Molecular profiling of driver events in metastatic uveal melanoma

Nat Commun. 2020 Apr 20;11(1):1894. doi: 10.1038/s41467-020-15606-0.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Female
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Lymphocytes
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Melanoma / genetics*
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mutation
  • Neoplasms, Second Primary / genetics*
  • Neoplasms, Second Primary / immunology
  • Neoplasms, Second Primary / metabolism
  • Neoplasms, Second Primary / pathology
  • Prognosis
  • Sequence Analysis, DNA
  • Transcriptome
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • Uveal Neoplasms / genetics*
  • Uveal Neoplasms / immunology
  • Uveal Neoplasms / metabolism
  • Uveal Neoplasms / pathology


  • BAP1 protein, human
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Uveal melanoma