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Cell DOI:10.1016/j.cell.2012.06.024

A landscape of driver mutations in melanoma.

Publication TypeJournal Article
Year of Publication2012
AuthorsHodis, E, Watson, IR, Kryukov, GV, Arold, ST, Imielinski, M, Theurillat, J-P, 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, DSB, Schadendorf, D, Lander, ES, Gabriel, SB, Getz, G, Garraway, LA, Chin, L
JournalCell
Volume150
Issue2
Pages251-63
Date Published2012 Jul 20
ISSN1097-4172
KeywordsAmino Acid Sequence, Cells, Cultured, Exome, Genome-Wide Association Study, Humans, Melanocytes, Melanoma, Models, Molecular, Molecular Sequence Data, Mutagenesis, Proto-Oncogene Proteins B-raf, rac1 GTP-Binding Protein, Sequence Alignment, Ultraviolet Rays
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(12)00778-7
DOI10.1016/j.cell.2012.06.024
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22817889?dopt=Abstract

Alternate JournalCell
PubMed ID22817889
PubMed Central IDPMC3600117
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R01 CA093947 / CA / NCI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
DP2OD002750 / OD / NIH HHS / United States
DP2 OD002750 / OD / NIH HHS / United States
R33 CA126674 / CA / NCI NIH HHS / United States
R33CA126674 / CA / NCI NIH HHS / United States
P50 CA093459 / CA / NCI NIH HHS / United States