Type II Enteropathy-associated T-cell Lymphoma Features a Unique Genomic Profile with Highly Recurrent SETD2 Alterations

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Sep 8

PMID 27600764

Citations 79

Authors

Annalisa Roberti

Maria Pamela Dobay

Bettina Bisig

David Vallois

Cloe Boechat

Evripidis Lanitis

Brigitte Bouchindhomme

Marie-Cecile Parrens

Celine Bossard

Leticia Quintanilla-Martinez

Edoardo Missiaglia

Philippe Gaulard

Laurence de Leval

Affiliations

Soon will be listed here.

Abstract

Enteropathy-associated T-cell lymphoma (EATL), a rare and aggressive intestinal malignancy of intraepithelial T lymphocytes, comprises two disease variants (EATL-I and EATL-II) differing in clinical characteristics and pathological features. Here we report findings derived from whole-exome sequencing of 15 EATL-II tumour-normal tissue pairs. The tumour suppressor gene SETD2 encoding a non-redundant H3K36-specific trimethyltransferase is altered in 14/15 cases (93%), mainly by loss-of-function mutations and/or loss of the corresponding locus (3p21.31). These alterations consistently correlate with defective H3K36 trimethylation. The JAK/STAT pathway comprises recurrent STAT5B (60%), JAK3 (46%) and SH2B3 (20%) mutations, including a STAT5B V712E activating variant. In addition, frequent mutations in TP53, BRAF and KRAS are observed. Conversely, in EATL-I, no SETD2, STAT5B or JAK3 mutations are found, and H3K36 trimethylation is preserved. This study describes SETD2 inactivation as EATL-II molecular hallmark, supports EATL-I and -II being two distinct entities, and defines potential new targets for therapeutic intervention.

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