Germline CDKN2A coding mutations are rare in the majority of cutaneous melanoma patients. M.L. Council¹, J. Gardner¹, J. Ivanovich², C. Kamp², L. Cornelius³, A. Bowcock¹. 1) Dept Human Genetics, Washington Univ, St Louis, MO; 2) Hereditary Cancer Core, Washington Univ, St Louis, MO; 3) Div of Dermatology, Washington Univ, St Louis, MO.
   Malignant melanoma is the most serious form of skin cancer, and its incidence has tripled in Europeans over the past 30 years. Intensive, episodic UV-exposure is felt to be contributory to this process. Rare germline mutations of CDKN2A, a tumor suppressor located at 9p21, are detected in affected members of some families where cutaneous melanoma is segregating. We have begun a genetic study of cutaneous melanoma at Washington University School of Medicine (St. Louis, Missouri). DNA from a cohort of 110 patients is currently available. These include 75 female and 35 male patients; all are of European origin. Twenty-two patients have at least one other first, second, or third-degree relative with melanoma. The majority (85%) of patients have a first, second, or third-degree relative with a second cancer: breast (40%), lung (27%), and colorectal (25%), most commonly. All patients have been screened for variants in CDKN2A and the overlapping p14 gene with dHPLC and/or direct sequencing. Only one germline mutation was detected within the coding region of CDKN2A (D125H); this mutation has been previously described. As this patient was adopted, we have no additional family history. Two patients had intronic variants of undetermined significance, and one patient harbored an A134A silent change. In summary, less than 1% of our cohort of melanoma patients were found to have a mutation altering the coding sequence of CDKN2A, although 20% of patients have a first, second, or third degree relative with melanoma. This is in agreement with other studies. It suggests that CDKN2A mutations are rare in the majority of melanoma patients and that a search for other susceptibility genes is warranted.