There is substantial variation in human pigmentation within and across populations. Melanin synthesized by melanocytes is the main contributor to human pigmentation. Lighter pigmentation is a risk factor for skin cancer. Human pigmentation is a polygenic quantitative trait with high heritability. Although a large number of single nucleotide polymorphisms (SNPs) were identified in pigmentation genes, very few SNPs were examined in relation to human pigmentary phenotypes. No studies were conducted for the risk of skin cancer except for the melanocortin 1 receptor (MC1R) gene. We evaluated the associations between 12 SNPs (including 8 non-synonymous SNPs) in 7 candidate pigmentation genes (TYR, OCA2, SLC24A5, SLC45A2, POMC, ASIP, and ATRN) involved in inducing the maturation from pheomelanine to eumelanine, and both pigmentary phenotypes (hair color, skin color, and tanning tendency) and skin cancer risk in a nested case-control study within the Nurses’ Health Study (NHS) among 219 melanoma cases, 286 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 873 common controls. Unconditional logistic regression and linear regression were used for data analysis. We found that the TYR Arg402Gln variant was significantly associated with skin color and tanning tendency (p-value < 10-4) while the SLC45A2 Leu374Phe variant was significantly associated with hair color (p-value < 10-7), skin color (p-value < 10-7), and tanning tendency (p-value < 10-4). A similar association pattern to the SLC45A2 Leu374Phe variant was also found for the SLC45A2 Glu272Lys variant. However, only for the TYR Arg402Gln and SLC45A2 Leu374Phe did these associations remain significant after controlling for MC1R variants. Notably, these three SNPs correlated with pigmentary phenotypes were not associated with skin cancer risk. We observed that the SLC45A2 -1721 C>G was associated with melanoma risk (adjusted OR, 0.75; 95% CI, 0.60-0.95); the TYR Ser192Tyr was associated with SCC risk (adjusted OR, 1.23; 95% CI, 1.00-1.50); the OCA2 Arg419Gln was associated with BCC risk (adjusted OR, 1.50; 95% CI, 1.06-2.13); and the ASIP g.8818 A>G was associated with BCC risk (adjusted OR, 0.73; 95% CI, 0.53-1.00). These associations remained essentially the same after adjusting for pigmentary phenotypes. We observed an interaction between hair color and the TYR Ser192Tyr on SCC risk (p, interaction, 0.02). This study provides evidence for the contribution of pigmentation genetic variants to variation in human pigmentary phenotypes and development of skin cancer.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA