Mutations in CDKN2A account for 35% to 40% of familial melanomas. A large case series from Britain found that CDKN2A mutations were present in 100% of families with seven to ten individuals affected with melanoma, 60% to 71% of families with four to six cases, and 14% of families with two cases. Many mutations reported among families consist of founder mutations, which are unique to specific populations and the geographic areas from which they originate.[72,73,74,75,76,77,78]
Depending on the study design and target population, melanoma penetrance related to deleterious CDKN2A mutations differs widely. One study of 80 multiple-case families demonstrated that the penetrance varied by country, an observation that was attributed to major differences in sun exposure. For example, in Australia, the penetrance was 30% by age 50 years and 91% by age 80 years; in the United States, the penetrance was 50% by age 50 years and 76% by age 80 years; in Europe, the penetrance was 13% by age 50 years and 58% by age 80 years. Another study of individuals with melanoma identified in eight population-based cancer registries and one hospital-based sample obtained a self-reported family history and sequenced CDKN2A in all individuals. The penetrance was estimated as 14% by age 50 years and 28% by age 80 years. The explanation for these differences lies in the method of identifying the individuals tested with penetrance estimates increasing with the number of affected family members. The method of family ascertainment in the latter study made it much less likely that "heavily loaded" melanoma families would be identified. Coinheritance of melanocortin 1 receptor (MC1R) variants increases CDKN2A penetrance as well; this genetic variant, described in further detail below, is therefore both a low-penetrance susceptibility gene and a modifier gene. (Refer to the MC1R section of this summary for more information.) Other modifier loci have been assessed in CDKN2A carriers as well; interleukin-9 (IL9) and GSTT1 were the only loci to reach statistical significance, suggesting that other minor risk factors may interact with major risk loci.[81,82]
CDKN2A exon 1� mutations (p14ARF) have been identified in a small percentage of families negative for p16INK4a mutations. In a study of 94 Italian families with two or more cases of melanoma, 3.2% of families had mutations in p14ARF. At this time, testing for p14ARF is not commercially available.
DNA repair genes
Xeroderma pigmentosum (XP) patients with defective DNA repair have a more than 1,000-fold increase in melanoma risk. These patients are diagnosed with melanoma at a significantly younger age than individuals in the general population; on average, melanoma diagnosis occurs at age 22 years in XP patients. The anatomic site distribution of melanomas in XP patients is similar to that of the general population.[85,86]