Purpose: Mutations in the ras genes often occur during tumorigenesis. In malignant melanoma, the most common ras alterations are N-ras codon 61 mutations. This study was aimed to measure the frequency of such mutations in a large series of paired primary and metastatic melanomas to determine their role in melanoma initiation and progression.
Experimental design: Seventy-four primary melanomas and 88 metastases originating from 54 of the primary tumors were screened for N-ras codon 61 mutations using single-strand conformation polymorphism and nucleotide sequence analyses.
Results: Twenty-one of the 74 primary tumors (28%) had activating N-ras codon 61 mutations. From 20 of the mutated primary tumors, a total of 34 metastases were analyzed, and all but one showed the same mutation as the primary tumor from which they originated. The remaining 53 primary tumors and corresponding metastases (n = 54) were wild-type for N-ras codon 61. Analysis of the different growth phases of the mutated primary tumors showed that the mutations were already present in the radial growth phase. Mutations were also detected in tumor-associated nevi. N-ras codon 61 mutations were associated with a higher Clark level of invasion (P = 0.012) and a lower age at diagnosis (P = 0.042) but did not affect survival (P = 0.671).
Conclusions: This study shows that N-ras codon 61 mutations occur early in primary melanomas rather than in the metastatic stage and that once the mutations have occurred, they persist throughout tumor progression. This suggests that activated N-ras may be an attractive target for therapy in the subset of melanoma patients carrying such mutations.