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

Author

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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
    SIB Swiss Institute of Bioinformatics – Quartier Sorge, bâtiment Génopode)

  • 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)

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.

Suggested Citation

  • Annalisa Roberti & Maria Pamela Dobay & Bettina Bisig & David Vallois & Cloé Boéchat & Evripidis Lanitis & Brigitte Bouchindhomme & Marie- Cécile Parrens & Céline Bossard & Leticia Quintanilla-Martine, 2016. "Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12602
    DOI: 10.1038/ncomms12602
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