Melanoma genetics: An update with focus on the CDKN2A(p16)/ARF tumor suppressors

Investigative interest in atypical nevi and familial melanoma has contribut ed to the identification of several candidate melanoma loci within the huma n genome. Molecular defects in both tumor suppressor genes and oncogenes ha ve been pathogenically linked to melanoma in recent studies. Of the loci cu rrently characterized, the major gene resides on chromosome 9p and encodes a tumor suppressor designated p16. This gene, which is also known as CDKN2A , is either mutated or deleted in a large majority of melanoma cell lines, as well as in many uncultured melanoma cells and in the germline of melanom a kindreds. A novel aspect of the p16 locus is that it encodes not just one but two separate gene products that are transcribed in alternative reading frames. Both products function as negative regulators of cell cycle progre ssion. The p16 protein itself executes its effects by competitively inhibit ing cyclin-dependent kinase 4, which is a factor necessary for cellular pro gression through a major regulatory transition of the cell division cycle. Inherited and acquired deletions or point mutations in the p16 gene increas e the likelihood that potentially mutagenic DNA damage will escape repair b efore cell division. Notably, the second product of the locus, ARF (for alt ernative reading frame), regulates cell growth through independent effects on the p53 pathway. Although there is little evidence that ARF by itself is involved in the pathogenesis of melanoma, deletions at the p16 locus disab le two separate pathways that control cell growth. These recent advances op en up the possibility of genetic testing for melanoma susceptibility in the setting of familial melanoma and suggest novel therapeutic strategies for melanoma based on gene therapy or small molecule mimicry targeted to the co rrection of defects in the p16 regulatory pathway.