INFREQUENT MUTATION OF P16(INK4) IN SPORADIC MELANOMA

Loss of heterozygosity of chromosome region 9p21 occurs commonly and e arly in sporadic melanoma, suggesting the involvement of a tumor suppr essor gene at this locus in the pathogenesis of this neoplasm. Althoug h germline mutations and deletions of the p16(INK4) gene located at 9p 21 have been reported in familial melanoma, the relative contributions of mutation and deletion in sporadic melanoma are at present unclear. In this study, we investigated 26 cases of sporadic cutaneous melanom a (14 of which demonstrated loss of heterozygosity at 9p21) for mutati ons of p16(INK4). One tumor with allelic loss of 9p contained a CC --> TT mutation at codons 57/58, altering an arginine to a stop codon, co nsistent with bi-allelic inactivation of p16(INK4) in this case. No mu tations were identified in any of the other melanomas, or in one benig n intradermal nevus with atypical features and two Spitz nevi that als o showed loss of heterozygosity of 9p. The inactivation of both copies of p16(INK4) in the one case of melanoma adds support to the theory t hat p16(INK4) is important in the development of sporadic cutaneous me lanoma, although allelic loss or other methods of inactivation of p16( INK4) rather than point mutation appears to be numerically more import ant. The low frequency of mutation of p16(INK4) cases of sporadic mela noma with loss of heterozygosity of 9p is, however, also consistent wi th there being another tumor suppressor gene near this locus that is i nvolved in some cases of sporadic melanoma.