EGAGenomicsData Sharinghttps://ega-archive.org/dacs/EGAC00001000538EGAEGA DAC EGAC00001000538EGAdata.davelab@gmail.comHepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.The Genetic Basis of Hepatosplenic T-cell Lymphoma.Reddy Anupama A, Zhang Jenny J, Davis Nicholas S NS, Moffitt Andrea B AB, Love Cassandra L CL, Waldrop Alexander A, Leppa Sirpa S, Pasanen Annika A, Meriranta Leo L, Karjalainen-Lindsberg Marja-Liisa ML, Nørgaard Peter P, Pedersen Mette M, Gang Anne O AO, Høgdall Estrid E, Heavican Tayla B TB, Lone Waseem W, Iqbal Javeed J, Qin Qiu Q, Li Guojie G, Kim So Young SY, Healy Jane J, Richards Kristy L KL, Fedoriw Yuri Y, Bernal-Mizrachi Leon L, Koff Jean L JL, Staton Ashley D AD, Flowers Christopher R CR, Paltiel Ora O, Goldschmidt Neta N, Calaminici Maria M, Clear Andrew A, Gribben John J, Nguyen Evelyn E, Czader Magdalena B MB, Ondrejka Sarah L SL, Collie Angela A, Hsi Eric D ED, Tse Eric E, Au-Yeung Rex K H RKH, Kwong Yok-Lam YL, Srivastava Gopesh G, Choi William W L WWL, Evens Andrew M AM, Pilichowska Monika M, Sengar Manju M, Reddy Nishitha N, Li Shaoying S, Chadburn Amy A, Gordon Leo I LI, Jaffe Elaine S ES, Levy Shawn S, Rempel Rachel R, Tzeng Tiffany T, Happ Lanie E LE, Dave Tushar T, Rajagopalan Deepthi D, Datta Jyotishka J, Dunson David B DB, Dave Sandeep S SSMcKinney Matthew M, Moffitt Andrea B AB, Gaulard Philippe P, Travert Marion M, De Leval Laurence L, Nicolae Alina A, Raffeld Mark M, Jaffe Elaine S ES, Pittaluga Stefania S, Xi Liqiang L, Heavican Tayla T, Iqbal Javeed J, Belhadj Karim K, Delfau-Larue Marie Helene MH, Fataccioli Virginie V, Czader Magdalena B MB, Lossos Izidore S IS, Chapman-Fredricks Jennifer R JR, Richards Kristy L KL, Fedoriw Yuri Y, Ondrejka Sarah L SL, Hsi Eric D ED, Low Lawrence L, Weisenburger Dennis D, Chan Wing C WC, Mehta-Shah Neha N, Horwitz Steven S, Bernal-Mizrachi Leon L, Flowers Christopher R CR, Beaven Anne W AW, Parihar Mayur M, Baseggio Lucile L, Parrens Marie M, Moreau Anne A, Sujobert Pierre P, Pilichowska Monika M, Evens Andrew M AM, Chadburn Amy A, Au-Yeung Rex K H RK, Srivastava Gopesh G, Choi William W L WW, Goodlad John R JR, Aurer Igor I, Basic-Kinda Sandra S, Gascoyne Randy D RD, Davis Nicholas S NS, Li Guojie G, Zhang Jenny J, Rajagopalan Deepthi D, Reddy Anupama A, Love Cassandra C, Levy Shawn S, Zhuang Yuan Y, Datta Jyotishka J, Dunson David B DB, Davé Sandeep S SSfbwd4, l(2)04454, DmelCG1772, dac, CIB1, shsf3, shfm3, E(Sev-CycE)2B, p21[dacapo], Fbw4, FBW4, dactylin, E130112M23Rik, Dach, CDKN2B, cdi4, SHFM3, Dac, DAC, p27[Dap], dactylyn, dacapo/cyclin-dependent kinase interactor 4, AI182278, p21, CG1772, FBWD4, Dap, Cdi4, CDI4, CES5A1, p27, P15, fbw4, SHSF3, Decapo, University.dTAF[[II]]230, TAF[[II]]250, d230, gyltl1b-b, acetylglucosaminyltransferase-like protein, familial, Mbp1, TAF200, l(3)84Ab, dTAFII250, BG:DS00004.13, Germinoblastoma, TAFII-250, TAF250/230, EfW1, Malignant, Germinoblastic Sarcoma, Reticulolymphosarcoma., LARGE1, Cell, froggy, Gyltl1a, dTAF230, dmTAF[[II]]230, Malignant Lymphomas, TAFII250, Reticulolymphosarcomas, dmTAF1, Taf230, MDDGA6, p230, mKIAA0609, TAF[[II]]250/230, TFIID, Germinoblastic Sarcomas, Germinoblastic, KIAA0609, myd, Lymphomas, acetylglucosaminyltransferase-like 1A, TAF250, fg, Taf[[II]]250, Sarcomas, Taf200, gyltl1b, dTAF[[II]]250, TAF[[II]]230, like-acetylglucosaminyltransferase, TFIID TAF250, cel, cell, MDDGB6, mdc1d, Mbp-1, Taf1p, LARGE, TAF[II]250, MLYM, Germinoblastomas, CG17603, LARGE_HUMAN, TAF[[II]], genetic, BPFD#36, dTAF250, MDC1D, Malignant Lymphoma, Sarcoma, DmelCG17603, lymphoma, like-glycosyltransferase, enr, Taf250, SR3-5, Lymphoma, inherited genetic, TAF, constitutitional genetic, hereditary, TAF230, glycosyltransferase-like protein LARGE1, lymphoid cancer, TAF1p231HBP, Materials, Ardi1b, 2410099E07Rik, tumor suppressor, AI836955, ezh2, ezh1, positive regulation by symbiont of host non-apoptotic programmed cell death, PI3K, EZH2b, SET2, Progress Reports, Germinoblastoma, UniProtKB:P40763-1, Viabilities, Tumor, ATINO80, Tp53, ELD|OSA1, Mutations, Malignant Lymphomas, APRF Transcription Factor, ras, cell cycle regulator, diseases, Summary Report, 2610208K16Rik, bbl, AA959943, pathogenesis, B230217J03Rik, diseases and disorders, Whole Transcriptome, Transcriptome Sequencing, Lymphomas, C-K-RAS, k-ras, Summary Reports, Chromatins, Viability, Reticulolymphosarcoma, rask2, treatment, human disease, stimulation by symbiont of host programmed cell death, BCC7, Second-Site Suppressor Genes, Progress Report, Complete Exome Sequencing, Whole Transcriptome Sequencing, ALC-ALPHA, CG3602, Acts, genetic, Progress, Malignant Lymphoma, Sarcoma, high frequency, Field Reports, malignant neoplasm, INO80, chromosome scaffold, 4921524K10Rik, disease management, Therapies, Homo sapiens disease, IL6-Response Factor, Malignancies, signal transducer and activator of transcription 3 (acute-phase response factor), EZH1, single organism signaling, Tumors, nuclear chromatin, Acta-2, Therapy, dIno80, Opal Suppressor Gene, ADMIO, DAN15, P110DELTA, Ki-ras, aprf, Exome, familial, dINO80, Actsk-1, Frameshift, CG31212, Ochre, 8030481M12, Reticulolymphosarcomas, Benign, Investigative Report, p21, Diseases, INO80 ORTHOLOG, modulation by symbiont of host system process, Genetic Materials, Kif9, acute-phase response factor, Enx-1, bfy, Second-Site Suppressor Gene, Germinoblastic, STAT3_HUMAN, CDHR12, Genetic Material, Amber Suppressor Genes, APRF, Complete Transcriptome, HSTCL, OSA2, 2310079N15Rik, Field, Benign Neoplasms, stat3, INSDC_feature:gene, MLYM, CG18491, Nonsense Mutation Suppressor, Germinoblastomas, STAT5, Aprf, Treatments, AW109958, APDS, HYPB, 4632409L19Rik, disease, p110D, Report, lymphoma, STAT3, RASK2, Material, stat5, Lymphoma, activation by symbiont of host programmed cell death, Whole Exome Sequencing, P53, p44, bhy, Cistron, inherited genetic, mKIAA1235, Transcriptome Sequencings, mKIAA4065, Malignant Neoplasms., KI-RAS, Frameshift Suppressor, other disease, cytoplasmic chromatin, Amber, LIF-Response Factor, Complete Exome, enx1, XB31alpha, regulation by symbiont of host system process, Neoplasms, Kras2, NS3, p53, enx-1, number, 9330189K18Rik, Second Site Suppressor Genes, Benign Neoplasm, Gene, kmt6, Malignant, Germinoblastic Sarcoma, LFS1, presence, HSPC069, HBP231, AW545373, Investigative, induction by organism of non-apoptotic programmed cell death in other organism during symbiotic interaction, xez, Survival, LIF(leukemia inhibitory factor)-Response Factor, disease or disorder, Kras-2, KIAA1732, KMT6A, Second-Site Suppressor, INO80A, KRAS2, KRAS1, Inoc1, p21B, Sarcomas, ENX-1, WES, Complete, Exome Sequencings, Genetic, Malignancy, HIP-1, HIF1, HIES, K-RAS4B, CSTN1, K-RAS4A, hypothetical protein MGC16063, WVS, causes, Sequencing, hies, CST-1, Suppressor Gene, Ochre Suppressor Gene, non-neoplastic, Neoplasias, ENX1, Whole Exome, KMT3A, Trp53, Enx1h, 6A3-5, KMT6, Amber Suppressor Gene, Second-Site, Whole, causality, disorder, WVS2, TRP53, Investigative Reports, constitutitional genetic, FLJ20882, hINO80, Second Site Suppressor, Cancer, Frameshift Suppressor Gene, Frameshift Suppressor Genes, activation by organism of non-apoptotic programmed cell death in other organism, Complete Exome Sequencings, Malignant Neoplasm, ELD/OSA1, PIK3CD, alcalpha1, hemolysin activity, P250R, K-RAS2B, alcalpha2, K-RAS2A, Ochre Suppressor, disorders, DmelCG31212, K-ras, medical condition, Amber Suppressor, CG14279, c-Ki-ras, Cistrons, Cell, Xp53, Ochre Suppressor Genes, Opal Suppressor, Cell Viabilities, Exome Sequencing, count in organism, MT, p110delta, Research Reports, Neoplasm, INOC1, condition, Xstat3, Germinoblastic Sarcomas, rare (European definition), AI929937, BRIGHT, MRD12, BAF250B, NS, primary cancer, Genes, Complete Transcriptome Sequencing, frequent, Opal, DNA-binding protein APRF, HIF-1, Nonsense Mutation Suppressor Genes, huntingtin-interacting protein 1, Cancers, Opal Suppressor Genes, Suppressor, malignant tumor, 2-770, SPAC3G6.12, 1110034C02Rik, signalling process, Therapeutic, Reports, IMD14, kras, CFC2, Suppressor Genes, cardinality, Treatment, INO80 ortholog, BC031601, Summary, hereditary, Cell Viability, Neoplasia, Field Report, lymphoid cancerfalseDAC for Dave Lab, Duke UniversityData Access Committee EGAC000010005382025-1-9EGAC0000100053896062812286728985567EGAS00001003778EGAS00001002606EGAS00001002182EGAS00001001954EGAD00001003284EGAD00001003246EGAD00001003600EGAD00001005781