NRAS Hypermutability in Familial Melanoma With CDKN2A Mutations—Cause and Effect?

The frequency of cutaneous melanoma has been increasing worldwide for several decades. Approximately 8%–12 % of melanomas occur in individuals with a history of cutaneous melanoma in a blood relative. Germline mutations in the CDKN2A tumor suppressor gene have been identified in approximately 20 % of familial melanoma families, including many with dys-plastic nevi (DN) (1). The CDKN2A region of chromosome 9p21 codes for p16 (INK4A), which functions in the retinoblas-toma (Rb) protein cell-cycle control pathway, and also p14ARF, the product of an alternatively spliced transcript, which partici-pates in the p53-mediated cell-cycle control pathway. Melanoma cell lines that do not express p16, or that express a mutant form of p16, do not show the normal G2 cell-cycle delay after UV exposure (2). In this issue of the Journal, Eskandarpour et al. (3) describe a study in which NRAS mutations in melanomas fro