Molecular profiling of driver events in metastatic uveal melanoma

• 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 ahigh 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 genesassociated 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. © 2020, The Author(s).

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

BRCA1 associated ring domain protein 1

CD39 antigen

cyclin dependent kinase inhibitor 2A

hepatitis A virus cellular receptor 2

programmed death 1 receptor

allele

cell

gene expression

genetic analysis

genome

mutation

skin

tumor

animal cell

animal experiment

animal model

animal tissue

Article

controlled study

cryopreservation

DNA sequencing

down regulation

female

flow cytometry

gene dosage

gene knockdown

gene mutation

genotyping technique

HLA typing

human

human tissue

immunohistochemistry

liquid chromatography-mass spectrometry

metastasis

metastatic uvea melanoma

molecular fingerprinting

mouse

nonhuman

protein expression

protein protein interaction

proteomics

real time reverse transcription polymerase chain reaction

single cell RNA seq

transcriptomics

tumor associated leukocyte

tumor biopsy

upregulation

whole genome sequencing

Publication and Content Type

ref (subject category)

art (subject category)