To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.
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Special thanks to S. Rosenberg for providing the melanoma samples for the tissue array, R. Bonner and M. Mertts for the use of their Leica AS LMD Microscope and for advice regarding laser microdissection and D. Leja for assistance preparing figures. This work was supported in part by a grant from the Queensland Cancer Fund and the US National Institutes of Health (N.K.H. and M.S.) and an Australian National Health and Medical Research Council C.J. Martin Fellowship (to P.M.P.). These studies were approved by the institutional review boards of both Queensland Institute of Medical Research and the National Human Genome Research Institute, US National Institutes of Health. The National Human Genome Research Institute Institutional Review Board has approved the use of previously collected, stored tissue samples, which remain anonymous to protect individuals' confidentiality.
The authors declare no competing financial interests.
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Pollock, P., Harper, U., Hansen, K. et al. High frequency of BRAF mutations in nevi. Nat Genet 33, 19–20 (2003). https://doi.org/10.1038/ng1054
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