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Molecular profiling of driver events in metastatic uveal melanoma

Author

Listed:
  • Joakim Karlsson

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Lisa M. Nilsson

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Suman Mitra

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Samuel Alsén

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Ganesh Vilas Shelke

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Vasu R. Sah

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Elin M. V. Forsberg

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Ulrika Stierner

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Charlotta All-Eriksson

    (St. Erik Eye Hospital)

  • Berglind Einarsdottir

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Henrik Jespersen

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Lars Ny

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Per Lindnér

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Erik Larsson

    (University of Gothenburg)

  • Roger Olofsson Bagge

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

  • Jonas A. Nilsson

    (Institute of Clinical Sciences at University of Gothenburg and Sahlgrenska University Hospital)

Abstract

Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations are overrepresented and found in 29/32 of cases. Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease. One outlier tumor has a high mutational burden associated with UV-damage. CDKN2A deletions also occur, which are rarely present in primaries. A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains. Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 is also abundant. This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease.

Suggested Citation

  • Joakim Karlsson & Lisa M. Nilsson & Suman Mitra & Samuel Alsén & Ganesh Vilas Shelke & Vasu R. Sah & Elin M. V. Forsberg & Ulrika Stierner & Charlotta All-Eriksson & Berglind Einarsdottir & Henrik Jes, 2020. "Molecular profiling of driver events in metastatic uveal melanoma," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15606-0
    DOI: 10.1038/s41467-020-15606-0
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