The Genetic Basis of Hepatosplenic T-cell Lymphoma

• Published in: Cancer discovery Vol. 7; no. 4; p. 369
• Main Authors: McKinney, Matthew, Moffitt, Andrea B, Gaulard, Philippe, Travert, Marion, De Leval, Laurence, Nicolae, Alina, Raffeld, Mark, Jaffe, Elaine S, Pittaluga, Stefania, Xi, Liqiang, Heavican, Tayla, Iqbal, Javeed, Belhadj, Karim, Delfau-Larue, Marie Helene, Fataccioli, Virginie, Czader, Magdalena B, Lossos, Izidore S, Chapman-Fredricks, Jennifer R, Richards, Kristy L, Fedoriw, Yuri, Ondrejka, Sarah L, Hsi, Eric D, Low, Lawrence, Weisenburger, Dennis, Chan, Wing C, Mehta-Shah, Neha, Horwitz, Steven, Bernal-Mizrachi, Leon, Flowers, Christopher R, Beaven, Anne W, Parihar, Mayur, Baseggio, Lucile, Parrens, Marie, Moreau, Anne, Sujobert, Pierre, Pilichowska, Monika, Evens, Andrew M, Chadburn, Amy, Au-Yeung, Rex K H, Srivastava, Gopesh, Choi, William W L, Goodlad, John R, Aurer, Igor, Basic-Kinda, Sandra, Gascoyne, Randy D, Davis, Nicholas S, Li, Guojie, Zhang, Jenny, Rajagopalan, Deepthi, Reddy, Anupama, Love, Cassandra, Levy, Shawn, Zhuang, Yuan, Datta, Jyotishka, Dunson, David B, Davé, Sandeep S
• Format: Journal Article
• Language: English
• Published: United States 01-04-2017
• Subjects: Adolescent; Adult; Aged; ATPases Associated with Diverse Cellular Activities; Base Sequence; Child; Child, Preschool; DNA Helicases - genetics; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Exome - genetics; Female; Histone-Lysine N-Methyltransferase - genetics; Humans; Liver Neoplasms - complications; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Lymphoma, T-Cell - complications; Lymphoma, T-Cell - genetics; Lymphoma, T-Cell - pathology; Male; Middle Aged; Proto-Oncogene Proteins p21(ras); Splenic Neoplasms - complications; Splenic Neoplasms - genetics; Splenic Neoplasms - pathology; Transcription Factors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - genetics; Young Adult
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.CD-16-0330

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
, and
, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in
(31%),
(9%), and
(9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in
, and
was the most frequently silenced gene in HSTL. We experimentally demonstrated that
acts as a tumor suppressor gene. In addition, we found that mutations in
and
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.
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
as a tumor suppressor gene in HSTL and implicates genes including
and
in the disease.
.