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Cancer Discov. 2017 Apr;7(4):369-379. doi: 10.1158/2159-8290.CD-16-0330. Epub 2017 Jan 25.

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Author information

1
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
2
Duke Center for Genomics and Computational Biology, Duke University, Durham, North Carolina.
3
Hôpital Henri Mondor, Department of Pathology, AP-HP, Créteil, France, INSERM U955, Créteil, France, and University Paris-Est, Créteil, France.
4
Pathology Institute, CHUV Lausanne, Switzerland.
5
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
6
University of Nebraska, Omaha, Nebraska.
7
Indiana University, Indianapolis, Indiana.
8
University of Miami, Miami, Florida.
9
University of North Carolina, Chapel Hill, North Carolina.
10
Cleveland Clinic, Cleveland, Ohio.
11
City of Hope Medical Center, Duarte, California.
12
Memorial Sloan Kettering Cancer Center, New York, New York.
13
Emory University, Atlanta, Georgia.
14
Tata Medical Center, Kolkata, India.
15
Centre Lyon-Sud, Pierre-Bénite, France.
16
Hôpital Pessac, Bordeaux, France.
17
Pathology, Hôpital Hôtel-Dieu, Nantes, France.
18
Faculté de Médecine Lyon-Sud Charles Mérieux, Université Claude Bernard, Lyon, France.
19
Tufts University Medical Center, Boston, Massachusetts.
20
Presbyterian Hospital, Pathology and Cell Biology, Cornell University, New York, New York.
21
University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
22
Department of Pathology, Western General Hospital, Edinburgh, UK.
23
University Hospital Centre Zagreb, Zagreb, Croatia.
24
British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada.
25
Hudson Alpha Institute for Biotechnology, Huntsville, Alabama.
26
Department of Statistical Science, Duke University, Durham, North Carolina.
27
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina. ssd9@duke.edu.

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.

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PMID:
28122867
PMCID:
PMC5402251
DOI:
10.1158/2159-8290.CD-16-0330
[Indexed for MEDLINE]
Free PMC Article

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