title: Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.
abstract: We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Michael
authors: M
authors: Krauthammer
authors: Yong
authors: Y
authors: Kong
authors: Byung Hak
authors: BH
authors: Ha
authors: Perry
authors: P
authors: Evans
authors: Antonella
authors: A
authors: Bacchiocchi
authors: James P
authors: JP
authors: McCusker
authors: Elaine
authors: E
authors: Cheng
authors: Matthew J
authors: MJ
authors: Davis
authors: Gerald
authors: G
authors: Goh
authors: Murim
authors: M
authors: Choi
authors: Stephan
authors: S
authors: Ariyan
authors: Deepak
authors: D
authors: Narayan
authors: Ken
authors: K
authors: Dutton-Regester
authors: Ana
authors: A
authors: Capatana
authors: Edna C
authors: EC
authors: Holman
authors: Marcus
authors: M
authors: Bosenberg
authors: Mario
authors: M
authors: Sznol
authors: Harriet M
authors: HM
authors: Kluger
authors: Douglas E
authors: DE
authors: Brash
authors: David F
authors: DF
authors: Stern
authors: Miguel A
authors: MA
authors: Materin
authors: Roger S
authors: RS
authors: Lo
authors: Shrikant
authors: S
authors: Mane
authors: Shuangge
authors: S
authors: Ma
authors: Kenneth K
authors: KK
authors: Kidd
authors: Nicholas K
authors: NK
authors: Hayward
authors: Richard P
authors: RP
authors: Lifton
authors: Joseph
authors: J
authors: Schlessinger
authors: Titus J
authors: TJ
authors: Boggon
authors: Ruth
authors: R
authors: Halaban
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics*; D014604:Uveal Neoplasms / Q000453:epidemiology / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000235:genetics*; D000098943:Uveal Melanoma
chemical_list: C107953:RAC1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D020830:rac1 GTP-Binding Protein