Molecular profiling of driver events in metastatic uveal melanoma.
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
Mice
Mutation
Neoplasms, Second Primary
/ genetics
Prognosis
Sequence Analysis, DNA
Transcriptome
Tumor Suppressor Proteins
/ genetics
Ubiquitin Thiolesterase
/ genetics
Uveal Neoplasms
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 04 2020
20 04 2020
Historique:
received:
02
07
2019
accepted:
19
03
2020
entrez:
22
4
2020
pubmed:
22
4
2020
medline:
5
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32313009
doi: 10.1038/s41467-020-15606-0
pii: 10.1038/s41467-020-15606-0
pmc: PMC7171146
doi:
Substances chimiques
BAP1 protein, human
0
CDKN2A protein, human
0
Cyclin-Dependent Kinase Inhibitor p16
0
Tumor Suppressor Proteins
0
Ubiquitin Thiolesterase
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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