Somatic structural variants drive distinct modes of oncogenesis in melanoma.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38758740.
- Also identified by DOI 10.1172/JCI177270 and PMC identifier 11213511.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histologic and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the impact on cancer-related genes of SVs that alter topologically associated domain (TAD) boundaries. Following our prior identification of double-stranded break repair deficiency in a subset of triple-wild-type cutaneous melanoma, we identified MRE11 and NBN loss-of-function SVs in melanomas with this mutational signature. Experimental knockouts of MRE11 and NBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARP inhibitors in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact.
Medical subject headings
- Melanoma