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

Ruth Halaban, Michael Krauthammer and colleagues report exome sequencing of 213 melanomas and identify a distinct co-mutation pattern of NF1 with known RASopathy genes. They identify novel melanoma mutations in several RASopathy genes and suggest that mutations in these genes may enhance the pathogenicity of NF1 mutation. 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.