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J Exp Med. 2017 May 1;214(5):1371-1386. doi: 10.1084/jem.20160894. Epub 2017 Apr 19.

Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2.

Author information

1
Duke Center for Genomics and Computational Biology, Duke University, Durham, NC 27708.
2
Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710.
3
Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195.
4
Haematological Malignancy Diagnostic Service, St. James's University Hospital, Leeds LS9 7TF, England, UK.
5
Haematology Department, Western General Hospital, Edinburgh EH14 1TY, Scotland, UK.
6
Department of Oncology and Research Program Unit, Faculty of Medicine, Helsinki University Hospital Cancer Center and University of Helsinki, 00014 Helsinki, Finland.
7
HUSLAB and Medicum, Helsinki University Hospital Cancer Center and University of Helsinki, 00014 Helsinki, Finland.
8
University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
9
University of Nebraska Medical Center, Omaha, NE 68198.
10
Imperial College London, London SW7 2AZ, England, UK.
11
British Columbia Cancer Agency, University of British Columbia, Vancouver, BC V6R 1ZE, Canada.
12
University of California, Los Angeles, Los Angeles, CA 90095.
13
Indiana University, Indianapolis, IN 46202.
14
Presbyterian Hospital, Pathology and Cell Biology, Cornell University, New York, NY 10065.
15
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
16
Department of Medicine, Duke University School of Medicine, Durham, NC 27710.
17
Department of Statistical Science, Duke University, Durham, NC 27708.
18
Hudson Alpha Institute for Biotechnology, Huntsville, AL 35806.
19
Department of Immunology, Duke University School of Medicine, Durham, NC 27710.

Abstract

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.

PMID:
28424246
PMCID:
PMC5413324
DOI:
10.1084/jem.20160894
[Indexed for MEDLINE]
Free PMC Article

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