Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF

Summary Background Nearly 10% of all cases of cutaneous melanoma (CM) occur in patients with a personal or family history of the disease. Objectives To obtain information about genetic predisposition to CM in Ticino, the southern region of Switzerland, a zone with moderate‐to‐high CM incidence. Methods We identified germline mutations in highly CM‐associated genes (CDKN2A and CDK4) and low/medium‐penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first‐ or second‐degree relatives. Healthy blood donors (n = 146) were included as a control group. Results From July 2010 to July 2012, 57 patients (41 pedigrees) were included. Twenty‐six were melanoma‐prone families (with at least two cases) and 15 had multiple CMs. Pancreatic cancer was found in six families. The CDKN2A mutation p.V126D was identified in seven patients (four families) with a founder effect, whereas CDKN2A A148T was detected in seven cases (five families) and seven healthy donors (odds ratio 2·76, 95% confidence interval 0·83–9·20). At least one MC1R melanoma‐associated polymorphism was detected in 32 patients (78%) and 97 healthy donors (66%), with more than one polymorphism in 12 patients (29%) and 25 healthy donors (17%). The MITF variant p.E318K was identified in four patients from three additional pedigrees (7%) and one healthy control (0·7%). Conclusions Inclusion criteria for the Ticino population for genetic assessment should follow the rule of two (two affected individuals in a family or a patient with multiple CMs), as we detected a CDKN2A mutation in almost 10% of our pedigrees (four of 41), MITF p.E318K in 7% (three of 41) and a higher number of MC1R variants than in the control population. What's already known about this topic? CDKN2A as a high‐penetrance risk factor and MITF and MCR1, with low‐to‐intermediate penetrance, are the most important genes involved in melanoma susceptibility. Mutation detection rates in these genes are highly variable across regions. CDKN2A mutation detection increases with the number of melanomas, young age at diagnosis and concomitant pancreatic cancer in the family. What does this study add? The genetic predisposition to melanoma in southern Switzerland is analysed for the first time. A CDKN2A high‐risk mutation is detected in almost 10% of pedigrees and MITF p.E318K mutation in 7%. It is difficult to establish a rule for recommend