title: A landscape of driver mutations in melanoma.
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.
authors: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Eran
authors: E
authors: Hodis
authors: Ian R
authors: IR
authors: Watson
authors: Gregory V
authors: GV
authors: Kryukov
authors: Stefan T
authors: ST
authors: Arold
authors: Marcin
authors: M
authors: Imielinski
authors: Jean-Philippe
authors: JP
authors: Theurillat
authors: Elizabeth
authors: E
authors: Nickerson
authors: Daniel
authors: D
authors: Auclair
authors: Liren
authors: L
authors: Li
authors: Chelsea
authors: C
authors: Place
authors: Daniel
authors: D
authors: Dicara
authors: Alex H
authors: AH
authors: Ramos
authors: Michael S
authors: MS
authors: Lawrence
authors: Kristian
authors: K
authors: Cibulskis
authors: Andrey
authors: A
authors: Sivachenko
authors: Douglas
authors: D
authors: Voet
authors: Gordon
authors: G
authors: Saksena
authors: Nicolas
authors: N
authors: Stransky
authors: Robert C
authors: RC
authors: Onofrio
authors: Wendy
authors: W
authors: Winckler
authors: Kristin
authors: K
authors: Ardlie
authors: Nikhil
authors: N
authors: Wagle
authors: Jennifer
authors: J
authors: Wargo
authors: Kelly
authors: K
authors: Chong
authors: Donald L
authors: DL
authors: Morton
authors: Katherine
authors: K
authors: Stemke-Hale
authors: Guo
authors: G
authors: Chen
authors: Michael
authors: M
authors: Noble
authors: Matthew
authors: M
authors: Meyerson
authors: John E
authors: JE
authors: Ladbury
authors: Michael A
authors: MA
authors: Davies
authors: Jeffrey E
authors: JE
authors: Gershenwald
authors: Stephan N
authors: SN
authors: Wagner
authors: Dave S B
authors: DS
authors: Hoon
authors: Dirk
authors: D
authors: Schadendorf
authors: Eric S
authors: ES
authors: Lander
authors: Stacey B
authors: SB
authors: Gabriel
authors: Gad
authors: G
authors: Getz
authors: Levi A
authors: LA
authors: Garraway
authors: Lynda
authors: L
authors: Chin
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D059472:Exome; D055106:Genome-Wide Association Study; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016415:Sequence Alignment; D014466:Ultraviolet Rays; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: C107953:RAC1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020830:rac1 GTP-Binding Protein