Role of the CDKN2A locus in patients with multiple primary melanomas

Purpose We have studied a consecutive case series of patients with multiple primary melanoma (MPM) for the involvement of the melanoma susceptibility loci CDKN2A and CDK4. Patients and Methods One hundred four MPM patients (81 patients with two primary melanomas, 14 with three, five with four, one with five, two with six, and one with seven) were included. Results Seven different CDKN2A germline mutations were identified in 17 patients (16.3%). In total, we identified 15 CDKN2A exon 2, one exon I a missense mutation, and one exon 1 beta frameshift mutation. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were more frequent in patients with familial history of melanoma (35.5%) compared with patients without (8.2%), with a relative risk (RR) of 4.32 (95% CI, 1.76 to 10.64; P = .001), and in patients with more than two melanomas (39.1%) compared with patients with only two melanomas (10%) with an RR of 3.29 (95% CI, 1.7 to 6.3; P = .002). The A148T polymorphisim was more frequent in patients with MPMs than in the control population (P = .05). A variant of uncertain significance, A127S, was also detected in one patient. No CDK4 mutations were identified, suggesting that it has a low impact in susceptibility to MPM. Conclusion MPM patients are good candidates for CDKN2A mutational screening. These patients and some of their siblings should be included in a program of specific follow-up with total body photography and digital dermoscopy, which will result in the early detection of melanoma in this subset of high-risk patients and improve phenotypic characterization.