Genetics of Skin Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Melanoma
Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa continued...
CDKN2A encodes two proteins, p16INK4a and p14ARF, both inhibitors of cellular senescence. The protein produced when the alternate reading frame (ARF) for exon 1 is transcribed instead of the standard reading frame exerts its biological effects through the p53 pathway. It mediates cell cycle arrest at the G1 and G2/M checkpoints, complementing p16's block of G1/S progression—thereby facilitating cellular repair of DNA damage.
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. The frequency of CDKN2A mutations is as high as 22% in families with two cases of melanoma who have other features of hereditary melanoma, such as an age at diagnosis younger than 50 years or one or more individuals diagnosed 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.[75,76,77,78,79,80,81]
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 CDKN2Acarriers, 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.[85,86]