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A landscape of driver mutations in melanoma |
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| Authors: | 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 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 |
| Institution: | 1 The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA 2 Harvard Medical School, Boston, MA 02115, USA 3 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 4 Department of Biochemistry and Molecular Biology and Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 5 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 6 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 7 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 8 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 9 Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA 11 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA 12 Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA 13 Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA 14 Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA 15 Melanoma Department, John Wayne Cancer Institute, Santa Monica, CA 90404, USA 16 Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna and CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria 17 Department of Dermatology, University Hospital Essen, 45122 Essen, Germany 18 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA |
| 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. |
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