Purpose of review: The clinical phenotypes of familial melanoma syndromes and genetic and environmental interactions are reviewed to summarize the current status of the field and to identify gaps in molecular and clinical investigations.
Recent findings: The familial melanoma syndromes are associated with germline mutations in three highly penetrant gene products: p16, alternate reading frame, and cyclin-dependent kinase 4. Certain variants in a low-penetrance gene, MC1R, the melanocortin 1 receptor gene, increase melanoma risk to a lesser extent and act as a genetic modifier when cosegregating with a deleterious p16 gene. The penetrance of these melanoma-predisposing genes is largely influenced by ultraviolet exposure across geographic latitude. Yet cumulative studies are conflicting on whether ultraviolet radiation, including sunburns, early childhood and adolescent sun exposure, and chronic exposure, increases melanoma risk in familial melanoma. To date, the clinical phenotypes of increased number of atypical nevi and nevi body distribution are independent risk factors for melanoma risk, regardless of family history. The atypical mole syndrome cannot reliably predict melanoma germline mutations but increases melanoma risk in p16 mutation carriers. Familial melanoma patients develop melanomas earlier and are prone to developing multiple primary melanomas. Other than these two differences, familial and sporadic melanoma share similar histopathology, prognostic factors, and survival rates.
Summary: Familial melanoma is an excellent human model system for the investigation of melanoma. Understanding genotype-phenotype and environmental relationships in familial melanoma will likely lead to improved understanding of pathogenesis for all melanoma patients.