Molecular genetic aspects of cutaneous melanoma

The etiopathogenesis of cutaneous melanoma has been correlated to both genetic and environmental factors. During the last decade, molecular-genetic studies have demonstrated that high-penetrance genes such as cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase (CDK4), and low-penetrance genes such as MC1R play an important role in the pathogenesis of melanoma. CDKN2A and CDK4 genes function as cell cycle regulators, while MC1R gene is an important determinant of cutaneous pigmentation. Several studies have emphasized that CDKN2A gene, a tumor suppressor gene located at 9p21, has a crucial role in the development of familial, multiple and sporadic melanoma. Germline mutations of the CDKN2A gene have been identified in approximately 25-40% of familial melanoma kindreds worldwide and in 8-20% of patients with multiple primary melanoma (MPM). In contrast, somatic mutations of the CDKN2A gene have been frequently identified in sporadic melanoma. Mutations of the CDK4 oncogene have been described at a low frequency in familial and sporadic melanoma, and no alterations have been identified in patients with MPM. Recent studies showed that specific allelic variants of the MC1R gene confer susceptibility to melanoma and modify the risk of developing melanoma in patients who harbor CDKN2A mutations. Finally, based on the low number of studies, it is not yet clear the precise role of some putative oncogene or tumor suppressor genes located on chromosomes 1, 6, 7, 10, 11 and 17, which have been previously shown to be altered in cutaneous melanoma.