|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Hodis, E, Watson, IR, Kryukov, GV, Arold, ST, Imielinski, M, Theurillat, JP, Nickerson, E, Auclair, D, Li, L, Place, C, Dicara, D, Ramos, AH, Lawrence, MS, Cibulskis, K, Sivachenko, A, Voet, D, Saksena, G, Stransky, N, Onofrio, RC, Winckler, W, Ardlie, K, Wagle, N, Wargo, J, Stemke-Hale, K, Noble, M, Meyerson, M, Davies, MA, Wagner, SN, Schadendorf, D, Lander, ES, Gabriel, SB, Getz, G, Garraway, LA, Chin, L|
Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.