Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa continued...
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. A similar study of Greek individuals with melanoma found CDKN2A mutations in 3.3% of single melanoma cases, 22% of familial melanoma cases, and 57% of individuals with multiple primary melanomas. Many mutations reported among families consist of founder mutations, which are unique to specific populations and the geographic areas from which they originate.[74,75,76,77,78,79,80]
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. In contrast, a comparison of families with the CDKN2A mutation in the United Kingdom and Australia demonstrated the same cumulative risk of melanoma; for CDKN2A carriers, the risk of developing melanoma seemed independent of ambient UV radiation. 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 also increases CDKN2A penetrance; 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 also been assessed in CDKN2A carriers; 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.[84,85]
A comparison of clinical features from 182 patients with CDKN2A mutations and 7,513 individuals without mutations found that individuals with CDKN2A mutations had a statistically significant younger age at diagnosis (mean age at diagnosis: 39.0 years vs. 54.3 years; P < .001). There was also a 5-year cumulative incidence of a second melanoma of 23.4% in mutation carriers and a rate of 2.3% in mutation-negative controls. An Italian study performed genotype-phenotype correlations in 100 families with familial melanoma to determine clinical features predictive of the identification of a CDKN2A mutation. Probands with multiple primary melanomas, at least one melanoma with Breslow thickness greater than 0.4 mm, and more than three affected family members had a greater than 90% likelihood of having a mutation; probands with none of these features had less than a 1% likelihood of having a CDKN2A mutation. The most predictive feature was multiple primary melanomas. Results from the Genes, Environment, and Melanoma study showed that first-degree relatives of CDKN2A mutation carriers with melanoma had an approximately 50% increased risk of cancers other than melanoma, compared with first-degree relatives of other melanoma patients. Cancers with increased risk in this population included gastrointestinal cancers (relative risk [RR], 2.4; 95% CI, 1.4–3.7), pancreatic cancers (RR, 7.4; 95% CI, 2.3–18.7), and Wilms tumor (RR, 40.4; 95% CI, 3.4–352.7).