A Landscape of Driver Mutations in Melanoma
Author(s)Lander, Eric S.; Hodis, Eran; Watson, Ian R.; Kryukov, Gregory V.; Arold, Stefan T.; Imielinski, Marcin; Theurillat, Jean-Philippe; Nickerson, Elizabeth; Auclair, Daniel; Li, Liren; Place, Chelsea; DiCara, Daniel; Ramos, Alex H.; Lawrence, Michael S.; Cibulskis, Kristian; Sivachenko, Andrey; Voet, Douglas; Saksena, Gordon; Stransky, Nicholas; Onofrio, Robert; ... Show more Show less
MetadataShow full item record
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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Hodis, Eran, Ian R. Watson, Gregory V. Kryukov, Stefan T. Arold, Marcin Imielinski, Jean-Philippe Theurillat, Elizabeth Nickerson, et al. “A Landscape of Driver Mutations in Melanoma.” Cell 150, no. 2 (July 2012): 251-263. Copyright © 2012 Elsevier Inc.
Final published version