Ras gene mutations: a rare event in nonmetastatic primary malignant melanoma

Ras gene mutations have been implicated in the pathogenesis of a variety of human tumors. Mutated ras genes have been isolated from human melanoma cell lines, but subsequent studies indicated that ras gene mutations may be a rare event in melanocytic lesions. Recently, a study reported a high frequency of ras mutations correlated with increasing invasion level. To address this inconsistency in the published data, we analyzed 50 primary melanomas to correlate invasion level, tumor thickness, histologic typing, and body localization with point mutations around codons 12/13/61 of the three ras genes. After micro-dissection of paraffin-embedded tumor tissue, ras gene mutations were analyzed by direct sequencing of tumor DNA amplified by polymerase chain reaction. Only two melanomas exhibited ras gene mutations, one sample containing a transition from A to G at position 2 of N-ras codon 61 and the other exhibiting a transversion from C to A at position 1 and a transition from A to G at position 2 of N-ras codon 61. Both tumors were classified as Clark level IV, with a tumor thickness of 2.5 and 1.2 mm, respectively. Both were typed as superficial spreading melanoma and localized to intermittently sun-exposed body sites. The low frequency of ras mutations in malignant melanoma and the lack of ras mutations in melanoma samples from constantly sun-exposed body sites argue against the hypothesis of ras mutations as a marker of progression in malignant melanoma and the suggestion that ras mutations occur predominantly in melanomas from constantly sun-exposed body sites.