Dataset Information

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

ABSTRACT: 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.

SUBMITTER: McKinney M

PROVIDER: S-EPMC5402251 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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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 SS

Cancer discovery 20170125 4

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 cur ...[more]

PMID: 28122867

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Project description:Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620-124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620-99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.

Dataset Information

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Publications

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

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