期刊
CELL
卷 150, 期 2, 页码 251-263出版社
CELL PRESS
DOI: 10.1016/j.cell.2012.06.024
关键词
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资金
- NHGRI [U54 HG003067]
- Melanoma Research Alliance
- University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence and Melanoma Informatics, Tissue Resource, and Pathology [P50 CA93459]
- NCI [CA-16672, R33CA126674, R01 CA093947]
- Canadian Institutes of Health Research
- Swiss National Science Foundation [PASMP3_134379/1]
- G. Harold and Leila Y. Mathers Charitable Foundation
- FWF-Austrian Science Fund [L590-B12]
- NIH [DP2OD002750]
- Starr Cancer Consortium
- TCGA GDAC [U24 CA143845]
- Milestein Innovation Award in Melanoma Research
- Novartis
- Austrian Science Fund (FWF) [L590] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [L 590] Funding Source: researchfish
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.
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