A landscape of driver mutations in melanoma

Eran Hodis, 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 WincklerKristin 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1995 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)251-263
Number of pages13
Issue number2
StatePublished - Jul 20 2012
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


Dive into the research topics of 'A landscape of driver mutations in melanoma'. Together they form a unique fingerprint.

Cite this