1. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.
- Author
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Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, McCusker JP, Ma S, Cheng E, Straub R, Serin M, Bosenberg M, Ariyan S, Narayan D, Sznol M, Kluger HM, Mane S, Schlessinger J, Lifton RP, and Halaban R
- Subjects
- Antineoplastic Agents pharmacology, Benzimidazoles pharmacology, DNA Mutational Analysis, Drug Resistance, Neoplasm, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Inhibitory Concentration 50, Kaplan-Meier Estimate, Loss of Heterozygosity, Male, Melanoma drug therapy, Melanoma etiology, Mutation, Missense, Sequence Analysis, RNA, Skin Neoplasms drug therapy, Skin Neoplasms etiology, Sunlight adverse effects, Tumor Cells, Cultured, ras Proteins genetics, Exome, Melanoma genetics, Neurofibromin 1 genetics, Skin Neoplasms genetics
- 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.
- Published
- 2015
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