| Literature DB >> 28122867 |
Matthew McKinney1, Andrea B Moffitt2, Philippe Gaulard3, Marion Travert3, Laurence De Leval4, Alina Nicolae5, Mark Raffeld5, Elaine S Jaffe5, Stefania Pittaluga5, Liqiang Xi5, Tayla Heavican6, Javeed Iqbal6, Karim Belhadj3, Marie Helene Delfau-Larue3, Virginie Fataccioli3, Magdalena B Czader7, Izidore S Lossos8, Jennifer R Chapman-Fredricks8, Kristy L Richards9, Yuri Fedoriw9, Sarah L Ondrejka10, Eric D Hsi10, Lawrence Low11, Dennis Weisenburger11, Wing C Chan11, Neha Mehta-Shah12, Steven Horwitz12, Leon Bernal-Mizrachi13, Christopher R Flowers13, Anne W Beaven1, Mayur Parihar14, Lucile Baseggio15, Marie Parrens16, Anne Moreau17, Pierre Sujobert18, Monika Pilichowska19, Andrew M Evens19, Amy Chadburn20, Rex K H Au-Yeung21, Gopesh Srivastava21, William W L Choi21, John R Goodlad22, Igor Aurer23, Sandra Basic-Kinda23, Randy D Gascoyne24, Nicholas S Davis1, Guojie Li1, Jenny Zhang1, Deepthi Rajagopalan1, Anupama Reddy1, Cassandra Love1, Shawn Levy25, Yuan Zhuang1, Jyotishka Datta26, David B Dunson26, Sandeep S Davé27,2.
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. ©2017 American Association for Cancer Research.Entities:
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Year: 2017 PMID： 28122867 PMCID： PMC5402251 DOI： 10.1158/2159-8290.CD-16-0330
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 39.397