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,Chong K,Morton DL,Stemke-Hale K,Chen G,Noble M,Meyerson M,Ladbury JE,Davies MA,Gershenwald JE,Wagner SN,Hoon DS,Schadendorf D,Lander ES,Gabriel SB,Getz G,Garraway LA and 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.