Genetics update: Cutaneous malignant melanoma and melanocytic nevi

Although the first English-language report describing melanoma in 1820 contained a description of a melanoma-prone family, it was the seminal studies of investigators at the National Cancer Institute (NCI) and the University of Pennsylvania that identified dysplastic nevi as an important precursor to melanoma, suggested an autosomal dominant mode of inheritance for both melanoma and dysplastic nevi, and proposed that a melanoma susceptibility gene (CMM1) was located on chromosome 1p36. This gene assignment has not yet been confirmed by independent investigators. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed independently, and the cell cycle regulator p16(INK4a) has been proposed as a candidate gene, and germline mutations in this gene have been identified in about half of melanoma-prone families. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have recently been described in two melanoma kindreds, and this likely represents a third melanoma gene. A heritable determinant for total nevus number has been suggested, as has the presence of a major gene responsible for total nevus density in melanoma-prone families. Dysplastic nevi cluster in families, and an autosomal dominant mode of inheritance for dysplastic nevi, has been proposed, and evidence developed that dysplastic nevi may be a pleiotropic manifestation of the 1p36 familial melanoma gene.