Genetics of Skin Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Melanoma
Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa continued...
Minor genes (genetic modifiers) for melanoma
The MC1R gene, otherwise known as the alpha melanocyte-stimulating hormone receptor, is located on chromosome 8. Partial loss-of-function mutations are associated not only with red hair, fair skin, and poor tanning, but also with increased skin cancer risk independent of cutaneous pigmentation.[119,120,121] A comprehensive meta-analysis of over 8,000 cases and 50,000 controls showed the highest risk of melanoma in individuals with MC1R variants associated with red hair. However, this association remains controversial. Another meta-analysis showed that melanoma risk was highest in individuals who carry MC1R variants and have phenotypes generally considered protective for melanoma, including good tanning ability, darker hair, and darker skin. Data from a study of individuals diagnosed with BCC before age 40 years also found a stronger association between BCC and MC1R variants in those with phenotypic characteristics not traditionally considered high risk. Although variants in this gene are associated with increased risk of all three types of skin cancer, adding MC1R information to predictions based on age, sex, and cutaneous melanin density offers only a small improvement to risk prediction.[124,125]
MC1R variants can also modify melanoma risk in individuals with CDKN2A mutations. A study consisting of 815 CDKN2A mutation carriers looked at four common non-synonymous MC1R variants and found that having one variant increased the melanoma risk twofold, but having two or more variants increased melanoma risk nearly sixfold. After stratification for hair color, the increased risk of melanoma appeared to be limited to subjects with brown or black hair. These data suggest that MC1R variants increase melanoma risk in a manner independent of their effect on pigmentation. A meta-analysis of individuals with CDKN2A mutations showed that those with greater than one variant in MC1R had approximately fourfold increased risk of melanoma. Individuals with one or more variants in MC1R showed an average 10-year decrease in age of onset from 47 to 37 years. In contrast, a large consortium study did not show as large a decrease in age at onset of melanoma. Another study of Norwegian melanoma cases and controls showed that CDKN2A mutation carriers had an increased risk of melanoma when they carried either the Arg160Trp or Asp84Glu MC1R variants. However, MC1R status may play a prognostic role in melanoma patients. Pooled analyses of cohorts of melanoma patients with MC1R variants suggest that the presence of one or more variants conveys an overall survival benefit (hazard ratio = 0.78; 95% CI, 0.65–0.94).