Molecular profiling of driver events in metastatic uveal melanoma.

Karlsson J, Nilsson LM, Mitra S, Alsén S, Shelke GV, Sah VR, Forsberg EMV, Stierner U, All-Eriksson C, Einarsdottir B, Jespersen H, Ny L, Lindnér P, Larsson E, Olofsson Bagge R, Nilsson JA

Nat Commun 11 (1) 1894 [2020-04-20; online 2020-04-20]

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.

NGI Stockholm (Genomics Applications) [Service]

NGI Stockholm (Genomics Production) [Service]

National Genomics Infrastructure [Service]

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PubMed 32313009

DOI 10.1038/s41467-020-15606-0

Crossref 10.1038/s41467-020-15606-0

10.1038/s41467-020-15606-0

pmc PMC7171146