Somatic structural variants drive distinct modes of oncogenesis in melanoma

• Published in: The Journal of clinical investigation Vol. 134; no. 13; pp. 1 - 14
• Main Authors: Conway, Jake R., Gillani, Riaz, Crowdis, Jett, Reardon, Brendan, Park, Jihye, Han, Seunghun, Titchen, Breanna, Benamar, Mouadh, Haq, Rizwan, Van Allen, Eliezer M.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2024
• Subjects: Analysis; Cancer; Carcinogenesis; Carcinogenesis - genetics; Care and treatment; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell viability; Chromosomes; Diagnosis; Double-strand break repair; Gene frequency; Genes; Genetic aspects; Genomes; Genomic analysis; Genomic Structural Variation - genetics; Humans; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; MRE11 Homologue Protein - genetics; MRE11 Homologue Protein - metabolism; MRE11 protein; Mutagenesis; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tumorigenesis; Tumors; United States; Massachusetts; Oncology; DNA repair; Melanoma; Cancer
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI177270

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.