Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations

Annalisa Roberti, Maria Pamela Dobay, Bettina Bisig, David Vallois, Cloé Boéchat, Evripidis Lanitis, Brigitte Bouchindhomme, Marie- Cécile Parrens, Céline Bossard, Leticia Quintanilla-Martinez, Edoardo Missiaglia, Philippe Gaulard and Laurence de Leval ()
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Annalisa Roberti: University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois
Maria Pamela Dobay: SIB Swiss Institute of Bioinformatics – Quartier Sorge, bâtiment Génopode
Bettina Bisig: University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois
David Vallois: University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois
Cloé Boéchat: University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois
Evripidis Lanitis: Ludwig Cancer Research Center Lausanne
Brigitte Bouchindhomme: Institute of Pathology, CHR-U de Lille/Université de Lille II
Marie- Cécile Parrens: CHU de Bordeaux, Hopital du Haut Lévêque
Céline Bossard: CHU de Nantes – Hôtel Dieu
Leticia Quintanilla-Martinez: Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen
Edoardo Missiaglia: University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois
Philippe Gaulard: Hôpital Henri Mondor, AP-HP, INSERM U955, and University Paris-Est
Laurence de Leval: University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12602

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