Etiology and Clinical Features of Hereditary Melanoma Syndrome

There are approximately 70,000 new cases of melanoma in the United States each year, and the incidence continues to rise.131 Increased surveillance is critical to the prevention, early detection and treatment of melanoma in patients at increased risk.  Approximately 10% of melanoma cases are hereditary.280-281 Several genes have been associated with hereditary melanoma, including CDKN2A and CDK4.  The CDKN2A gene encodes for two proteins p16INK4a (also called p16) and p14ARF.  Mutations in CDKN2A account for 20-40% of hereditary melanoma cases.280  CDK4 gene mutations may account for approximately 2% and unknown, or as yet unidentified genes, account for the remainder of hereditary melanoma cases.282-283  In the United States, p16 mutations are likely responsible for approximately 1400-2800 new melanoma cases each year.  Therefore, mutations in the p16 gene are the most significant known cause of hereditary melanoma.  Additionally, p16 mutations are associated with an increased risk for pancreatic cancer in some families.

The CDKN2A gene is a tumor suppressor gene involved in regulating cell growth.  Mutations in p16 that disrupt its function lead to unregulated cell growth.  Thep16 gene was identified through family linkage studies and is located on chromosome 9p21.132 Hereditary Melanoma, caused by mutations in the p16 gene, is inherited in an autosomal dominant pattern.