Ultraviolet radiation cooperates with individual oncogenes to drive melanomagenesis through distinct molecular mechanisms

VIROS A, PEDERSEN M, FURNEY SJ, GIROTTI MR, SATURNO G, GALVANI G, SANCHEZ-LAORDEN B, HOGAN K, NG C, REIS-FILHO J, LORIGAN P, COOK M, MARAIS R.

NEW ORLEANS

Conferencia; AACR Annual Meeting 2016; 2016

In this study we show excessive sun exposure and NRAS-driven melanoma can co-occur by juxtaposing the epidemiological, clinical and genetic characteristics of a G12DNRAS-driven human melanoma case subject to extreme UVR exposure. To model the interaction of UVR with specific oncogenes and mimic human disease, we used mouse melanoma models driven by V600EBRAF or G12DNRAS. We previously reported that UVR cooperates with V600EBRAF by targeting the tumour suppressor TP53. In this study we confirm that UVR cooperates with G12DNRAS to drive melanoma and, as observed in humans, murine UVR-G12DNRAS melanoma occurs in older animals that accumulate higher lifetime exposure to UVR. Furthermore, we find murine UVR-G12DNRAS melanomas are histologically and genetically heterogeneous, and distinct to UVR-V600EBRAF murine and human melanomas. UVR-G12DNRAS melanomas present more UVR-induced mutations, a longer latency to tumour development and secondary driver mutations distinct from UVR-V600EBRAF melanoma. We investigated whether UVR cooperates equally with other RAS isoforms, and exposed G12DKRAS animals to UVR. These animals presented a different latency to melanoma development and specific cooperating secondary targets distinct from UVR-V600EBRAF and UVR- G12DNRAS. This implies that different RAS isoforms activate oncogenic pathways differently. Critically, UVR-V600EBRAF, UVR-G12DNRAS, UVR-G12DKRAS tumors present similar mutation rates when UVR exposure is held constant, which suggests that the differences in tumour latency might be explained if melanomas driven by different oncogenes require varying numbers of subsequent co-operators.Finally, we present preclinical evidence showing how targeting the UVR-induced mutations found in the ?long tail? of UVR-related mutations in NRAS melanoma can provide therapeutic options for NRAS mutant melanoma patients.The insight gained begins to provide a molecular explanation for distinct associations between UVR and individual oncogenes in melanomagenesis, and we show how UVR-induced damage can be exploited to stratify patients for personalised therapy approaches.