CDKN2A

Gene

Metastasis

Biology

BAP1

TIGIT

Immune checkpoint

Primary tumor

Cancer research

Melanoma

Immunology

Genetics

Transcriptome

Immune system

Gene knockdown

Medicine

Immunotherapy

Tumor-infiltrating lymphocytes

Gene expression profiling

Disease

Cancer

Gene expression

Pathology

Nature Communications

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.

Molecular profiling of driver events in metastatic uveal melanoma