. 2015) demonstrated that fragments ca. 32nt in length, especially belonging to there is a specific signature of Y RNA present in EV, hY1, hY4 and hY5. with hY1, hY4 and hY5 significantly more abundant Martinez and collaborators reported that in in EV than inside melanoma cells, while hY3 (HNSCC), Y RNA-derived small RNAs are amount is similar inside EV and MML-1 cells. These significantly deregulated in the sera of patients data were partly validated by the recent work of Sole (Martinez et al. 2015). These patients have, among and collaborators (Sole et al. 2019) who found an the others, an enrichment of 30-33nt-long fragments enrichment of hY4 and, to a lesser extent, of hY1 and deriving from Y RNA degradation, and these hY3, but only in patients with stage 0 disease. fragments proportion either increases or decreases Quantification of Y RNA in samples (Tolkach et al. significantly for specific RNA species, suggesting a 2018) revealed a down-regulation of these molecules remodeling of the small non-coding RNA networks two to fourfold, compared to normal tissue. The in HNSCC. Recently, Dhahbi and coworkers authors also found that higher RNY5 expression is analyzed Y RNA fragments in (OSCC), a form of associated with poor prognosis, measured as HNSCC and the most common type of head and neck biochemical recurrence-free survival. Interestingly, cancer (Dhahbi et al. 2019). Also in this case, the these results are in contrast with those found for authors found that multiple 5' Y RNA fragments bladder cancer (see above), further supporting the displayed significant differential expression levels in use of Y RNA as a valid biomarker for cancer circulation and/or tumor tissue, as compared to their identification. Also for prostate cancer, these data control counterparts. contrast with those reported before (Christov et al. Bernatsky and collaborators demonstrated that many 2008) thus a more in depth analysis is required to cancer types, and hematologic malignancies in validate either results.

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of 5' tRNA Half and YRNA Fragment Expression Associated References with Breast Cancer Biomark Cancer 2014 Dec 8;6:37-47 Belisova A, Semrad K, Mayer O, Kocian G, Waigmann E, Donovan J, Rath S, Kolet-Mandrikov D, Korennykh A. Rapid Schroeder R, Steiner G. RNA chaperone activity of protein RNase L-driven arrest of protein synthesis in the dsRNA components of human Ro RNPs. RNA. 2005 response without degradation of translation machinery RNA Jul;11(7):1084-94 2017 Nov;23(11):1660-1671 Ben-Chetrit E, Gandy BJ, Tan EM, Sullivan KF. Isolation Duarte Junior FF, de Lima Neto QA, Rando Fdos S, de and characterization of a cDNA clone encoding the 60-kD Freitas DV, Pattaro Júnior JR, Polizelli LG, Munhoz RE, component of the human SS-A/Ro ribonucleoprotein Seixas FA, Fernandez MA. Identification and molecular autoantigen. 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Cancer risk in systemic lupus: an updated murine Y1 and Y3 Ro RNAs have class 3 RNA polymerase international multi-centre cohort study. J Autoimmun. 2013 III promoter structures and are unlinked on mouse May;42:130-5 chromosome 6 Gene 1996 Sep 26;174(1):35-42 Boccitto M, Wolin SL. Ro60 and Y RNAs: structure, Fouraux MA, Bouvet P, Verkaart S, van Venrooij WJ, Pruijn functions, and roles in autoimmunity. Crit Rev Biochem Mol GJ. Nucleolin associates with a subset of the human Ro Biol. 2019 Apr;54(2):133-152 ribonucleoprotein complexes J Mol Biol 2002 Jul 12;320(3):475-88 Boria I, Gruber AR, Tanzer A, Bernhart SH, Lorenz R, Mueller MM, Hofacker IL, Stadler PF. Nematode sbRNAs: Fuchs G, Stein AJ, Fu C, Reinisch KM, Wolin SL. Structural homologs of vertebrate Y RNAs J Mol Evol 2010 and biochemical basis for misfolded RNA recognition by the Apr;70(4):346-58 Ro autoantigen Nat Struct Mol Biol 2006 Nov;13(11):1002- 9 Chakrabortty SK, Prakash A, Nechooshtan G, Hearn S, Gingeras TR. Extracellular vesicle-mediated transfer of Gallois-Montbrun S, Holmes RK, Swanson CM, Fernández- processed and functional RNY5 RNA RNA 2015 Ocaña M, Byers HL, Ward MA, Malim MH. Comparison of Nov;21(11):1966-79 cellular ribonucleoprotein complexes associated with the APOBEC3F and APOBEC3G antiviral proteins J Virol 2008 Chambers JC, Kenan D, Martin BJ, Keene JD. Genomic Jun;82(11):5636-42 structure and amino acid sequence domains of the human La autoantigen J Biol Chem 1988 Dec 5;263(34):18043-51 Gardiner TJ, Christov CP, Langley AR, Krude T. A conserved motif of vertebrate Y RNAs essential for Chen X, Smith JD, Shi H, Yang DD, Flavell RA, Wolin SL. chromosomal DNA replication RNA 2009 Jul;15(7):1375-85 The Ro autoantigen binds misfolded U2 small nuclear RNAs and assists mammalian cell survival after UV irradiation Godoy PM, Bhakta NR, Barczak AJ, Cakmak H, Fisher S, Curr Biol 2003 Dec 16;13(24):2206-11 MacKenzie TC, Patel T, Price RW, Smith JF, Woodruff PG, Erle DJ. Large Differences in Small RNA Composition Chen X, Wolin SL. The Ro 60 kDa autoantigen: insights into Between Human Biofluids Cell Rep 2018 Oct cellular function and role in autoimmunity J Mol Med (Berl) 30;25(5):1346-1358 2004 Apr;82(4):232-9 Guo Y, Yu H, Wang J, Sheng Q, Zhao S, Zhao YY, Christov CP, Trivier E, Krude T. Noncoding human Y RNAs Lehmann BD. The Landscape of Small Non-Coding RNAs are overexpressed in tumours and required for cell in Triple-Negative Breast Cancer Genes (Basel) 2018 Jan proliferation Br J Cancer 2008 Mar 11;98(5):981-8 10;9(1) Collart C, Christov CP, Smith JC, Krude T. The midblastula Haderk F, Schulz R, Iskar M, Cid LL, Worst T, Willmund KV, transition defines the onset of Y RNA-dependent DNA Schulz A, Warnken U, Seiler J, Benner A, Nessling M, Zenz replication in Xenopus laevis Mol Cell Biol 2011 T, Göbel M, Dürig J, Diederichs S, Paggetti J, Moussay E, Sep;31(18):3857-70 Stilgenbauer S, Zapatka M, Lichter P, Seiffert M. Tumor- derived exosomes modulate PD-L1 expression Deutscher SL, Harley JB, Keene JD. Molecular analysis of the 60-kDa human Ro ribonucleoprotein Proc Natl Acad Sci in monocytes Sci Immunol 2017 Jul 28;2(13) U S A 1988 Dec;85(24):9479-83 Hall AE, Turnbull C, Dalmay T. Y RNAs: recent Dhahbi J, Nunez Lopez YO, Schneider A, Victoria B, developments Biomol Concepts 2013 Apr;4(2):103-10 Saccon T, Bharat K, McClatchey T, Atamna H, Scierski W, Golusinski P, Golusinski W, Masternak MM. Profiling of Hendrick JP, Wolin SL, Rinke J, Lerner MR, Steitz JA. Ro tRNA Halves and YRNA Fragments in Serum and Tissue small cytoplasmic ribonucleoproteins are a subclass of La From Oral Squamous Cell Carcinoma Patients Identify Key ribonucleoproteins: further characterization of the Ro and Role of 5' tRNA-Val-CAC-2-1 Half Front Oncol 2019 Sep La small ribonucleoproteins from uninfected mammalian 26;9:959 cells Mol Cell Biol 1981 Dec;1(12):1138-49 Dhahbi JM. 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Ikoma M, Gantt S, Casper C, Ogata Y, Zhang Q, Basom R, O'Brien CA, Wolin SL. A possible role for the 60-kD Ro Dyen MR, Rose TM, Barcy S. KSHV oral shedding and autoantigen in a discard pathway for defective 5S rRNA plasma viremia result in significant changes in the precursors Genes Dev 1994 Dec 1;8(23):2891-903 extracellular tumorigenic miRNA expression profile in individuals infected with the malaria parasite PLoS One Perreault J, Perreault JP, Boire G. Ro-associated Y RNAs 2018 Feb 9;13(2):e0192659 in metazoans: evolution and diversification Mol Biol Evol 2007 Aug;24(8):1678-89 Köhn M, Pazaitis N, Hüttelmaier S. Why YRNAs? About Versatile RNAs and Their Functions Biomolecules 2013 Rutjes SA, Lund E, van der Heijden A, Grimm C, van Feb 8;3(1):143-56 Venrooij WJ, Pruijn GJ. Identification of a novel cis-acting RNA element involved in nuclear export of hY RNAs RNA Kheir E, Krude T. Non-coding Y RNAs associate with early 2001 May;7(5):741-52 replicating euchromatin in concordance with the origin recognition complex J Cell Sci 2017 Apr 1;130(7):1239- Rutjes SA, van der Heijden A, Utz PJ, van Venrooij WJ, 1250 Pruijn GJ. Rapid nucleolytic degradation of the small cytoplasmic Y RNAs during apoptosis J Biol Chem 1999 Kowalski MP, Krude T. Functional roles of non-coding Y Aug 27;274(35):24799-807 RNAs Int J Biochem Cell Biol 2015 Sep;66:20-9 Schotte D, Chau JC, Sylvester G, Liu G, Chen C, van der Krude T, Christov CP, Hyrien O, Marheineke K. Y RNA Velden VH, Broekhuis MJ, Peters TC, Pieters R, den Boer functions at the initiation step of mammalian chromosomal ML. Identification of new microRNA genes and aberrant DNA replication J Cell Sci 2009 Aug 15;122(Pt 16):2836- microRNA profiles in childhood acute lymphoblastic 45 leukemia Leukemia 2009 Feb;23(2):313-22 Langenberger D, akir MV, Hoffmann S, Stadler PF. Dicer- Shukla S, Parker R. PARN Modulates Y RNA Stability and processed small RNAs: rules and exceptions J Exp Zool B Its 3'-End Formation Mol Cell Biol 2017 Sep 26;37(20) Mol Dev Evol 2013 Jan;320(1):35-46 Sim S, Weinberg DE, Fuchs G, Choi K, Chung J, Wolin SL. Langley AR, Chambers H, Christov CP, Krude T. The subcellular distribution of an RNA quality control Ribonucleoprotein particles containing non-coding Y RNAs, protein, the Ro autoantigen, is regulated by noncoding Y Ro60, La and nucleolin are not required for Y RNA function RNA binding Mol Biol Cell 2009 Mar;20(5):1555-64 in DNA replication PLoS One 2010 Oct 27;5(10):e13673 Sim S, Wolin SL. Emerging roles for the Ro 60-kDa Lerner MR, Boyle JA, Hardin JA, Steitz JA. Two novel autoantigen in noncoding RNA metabolism Wiley Interdiscip classes of small ribonucleoproteins detected by antibodies Rev RNA 2011 Sep-Oct;2(5):686-99 associated with lupus erythematosus Science 1981 Jan 23;211(4480):400-2 Sim S, Yao J, Weinberg DE, Niessen S, Yates JR 3rd, Wolin SL. The zipcode-binding protein ZBP1 influences the Li C, Qin F, Hu F, Xu H, Sun G, Han G, Wang T, Guo M. subcellular location of the Ro 60-kDa autoantigen and the Characterization and selective incorporation of small non- noncoding Y3 RNA RNA 2012 Jan;18(1):100-10 coding RNAs in non-small cell lung cancer extracellular vesicles Cell Biosci 2018 Jan 10;8:2 Sole C, Arnaiz E, Manterola L, Otaegui D, Lawrie CH. The circulating transcriptome as a source of cancer liquid biopsy Lunavat TR, Cheng L, Kim DK, Bhadury J, Jang SC, Lässer biomarkers Semin Cancer Biol 2019 Oct;58:100-108 C, Sharples RA, López MD, Nilsson J, Gho YS, Hill AF, Lötvall J. Small RNA deep sequencing discriminates Stein AJ, Fuchs G, Fu C, Wolin SL, Reinisch KM. 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Evolution of bladder cancer patients BMC Cancer 2017 Nov the vertebrate Y RNA cluster Theory Biosci 2007 10;17(1):749 Aug;126(1):9-14 Tosar JP, Gámbaro F, Sanguinetti J, Bonilla B, Witwer KW, Nicolas FE, Hall AE, Csorba T, Turnbull C, Dalmay T. Cayota A. Assessment of small RNA sorting into different Biogenesis of Y RNA-derived small RNAs is independent of extracellular fractions revealed by high-throughput the microRNA pathway FEBS Lett 2012 Apr sequencing of breast cell lines Nucleic Acids Res 2015 Jun 24;586(8):1226-30 23;43(11):5601-16 Nientiedt M, Schmidt D, Kristiansen G, Müller SC, Ellinger Umu SU, Langseth H, Bucher-Johannessen C, Fromm B, J. YRNA Expression Profiles are Altered in Clear Cell Renal Keller A, Meese E, Lauritzen M, Leithaug M, Lyle R, Rounge Cell Carcinoma Eur Urol Focus 2018 Mar;4(2):260-266 TB. A comprehensive profile of circulating RNAs in human serum RNA Biol 2018 Feb 1;15(2):242-250

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Victoria Martinez B, Dhahbi JM, Nunez Lopez YO, Yamazaki F, Kim HH, Lau P, Hwang CK, Iuvone PM, Klein Lamperska K, Golusinski P, Luczewski L, Kolenda T, D, Clokie SJ. pY RNA1-s2: a highly retina-enriched small Atamna H, Spindler SR, Golusinski W, Masternak MM. RNA that selectively binds to Matrin 3 (Matr3) PLoS One Circulating small non-coding RNA signature in head and 2014 Feb 18;9(2):e88217 neck squamous cell carcinoma Oncotarget 2015 Aug 7;6(22):19246-63 Yeri A, Courtright A, Reiman R, Carlson E, Beecroft T, Janss A, Siniard A, Richholt R, Balak C, Rozowsky J, Vojtech L, Woo S, Hughes S, Levy C, Ballweber L, Kitchen R, Hutchins E, Winarta J, McCoy R, Anastasi M, Sauteraud RP, Strobl J, Westerberg K, Gottardo R, Tewari Kim S, Huentelman M, Van Keuren-Jensen K. Total M, Hladik F. Exosomes in human semen carry a distinctive Extracellular Small RNA Profiles from Plasma, Saliva, and repertoire of small non-coding RNAs with potential Urine of Healthy Subjects Sci Rep 2017 Mar 17;7:44061 regulatory functions Nucleic Acids Res 2014 Jun;42(11):7290-304 Zhang AT, Langley AR, Christov CP, Kheir E, Shafee T, Gardiner TJ, Krude T. Dynamic interaction of Y RNAs with Wang I, Kowalski MP, Langley AR, Rodriguez R, chromatin and initiation proteins during human DNA Balasubramanian S, Hsu ST, Krude T. Nucleotide replication J Cell Sci 2011 Jun 15;124(Pt 12):2058-69 contributions to the structural integrity and DNA replication initiation activity of noncoding y RNA Biochemistry 2014 van Balkom BW, Eisele AS, Pegtel DM, Bervoets S, Sep 23;53(37):5848-63 Verhaar MC. Quantitative and qualitative analysis of small RNAs in human endothelial cells and exosomes provides Wei Z, Batagov AO, Schinelli S, Wang J, Wang Y, El Fatimy insights into localized RNA processing, degradation and R, Rabinovsky R, Balaj L, Chen CC, Hochberg F, Carter B, sorting J Extracell Vesicles 2015 May 29;4:26760 Breakefield XO, Krichevsky AM. Coding and noncoding landscape of extracellular RNA released by human glioma van Gelder CW, Thijssen JP, Klaassen EC, Sturchler C, stem cells Nat Commun 2017 Oct 26;8(1):1145 Krol A, van Venrooij WJ, Pruijn GJ. Common structural features of the Ro RNP associated hY1 and hY5 RNAs Wolin SL, Belair C, Boccitto M, Chen X, Sim S, Taylor DW, Nucleic Acids Res 1994 Jul 11;22(13):2498-506 Wang HW. Non-coding Y RNAs as tethers and gates: Insights from bacteria RNA Biol 2013 Oct;10(10):1602-8 This article should be referenced as such: Wolin SL, Steitz JA. Genes for two small cytoplasmic Ro Piergentili R. Y RNA in cell cycle progression and cancer. RNAs are adjacent and appear to be single-copy in the Atlas Genet Cytogenet Oncol Haematol. 2020; human genome Cell 1983 Mar;32(3):735-44 24(10):379-386.

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