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Nat Genet. 2015 Sep;47(9):996-1002. doi: 10.1038/ng.3361. Epub 2015 Jul 27.

Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.

Author information

1
Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
3
Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA.
4
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
5
School of Public Health, Yale University School of Medicine, New Haven, Connecticut, USA.
6
Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
7
Comprehensive Cancer Center Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USA.
8
Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, Connecticut, USA.
9
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
10
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
11
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.

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.

PMID:
26214590
PMCID:
PMC4916843
DOI:
10.1038/ng.3361
[Indexed for MEDLINE]
Free PMC Article
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