Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations.
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.
University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois, 25 rue du Bugnon, 1011 Lausanne, Switzerland.
Annalisa
A
Roberti
SIB Swiss Institute of Bioinformatics - Quartier Sorge, bâtiment Génopode, 1015 Lausanne, Switzerland.
Maria Pamela
MP
Dobay
University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois, 25 rue du Bugnon, 1011 Lausanne, Switzerland.
Bettina
B
Bisig
University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois, 25 rue du Bugnon, 1011 Lausanne, Switzerland.
David
D
Vallois
University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois, 25 rue du Bugnon, 1011 Lausanne, Switzerland.
Cloé
C
Boéchat
Ludwig Cancer Research Center Lausanne, Chemin des Boveresses 155, Biopôle III, 1066 Epalinges, Switzerland.
Evripidis
E
Lanitis
Institute of Pathology, CHR-U de Lille/Université de Lille II, Avenue Oscar Lambret, 59037 Lille Cedex, France.
Brigitte
B
Bouchindhomme
Department of Pathology, CHU de Bordeaux, Hopital du Haut Lévêque, Avenue Magellan, 33604 Pessac, France.
Marie-Cécile
MC
Parrens
Department of Pathology, CHU de Nantes - Hôtel Dieu, 9 quai Moncousu - Plateau technique 1, 44093 Nantes, France.
Céline
C
Bossard
Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen 72076, Germany.
Leticia
L
Quintanilla-Martinez
University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois, 25 rue du Bugnon, 1011 Lausanne, Switzerland.|SIB Swiss Institute of Bioinformatics - Quartier Sorge, bâtiment Génopode, 1015 Lausanne, Switzerland.
Edoardo
E
Missiaglia
Department of Pathology, Hôpital Henri Mondor, AP-HP, INSERM U955, and University Paris-Est, 51 Avenue du Mal de Lattre de Tassigny, 94010 Créteil, France.
Philippe
P
Gaulard
University Institute of Pathology, Service of Clinical Pathology, Centre Hospitalier Universitaire Vaudois, 25 rue du Bugnon, 1011 Lausanne, Switzerland.
Laurence
L
de Leval
D058527:Enteropathy-Associated T-Cell Lymphoma / Q000145:classification / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020022:Genetic Predisposition to Disease; D023281:Genomics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007414:Intestinal Neoplasms / Q000145:classification / Q000235:genetics*; D009154:Mutation
D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human