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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.

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Figure 1: Melanoma mutational landscape (n = 213).
Figure 2: NF1 expression and NRAS activity.
Figure 3: Growth responses to selumetinib and SCH772984.
Figure 4: Changes in MEK1/2 and ERK phosphorylation in response to selumetinib.

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Acknowledgements

Research reported in this publication was supported by the Yale SPORE in Skin Cancer, funded by the National Cancer Institute, US National Institutes of Health, under award number 1 P50 CA121974 (R.H.); the Melanoma Research Alliance (Team award to R.H., M.B. and M.K.); Gilead Sciences, Inc. (J.S. and R.H.); the Howard Hughes Medical Institute (R.P.L.); the Department of Dermatology; and the Yale Comprehensive Cancer Center. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

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M.K. and R.H. designed and performed the research, analyzed and interpreted the data, and wrote the manuscript. R.P.L. and J.S. designed the experiments. A.B., E.C., R.S. and M. Serin conducted the experiments. M.K., Y.K., P.E., J.P.M., S. Mane and N.P. analyzed the data from whole-exome sequencing. S. Ma and C.W. performed statistical analysis. M.B. evaluated the tumor percentage in the clinical specimens. S.A., D.N., M. Sznol and H.M.K. provided the clinical specimens and clinical annotation, as well as input in writing the manuscript.

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Correspondence to Michael Krauthammer or Ruth Halaban.

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Krauthammer, M., Kong, Y., Bacchiocchi, A. et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet 47, 996–1002 (2015). https://doi.org/10.1038/ng.3361

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