Low prevalence of germline CDKN2A and CDK4 mutations in patients with early-onset melanoma

Background: In patients with cutaneous melanoma, early age at disease onset is characteristic in familial cases and in individuals with multiple prima ry melanomas. Both subsets of patients with melanoma are at risk for harbor ing germline CDKN2A or CDK4 mutations. Objective: We set out to prospectively determine the prevalence of CDKN2A a nd CDK4 mutations in a group of young patients with melanoma. Design: We prospectively screened 913 patients over a 6-month period and id entified 519 patients with invasive melanomas. We invited 172 patients with melanoma who were younger than 40 years to participate in the study, and 4 9 patients consented and donated peripheral blood samples. Forty-nine perce nt (n=24) of our patients developed cutaneous melanoma before the age of 30 years. Setting: A melanoma clinic in the Boston, Mass, area. Main Outcome Measurer We used a combination of single-strand conformation a nalysis and direct sequencing of samples of peripheral blood leukocyte DNA to search for mutations in exons 1 alpha, 1 beta, 2, and 3 of CDKN2A and in exon 2 of CDK4. Results: The mean and median ages at diagnosis in our group were 30 and 32 years, respectively. Among a group of 49 patients, we detected 1 (2%; 95% c onfidence interval, 0.07%-10.8%) Met 53 Ile CDKN2A mutation, which was foun d in a patient xith a strong family history of melanoma. This alteration ha s been previously shown to impair p16 function. One patient had an Ala 148 Thr change in CDKN2A, which has also been shown to be a polymorphism. We al so detected a sequence polymorphism tin the 3' untranslated region [3'UTR] of CDKN2A) in 27% of our patients. A similar incidence of this 3'UTR polymo rphism was observed in a control population. We found no CDK4 mutations. Conclusions: Germline CDKN2A and CDK4 mutations are not common in patients who develop melanoma at an early age. This finding contrasts with ether can cer-predisposition syndromes, in which there is an increased incidence of g ermline mutations among young patients. Selection of patients with melanoma for genetic testing based solely on age at onset may not be warranted at t he current time.