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Key Points

  • Disease summary:

    • The genetics of hereditary skin cancer susceptibility syndromes is complex and expression is influenced by confounding environmental factors, including solar ultraviolet radiation, as well as other genetic factors.

    • Hereditary melanoma is characterized by the presence of multiple diagnoses of cutaneous melanoma within a family. In addition, an increased risk for other types of cancer, including pancreatic cancer, has been observed in some families with hereditary melanoma.

  • Hereditary basis:

    • Germline mutations in the CDKN2A gene are estimated to account for approximately 20% to 40% of hereditary melanoma. Mutations in the CDK4 gene are uncommon and have been detected in a small number of hereditary melanoma families.,

    • Although the penetrance is complicated by environmental and confounding genetic factors, CDKN2A and CDK4 gene mutations are generally considered to be associated with an autosomal dominant pattern of inheritance with variable penetrance.

    • Geographic location has been associated with variable CDKN2A expression. A study of CDKN2A carriers with positive family histories of melanoma estimated the risk of developing melanoma by age 80 in CDKN2A carriers to be 58% in Europe, 76% in the United States, and 91% in Australia. This difference has been attributed to environmental influences as well as other inherited factors.

  • Other cancer susceptibility syndromes associated with high skin cancer risk:

    • In addition to CDKN2A and CDK4, other hereditary syndromes have been associated with a highly increased susceptibility for skin cancer (Table 107-1).

Table 107-1Other High-Risk Hereditary Skin Cancer Susceptibility Syndromes4,5

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