Frequency of UV-Inducible NRAS Mutations in Melanomas of Patients With Germline CDKN2A Mutations

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Abstract
Background: Germline alterations in cyclin-dependent kinase inhibitor 2A (CDKN2A) are important genetic factors in familial predisposition to melanoma. Activating mutations of the NRAS proto-oncogene are among the most common somatic genetic alterations in cutaneous malignant melanomas. We investigated the occurrence of NRAS mutations in melanomas and dysplastic nevi in individuals with germline CDKN2A mutations. Methods: Genomic DNA was extracted from 39 biopsy samples (including primary melanomas, metastatic melanomas, and dysplastic nevi) from 25 patients in six Swedish families with a hereditary predisposition to melanoma who carried germline CDKN2A mutations. DNA was also extracted from 10 biopsy samples from patients with sporadic melanomas. NRAS was analyzed using polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequence analysis. Differences in NRAS mutation frequency between hereditary and sporadic melanomas were analyzed by the chi-square test. All statistical tests were two-sided. Results: Activating mutations in NRAS codon 61, all of which were either CAA(Gln)-AAA(Lys) or CAA(Gln)-CGA(Arg) mutations, were found in 95% (20/21) of primary hereditary melanomas but in only 10% (1/10) of sporadic melanomas (P<.001). Multiple activating NRAS mutations were detected in tumor cells from different regions of individual primary melanomas in nine patients. Activating mutations that were detected in the primary melanomas of these patients were also retained in their metastases. NRAS mutations at sites other than codon 61 were also present in the primary melanomas, indicating genetic instability of this locus. NRAS codon 61 mutations were also detected in dysplastic nevi and in an in situ melanoma, suggesting a role for such mutations during early melanoma development. Conclusions: The high frequency of NRAS codon 61 mutations detected in these hereditary melanomas may be the result of a hypermutability phenotype associated with a hereditary predisposition for melanoma development in patients with germline CDKN2A mutations.