Details

Autor(en) / Beteiligte

• Conway, Jake R
• Gillani, Riaz
• Crowdis, Jett
• Reardon, Brendan
• Park, Jihye
• Han, Seung Hun
• Titchen, Breanna M
• Benamar, Mouadh
• Haq, Rizwan
• Van Allen, Eliezer M

Titel

Somatic structural variants drive distinct modes of oncogenesis in melanoma

Ist Teil von

• The Journal of clinical investigation, 2024-07, Vol.134 (13), p.1-14

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2024

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histological 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 role of topologically associated domain (TAD) boundary altering SVs on cancer-related genes. 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 PARPi in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact.