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Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.
- Source :
-
Nature genetics [Nat Genet] 2015 Sep; Vol. 47 (9), pp. 996-1002. Date of Electronic Publication: 2015 Jul 27. - Publication Year :
- 2015
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 47
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 26214590
- Full Text :
- https://doi.org/10.1038/ng.3361