| Literature DB >> 22817889 |
Eran Hodis1, Ian R Watson, Gregory V Kryukov, Stefan T Arold, Marcin Imielinski, Jean-Philippe Theurillat, Elizabeth Nickerson, Daniel Auclair, Liren Li, Chelsea Place, Daniel Dicara, Alex H Ramos, Michael S Lawrence, Kristian Cibulskis, Andrey Sivachenko, Douglas Voet, Gordon Saksena, Nicolas Stransky, Robert C Onofrio, Wendy Winckler, Kristin Ardlie, Nikhil Wagle, Jennifer Wargo, Kelly Chong, Donald L Morton, Katherine Stemke-Hale, Guo Chen, Michael Noble, Matthew Meyerson, John E Ladbury, Michael A Davies, Jeffrey E Gershenwald, Stephan N Wagner, Dave S B Hoon, Dirk Schadendorf, Eric S Lander, Stacey B Gabriel, Gad Getz, Levi A Garraway, Lynda Chin.
Abstract
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.Entities:
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Year: 2012 PMID： 22817889 PMCID： PMC3600117 DOI： 10.1016/j.cell.2012.06.024
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582