Genetic Basis of Hepatosplenic T Cell Lymphoma (HSTL)

EGAGenomicsIllumina HiSeq 2500;ILLUMINAhttps://ega-archive.org/datasets/EGAD0000100324690EGA dataset EGAD00001003246EGAGenetic Basis of Hepatosplenic T Cell Lymphoma (HSTL)Hepatosplenic 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.The Genetic Basis of Hepatosplenic T-cell Lymphoma.McKinney 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 SSVasp, VASP, Data Set., DmelCG15112, ENHANCER OF ATNSI ACTIVITY, MENA, NDPP1, l(2)02029, Enb, enb, ENA, Ena, CG15112, ENA/VASPwhole exome, BamF, bim, Complete Exome Sequencings, Malignant Neoplasm, biml, Edg, BamC, Complete Exome, T-cell non-Hodgkin's lymphoma, Neoplasms, bam, Exome, T-cell and NK-cell non-Hodgkin lymphoma, Benign Neoplasm, Cell Lines, T-cell non-Hodgkin lymphoma, ham, BOD, Tumor, Malignant, Cell, T-cell and NK-cell non-Hodgkin's lymphoma, fs(3)neo61, CG10422, Exome Sequencing, Benign, T-Cell, Neoplasm, Line, bim-beta7, Cell., Whole Transcriptome, Transcriptome Sequencing, bod, DmelCG10422, Lymphomas, T-cell NHL, END, bimel, Lines, average, WES, Complete Transcriptome, Complete, Complete Transcriptome Sequencing, Exome Sequencings, Malignancy, HCAP, bim-beta6, Complete Exome Sequencing, Whole Transcriptome Sequencing, Exomes, Benign Neoplasms, T cell lymphoma, Cancers, alpha, T Cell Lymphoma, CDLS3, BMH, Sequencing, Malignant Neoplasms, Neoplasias, Whole Exome, non-Hodgkin's T-cell lymphoma, BIM, Bam-C, Whole, Lymphoma, BAM, Whole Exome Sequencing, Bam, SMC3L1, T Cell, Malignancies, T-Cell Lymphoma, ORW1, CSPG6, other neoplasm, Transcriptome Sequencings, T-Cell Lymphomas, Neoplasia, HHT1, T-cell lymphoma, Cancer, Tumorsgenetic, familial, inherited genetic, constitutitional genetic, HSTCL., hereditaryUnknown if Another form of Birth Control was Used, Unknown/Not Stated, Materials, Ardi1b, 2410099E07Rik, odd(Oz), Metastasis, AI836955, Recessive, Tumor Suppressing Gene, Unknown if Chief Complaint Caused by Trauma, A1, ezh2, ezh1, Not Known if MET Mutation Analysis Was Performed, EZH2b, SET2, Biochemical Pathway, Progress Reports, Germinoblastoma, Unknown Tamoxifen Use, Viabilities, Tumor, Oncogenes, Mutations, APRF Transcription Factor, ras, Summary Report, bbl, ten-m, AA959943, Recessive Oncogenes, Importance Rating Score 0, Related, Activate, Not Known if ROS1 Rearrangement Analysis Was Performed, Lymphomas, Not Known if Fluorescence In Situ Hybridization Was Performed, C-K-RAS, Tumor Suppressing, Documentation Unknown, Viability, Gene Variation Not Detected, Not Known if PTEN Mutation Analysis Was Performed, Tumor Progression Unknown After Initial Treatment, treatment, l(3)rP126, stimulation by symbiont of host programmed cell death, BCC7, Progress Report, Anti Oncogenes, Unknown Clark Level, Pathways, U, ALC-ALPHA, 932, Not Known if BRAF Rearrangement Analysis Was Performed, {EVENTS}, Not Known if NF1 Mutation Analysis Was Performed, BcDNA:AT25108, CG3602, Based, Mutation Abnormality, replicate, Not Known if KRAS Mutation Analysis Was Performed, Be, ISL, high frequency, Field Reports, INO80, 4921524K10Rik, Homo sapiens disease, signal transducer and activator of transcription 3 (acute-phase response factor), Relationship, Unknown Molecular Analysis, EZH1, single organism signaling, Tumors, Ten-mc, Add, Acta-2, dIno80, Unknown Procedure Type for New Tumor Event, Issue, Unknown Age When Started using Smokeless Tobacco after Regular Use, ADMIO, Pathway, Not Known if 1p/19q Deletion Analysis Was Performed, Unknown History of Gestational Complication, Exome, familial, CG5723, AACR, Gene Mutation Detected, dINO80, Actsk-1, Unknown if Interferon Gamma Treatment was Administered Prior to Specimen Resection, CG31212, Adjuvant Post-operative Chemotherapy Administration Unknown, New Tumor Event After Initial Treatment Unknown, 8030481M12, Benign, Notable, Gene Variation Negative, Genetic Alteration, acute-phase response factor, bfy, Unknown History of Other Muscular Dystrophy or Glycogen Storage Disorder, STAT3_HUMAN, Not Known if Mutation Analysis Was Performed, Unknown if Routine Cytogenetics were Completed, statistical significance, Regular Smokeless Tobacco Use for Six Weeks or More Unknown, Definite Attribution, Unknown History of Congenital Heart Disease, OSA2, Field, UNK, Benign Neoplasms, INSDC_feature:gene, MLYM, CG18491, Germinoblastomas, STAT5, Tumor Suppressor Gene, Present, First Course Treatment Completion Measure of Success of Outcome Unknown, AW109958, Tumor Suppressor, Malignant Neoplasms, Not Known if Additional Molecular Studies Were Performed, APDS, 4632409L19Rik, Report, Oncogene, lymphoma, STAT3, RASK2, Material, Lymphoma, activation by symbiont of host programmed cell death, Whole Exome Sequencing, bhy, 2017, mKIAA4065, Molecular Abnormalities Unknown, WHOLE EXOME SEQUENCING, LIF-Response Factor, Unknown Number of Full Term Pregnancies, Chemical/Occupational Exposure History Unknown, 5301, Potential, enx1, XB31alpha, regulation by symbiont of host system process, Neoplasms, Evidence of Disease Unknown after Completion of Therapy, number, Not Known if BRAF Mutation Analysis Was Performed, LFS1, HBP231, Not Known if ERBB2 Mutation Analysis Was Performed, Odz, Not Known if IDH Family Mutation Analysis Was Performed, Antioncogene, induction by organism of non-apoptotic programmed cell death in other organism during symbiotic interaction, IS, disease or disorder, mutation, Kras-2, Adjuvant Post-operative Immunological Therapy Administration Unknown, KIAA1732, KMT6A, Tumor Suppressing Genes, ICELAND, Gene Variant Positive, INO80A, Inoc1, Additional Surgery for New Tumor Event Unknown, Sarcomas, ENX-1, odz, In, Unknown Use of Menopausal Hormone Therapy, Activation, HIP-1, HIF1, HIES, K-RAS4B, CSTN1, K-RAS4A, Unknown if Targeted Molecular Therapy Was Administered as an Additional Treatment for a New Tumor Event, Target, Emerogene, Not Known if 10q23/PTEN Locus Deletion Analysis Was Performed, Not Known if Lymph Node Dissection Was Performed, Events, WVS, l(3)rJ307, hies, CST-1, Suppressor Gene, Neoplasias, ENX1, l(3)05301, Unknown Daily Salt Intake, Unknown if Immunotherapy Was Administered as an Additional Treatment for a New Tumor Event, {Unknown}, KMT3A, 6A3-5, Gene Variation Detected, Statistically Significant, Unknown Oral Contraceptive Use, Not Mutated, WVS2, Investigative Reports, constitutitional genetic, FLJ20882, Unknown History of Myopathy, hINO80, Follow-Up Form Completion Outcome Measure of Success Unknown, Including, Cancer, Adjuvant Post-operative Targeted Molecular Therapy Administration Unknown, Not Known if NRAS Mutation Analysis Was Performed, Onco-Suppressor Genes, Unknown History of Kawasaki Disease, Malignant Neoplasm, Use of Smokeless Tobacco at Time of Diagnosis Unknown, ELD/OSA1, PIK3CD, hemolysin activity, K-RAS2B, K-RAS2A, disorders, WXS, copies, DmelCG31212, Frequently, Not Known if ATRX Mutation Analysis Was Performed, c-Ki-ras, Cell, Ten79E, Cell Viabilities, Addition, Genetic Change, Exome Sequencing, MT, Research Reports, Neoplasm, INOC1, condition, Germinoblastic Sarcomas, Replicate, Performance Status Scale Timing Unknown, Recessive Oncogene, Unknown if Hormone Therapy Was Administered as an Additional Treatment for a New Tumor Event, activate, Intercurrent Illness is Unknown at Onset of Chief Complaint, Mutation, American Association of Cancer Research, Hypertension Unknown, Destination, Definitely Related to Intervention, MRD12, Unknown Dosage Form Category, Paraneoplastic Syndrome Status is Unknown, BAF250B, Unknown if Patient Has Genetic Syndrome Associated with Congenital Heart Defect, NS, primary cancer, CT16449, Not Known, Unknown Data Entry Method, Metastasis Suppressor Genes, huntingtin-interacting protein 1, Cancers, Not Known if Bone Marrow Aspirate Immunophenotyping and Cytochemistry Were Performed, malignant tumor, Onco Suppressor, Tumor Laterality Unknown, Onco-Suppressor Gene, 1110034C02Rik, Not Known if SDH Complex Mutation Analysis Was Performed, signalling process, Reports, IMD14, Suppressor Genes, Multiple Known Primary Tumors Unknown at Initial Melanoma Diagnosis, ten(m), Tumor Suppressor Genes, hereditary, UNKNOWN, Neoplasia, CG11452, Unknown History of Non-Cardiac Surgery, p231HBP, Frequent, 352, Activated, Significant, positive regulation by symbiont of host non-apoptotic programmed cell death, Unknown, PI3K, UniProtKB:P40763-1, ATINO80, Tp53, ELD|OSA1, Driver Device, Malignant Lymphomas, Anti-Oncogene, Growth Suppressor Genes, DmelCG5723, diseases, Statistical Significance, 2610208K16Rik, pathogenesis, B230217J03Rik, diseases and disorders, Emerogenes, Unknown Daily Fluid Intake, {Copies}, k-ras, Summary Reports, Whole-Exome Sequencing, Chromatins, Definite, Reticulolymphosarcoma, Unknown Site of New Tumor Event, rask2, Chemotherapy Status Unknown, Targeting, human disease, Growth, Gene Mutation Negative, WXS (whole exome sequencing), Not Known if EGFR Mutation Analysis Was Performed, l(3)rL201, statistically significant, Not Known if PDGFRA Mutation Analysis Was Performed, Onco-Suppressor, Association, ten-m/odz, Copies, ten[m], Acts, Growth Suppressor, genetic, Unknown if Medication Taken, Progress, Malignant Lymphoma, Sarcoma, Unknown: Could not be determined or unsure, malignant neoplasm, CDISC Events Class, chromosome scaffold, disease management, Therapies, Event Unit, IL6-Response Factor, Malignancies, Importance Score 0, nuclear chromatin, Therapy, DAN15, Cancer History Unknown, Cancer Suppressor Genes, Unknown Daily Caloric Intake, P110DELTA, Ki-ras, aprf, Iceland, Not Known if Immunohistochemistry Was Performed, Importance 0, Metabolic Network, l(3)05309, Significance, Tumor Location Unknown, Feature., Not Known if ALK Rearrangement Analysis Was Performed, Reticulolymphosarcomas, Not Known if RET Rearrangement Analysis Was Performed, Investigative Report, significant, p21, Diseases, INO80 ORTHOLOG, Not Known if TP53 Mutation Analysis Was Performed, modulation by symbiont of host system process, Genetic Materials, Kif9, Enx-1, Germinoblastic, Unknown if Radiation Was Administered as an Additional Treatment for a New Tumor Event, Adverse Event Definitely Related to Intervention, Adverse Event Related to Intervention, Unknown if Chemotherapy Was Administered as an Additional Treatment for a New Tumor Event, CDHR12, Problem, Genetic Material, APRF, 1p/19q Codeletion Status Unknown, Unknown Family History Cardiovascular Disease or Cardiovascular Disease Risk Factors, Not Known if Peripheral Blood Immunophenotyping and Cytochemistry Were Performed, Mutated, Driver, Unknown if Caffeine Consumption is Routine, HSTCL, 2310079N15Rik, Unknown History of Alcohol Use, Exist, Unknown GENC, stat3, Presence, AX1, Features, Aprf, Treatments, Adjuvant Post-operative Pharmaceutical Therapy Administration Unknown, Gene Mutant Negative, HYPB, disease, Unknown if Chief Complaint was Witnessed, p110D, stat5, Noted, P53, Gene Mutation Positive, p44, Cistron, inherited genetic, mKIAA1235, History of Medical Treatment Unknown, molecular pathway, Unknown if New Disease is Multifocal, KI-RAS, Additional Surgery for New Loco-Regional Tumor Event Unknown, other disease, cytoplasmic chromatin, Antioncogenes, Important, Cancer Suppressor Gene, Unknown Route of Administration, Kras2, NS3, p53, enx-1, Importance, 9330189K18Rik, Benign Neoplasm, Gene, kmt6, Ten[m], Not Known if MGMT Promoter Methylation Testing Was Performed, Malignant, Germinoblastic Sarcoma, presence, HSPC069, AW545373, Unknown Transformation, Investigative, Relations, xez, Adjuvant Post-operative Radiation Therapy Administration Unknown, Survival, Unknown if Subsequent Known Primary Melanoma(s) Found During the Follow-Up, Gene Variant Negative, LIF(leukemia inhibitory factor)-Response Factor, Cancer Suppressor, KRAS2, KRAS1, p21B, WES, Article, Genetic, PRESENT, Malignancy, Being, hypothetical protein MGC16063, Anti-Oncogenes, causes, Unknown if Patient was Previously Evaluated for Current Chief Complaint, non-neoplastic, Trp53, Enx1h, KMT6, Device Status Unknown, Found, odz/ten-m, Gene Mutant Positive, causality, disorder, Metastasis Suppressor, Gene Mutation Not Detected, Characteristics, Average Daily Use Smokeless Tobacco after Use for Six Weeks Unknown, TRP53, Unknown History of Illicit Drug Use, Unknown History of Rheumatic Fever, EVENTS, activation by organism of non-apoptotic programmed cell death in other organism, Tumor Reoccurrence Unknown After Initial Treatment, alcalpha1, Critical, P250R, alcalpha2, Targeted, K-ras, Certain, medical condition, CG14279, Cistrons, Related Attribution, Immunotherapy Status Unknown, Xp53, Unknown when Chief Complaint Present, count in organism, Characteristic, p110delta, Xstat3, Unknown Release Mechanism of Action, rare (European definition), Copy, AI929937, Not Known if Additional Immunohistochemistry Was Performed, BRIGHT, Basic, Not Known if KIT Mutation Analysis Was Performed, Chemical/Occupational Exposure Type Unknown, Physician Diagnosed Diabetes Unknown, Genes, frequent, Growth Suppressor Gene, DNA-binding protein APRF, HIF-1, Basis, Metastasis Suppressor Gene, Not Known if Additional Testing Was Performed, Unknown History of Neonatal Complication, Interferon Gamma Treatment Administration 90 Days Prior to Specimen Resection Unknown, Gene Variation Positive, 2-770, SPAC3G6.12, Therapeutic, kras, CFC2, cardinality, Inclusive, Treatment, INO80 ortholog, BC031601, Additional Surgery for New Metastatic Tumor Event Unknown, Not Known if EGFR Amplification Analysis Was Performed, Duplicate, Summary, Cell Viability, l(3)00844, Field Report, lymphoid cancerfalseena-DATASET-DAVELAB-22-03-2017-21:30:50:663-38 - samplesWhole exome sequencing of hepatosplenic T cell lymphoma (HSTL) tumors, paired normals, and cell lines, including (1) 68 exome capture, paired-end Illumina Hiseq sequencing, BAM files from HSTL tumor samples, (2) 20 exome capture, paired-end Illumina Hiseq sequencing, BAM files from HSTL paired normal samples, and (3) 2 exome capture, paired-end Illumina Hiseq sequencing, BAM files from HSTL cell lines.2017-07-26 15:39:29EGAD00001003246960628122867EGAC00001000538EGAS00001002182