The genetic basis of hepatosplenic T-cell lymphoma

Matthew McKinney, Andrea B. Moffitt, Philippe Gaulard, Marion Travert, Laurence De Leval, Alina Nicolae Mark Raffeld, Elaine S. Jaffe, Stefania Pittaluga, Liqiang Xi, Tayla Heavican, Javeed Iqbal, Karim Belhadj, Marie Helene Delfau-Larue, Virginie Fataccioli, Magdalena B. Czader, Izidore S. Lossos, Jennifer R. Chapman-Fredricks, Kristy L. Richards, Yuri Fedoriw, Sarah L. OndrejkaEric D. Hsi, Lawrence Low, Dennis Weisenburger, Wing C. Chan, Neha Mehta-Shah, Steven Horwitz, Leon Bernal-Mizrachi, Christopher R. Flowers, Anne W. Beaven, Mayur Parihar, Lucile Baseggio, Marie Parrens, Anne Moreau, Pierre Sujobert, Monika Pilichowska, Andrew M. Evens, Amy Chadburn, Rex K.H. Au-Yeung, Gopesh Srivastava, William W.L. Choi, John R. Goodlad, Igor Aurer, Sandra Basic-Kinda, Randy D. Gascoyne, Nicholas S. Davis, Guojie Li, Jenny Zhang, Deepthi Rajagopalan, Anupama Reddy, Cassandra Love, Shawn Levy, Yuan Zhuang, Jyotishka Datta, David B. Dunson, Sandeep S. Davé

Research output: Contribution to journalArticle

70 Scopus citations

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 TP53. SETD2 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.

Original languageEnglish (US)
Pages (from-to)369-379
Number of pages11
JournalCancer Discovery
Volume7
Issue number4
DOIs
StatePublished - Apr 2017

ASJC Scopus subject areas

  • Oncology

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    McKinney, M., Moffitt, A. B., Gaulard, P., Travert, M., Leval, L. D., Raffeld, A. N. M., Jaffe, E. S., Pittaluga, S., Xi, L., Heavican, T., Iqbal, J., Belhadj, K., Delfau-Larue, M. H., Fataccioli, V., Czader, M. B., Lossos, I. S., Chapman-Fredricks, J. R., Richards, K. L., Fedoriw, Y., ... Davé, S. S. (2017). The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discovery, 7(4), 369-379. https://doi.org/10.1158/2159-8290.CD-16-0330