P110 Mutational analysis of CDKN2A and CDK4 genes in a hospital-based series of Greek patients with melanoma

Background CDKN2A has been identified as a high penetrance melanoma susceptibility gene based on the presence of germline mutations in up to 25% of melanoma – prone families (FM) and in 15% of patients with multiple primary melanoma (MPM). The CDK4 gene represents an additional melanoma susceptibility locus, with activating mutations reported in a few families worldwide. Aim To investigate the CDKN2A and CDK4 genes for germline mutations in Greek patients with cutaneous melanoma. Methods We studied all melanoma cases diagnosed in a 5-year period at a melanoma referral center in Athens, Greece. Blood samples were collected and direct sequencing of the CDKN2A exons 1α, 1β, and 2 and of exon 2 of the CDK4 gene was performed. Results Three hundred fifty eight patients were diagnosed with invasive melanoma, including 16 patients belonging to 14 families with familial melanoma (3.9% of all cases) and 10 patients with MPM (2.8% of all cases). Two of the familial cases had multiple primaries as well. Genetic screening was done in 298 patients including 9 patients with FM and 7 patients with MPM. Overall, we detected germline CDKN2A mutations in 13 out of the 298 patetients (4.4%). Two of the 14 mutation carriers, were FM cases (2/9, 22.2%), and 4 had MPM (4/7, 57%). One familial case positive for CDKN2A mutation had MPM as well. The mutation rate of sporadic melanoma cases was 2.5% (7/282). The mutations detected included 4 missence mutations (R24P-8 cases, G101R-1 patient, G101E – 1 case, R87W- 1 case), a single Trp110Stop alteration and a novel C.41_43 deletion and insertion 20bp mutation in exon 1a. We also detected the G>T alteration at position -34 in the 5′UTR in one case. The A148 T polymorphism was detected in 24 patients (8%). Finally, an R24H substitution of the CDK4 gene was detected in 1 patient with FM and MPM. Conclusions Our results show that in the greek population, CDKN2A mutations occur more frequently in genetically predisposed groups as well as in sporadic melanoma cases compared to previously reported data. We showed a low rate of familial/multiple primary melanoma cases, but a higher than expected prevalence of CDKN2A/CDK4 mutations in these cases, suggesting a stronger influence of genetic mutations on melanoma-prone individuals in countries with a low incidence rate of the disease.