Abstract 4167: Ultraviolet radiation cooperates with individual oncogenes to drive melanomagenesis through distinct molecular mechanisms
Authors: Viros Amaya , Pedersen Malin , Furney Simon J. , Girotti Maria Romina , Saturno Grazia , Galvani Elena , Sanchez-Laorden Berta , Hogan Kate , Ng Charlotte , Reis-Filho Jorge S. , Lorigan Paul , Cook Martin , Marais Richard 
Published: July 2016

Abstract
The contribution ultraviolet radiation (UVR) makes to genetically distinct melanoma subtypes is unclear. Melanoma driven by oncogenic BRAF or oncogenic NRAS differ in their epidemiological, clinicopathological and genetic features. NRAS melanoma in humans occurs in older individuals and presents at sites most exposed to UVR damage such as the head and neck.
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.
Citation Format: Amaya Viros, Malin Pedersen, Simon J. Furney, Maria Romina Girotti, Grazia Saturno, Elena Galvani, Berta Sanchez-Laorden, Kate Hogan, Charlotte Ng, Jorge S. Reis-Filho, Paul Lorigan, Martin Cook, Richard Marais. Ultraviolet radiation cooperates with individual oncogenes to drive melanomagenesis through distinct molecular mechanisms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4167.