title: Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.
abstract: We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis.
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Krauthammer
authors.affiliation: Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yong
authors.identifier: 0000-0002-2881-5274
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchiocchi
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Perry
authors.initials: P
authors.lastname: Evans
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Natapol
authors.identifier: 0000-0002-3833-0537
authors.initials: N
authors.lastname: Pornputtapong
authors.affiliation: School of Public Health, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Cen
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jamie P.
authors.initials: JP
authors.lastname: McCusker
authors.affiliation: School of Public Health, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shuangge
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Cheng
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Straub
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Merdan
authors.initials: M
authors.lastname: Serin
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ariyan
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Narayan
authors.affiliation: Comprehensive Cancer Center Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.affiliation: Comprehensive Cancer Center Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Harriet M
authors.initials: HM
authors.lastname: Kluger
authors.affiliation: Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D059472:Exome; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D020125:Mutation, Missense; D025542:Neurofibromin 1 / Q000235:genetics*; D017423:Sequence Analysis, RNA; D012878:Skin Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D013472:Sunlight / Q000009:adverse effects; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D025542:Neurofibromin 1; D018631:ras Proteins