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

被引：128

作者：

Moffitt, Andrea B. ^{[1
,3
]}

Ondrejka, Sarah L. ^{[6
]}

McKinney, Matthew ^{[3
]}

Rempel, Rachel E. ^{[3
]}

Goodlad, John R. ^{[7
]}

Teh, Chun Huat ^{[8
]}

Leppa, Sirpa ^{[9
]}

Mannisto, Susanna ^{[9
]}

Kovanen, Panu E. ^{[10
,11
]}

Tse, Eric ^{[12
]}

Au-Yeung, Rex K. H. ^{[12
]}

Kwong, Yok-Lam ^{[12
]}

Srivastava, Gopesh ^{[12
]}

Iqbal, Javeed ^{[13
]}

Yu, Jiayu ^{[13
]}

Naresh, Kikkeri ^{[14
]}

Villa, Diego ^{[15
]}

Gascoyne, Randy D. ^{[15
]}

Said, Jonathan ^{[16
]}

Czader, Magdalena B. ^{[17
]}

Chadburn, Amy ^{[18
]}

Richards, Kristy L. ^{[19
]}

Rajagopalan, Deepthi ^{[3
]}

Davis, Nicholas S. ^{[3
]}

Smith, Eileen C. ^{[3
]}

Palus, Brooke C. ^{[3
]}

Tzeng, Tiffany J. ^{[3
]}

Healy, Jane A. ^{[3
]}

Lugar, Patricia L. ^{[4
]}

Datta, Jyotishka ^{[2
]}

Love, Cassandra ^{[3
]}

Levy, Shawn ^{[20
]}

Dunson, David B. ^{[2
]}

Zhuang, Yuan ^{[5
]}

Hsi, Eric D. ^{[6
]}

Dave, Sandeep S. ^{[1
,3
]}

机构：

[1] Duke Univ, Duke Ctr Genom & Computat Biol, Durham, NC 27708 USA

[2] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA

[3] Duke Univ, Sch Med, Duke Canc Inst, Durham, NC 27710 USA

[4] Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA

[5] Duke Univ, Sch Med, Dept Immunol, Durham, NC 27710 USA

[6] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44195 USA

[7] St James Univ Hosp, Haematol Malignancy Diagnost Serv, Leeds LS9 7TF, W Yorkshire, England

[8] Western Gen Hosp, Dept Hematol, Edinburgh EH14 1TY, Midlothian, Scotland

[9] Helsinki Univ Hosp, Fac Med, Ctr Canc, Dept Oncol & Res Program Unit, Helsinki, Finland

[10] Helsinki Univ Hosp, Ctr Canc, HUSLAB & Medicum, Helsinki, Finland

[11] Univ Helsinki, Helsinki 00014, Finland

[12] Univ Hong Kong, Queen Mary Hosp, Hong Kong, Hong Kong, Peoples R China

[13] Univ Nebraska Med Ctr, Omaha, NE 68198 USA

[14] Imperial Coll London, London SW7 2AZ, England

[15] Univ British Columbia, British Columbia Canc Agcy, Vancouver, BC V6R 1ZE, Canada

[16] Univ Calif Los Angeles, Los Angeles, CA 90095 USA

[17] Indiana Univ, Indianapolis, IN 46202 USA

[18] Cornell Univ, Presbyterian Hosp, Pathol & Cell Biol, New York, NY 10065 USA

[19] Univ North Carolina Chapel Hill, Chapel Hill, NC 27599 USA

[20] Hudson Alpha Inst Biotechnol, Huntsville, AL 35806 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2017年 / 214卷 / 05期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

INTERFERON-GAMMA; INTRAEPITHELIAL LYMPHOCYTES; GENOME ANALYSIS; READ ALIGNMENT; RNA-SEQ; MUTATIONS; GENE; IDENTIFICATION; LANDSCAPE; FRAMEWORK;

D O I：

10.1084/jem.20160894

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 gamma delta 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.

引用

页码：1371 / 1386

页数：16

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