Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians

Abstract

Human pigmentation is a polygenic quantitative trait with high heritability. Although a large number of single nucleotide polymorphisms (SNPs) have been identified in pigmentation genes, very few SNPs have been examined in relation to human pigmentary phenotypes and skin cancer risk. We evaluated the associations between 15 SNPs in 8 candidate pigmentation genes (TYR, TYRP1, OCA2, SLC24A5, SLC45A2, POMC, ASIP and ATRN) and both pigmentary phenotypes (hair color, skin color and tanning ability) and skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases and 870 common controls. We found that the TYR Arg402Gln variant was significantly associated with skin color (p-value 5 7.7 3 10 24 ) and tanning ability (p-value 5 7.3 3 10 24 ); the SLC45A2 Phe374Leu variant was significantly associated with hair color (black to blonde) (p-value 5 2.4 3 10 27 ), skin color (p-value 5 1.1 3 10 27 ) and tanning ability (p-value 5 2.5 3 10 24 ). These associations remained significant after controlling for MC1R variants. No significant associations were found between these polymorphisms and the risk of skin cancer. We observed that the TYRP1 rs1408799 and SLC45A2 1721 C>G were associated with melanoma risk (OR, 0.77; 95% CI, 0.60-0.98 and OR, 0.75; 95% CI, 0.60-0.95, respectively). The TYR Ser192Tyr was associated with SCC risk (OR, 1.23; 95% CI, 1.00-1.50). The TYR haplotype carrying only the Arg402Gln variant allele was significantly associated with SCC risk (OR, 1.35; 95% CI, 1.04-1.74). The OCA2 Arg419Gln and ASIP g.8818 A>G were associated with BCC risk (OR, 1.50; 95% CI, 1.06-2.13 and OR, 0.73; 95% CI, 0.53-1.00, respectively). The haplotype near ASIP (rs4911414[T] and rs1015362[G]) was significantly associated with fair skin color (OR, 2.28; 95% CI, 1.46-3.57) as well as the risks of melanoma (OR, 1.68; 95% CI, 1.18-2.39) and SCC (OR, 1.54; 95% CI, 1.08-2.19). These associations remained similar after adjusting for pigmentary phenotypes and MC1R variants. The statistical power of our study was modest and additional studies are warranted to confirm the associations observed in the present study. Our study provides evidence for the contribution of pigmentation genetic variants, in addition to the MC1R variants, to variation in human pigmentary phenotypes and possibly the development of skin cancer. ' 2009 UICC

Colorful DNA polymorphisms in humans

“…The association between genetic variants and skin color variation had been described in earlier investigations [46,47] and confirmed via GWAS [16,17,48]. Many of the human pigmentation traits are correlated with each other, and those that are correlated with light skin such as red and blond hair, and green and blue eyes, including their underlying genetic polymorphisms, are also correlated with skin cancer risk [49][50][51][52][53][54][55][56][57][58]. Cutaneous melanoma, a disease of fair skinned individuals with a rapidly increasing incidence over the past decades [59,60], is the most aggressive and treatment-resistant skin cancer.…”

Human skin pigmentation as an adaptation to UV radiation

“…With early reproduction and before the extension of the average human lifespan through improvements in diet and medicine, skin cancer had no effect on reproductive success. Further, the genetic pattern of skin cancer risk does not accord with predictions based on selection for resistance to skin cancer (22). In the context of human evolution, the evolution of tanning was a superb evolutionary compromise.…”

“…The effects of skin cancers on reproductive success in humans today are modest, and were probably statistically inconsequential in the centuries before rapid, long-distance travel and migration. This inference is further supported by genetic evidence indicating no significant association of 15 SNPs and skin cancer risk (22). Overproduction of vitamin D was refuted as the primary cause of the evolution of dark pigmentation by the discovery that hypervitamosis D due to sun exposure is physiologically impossible because of photochemical regulation (23).…”

Risk Factors for Developing Cutaneous Melanoma in Santa Catarina, Brazil: A Case-Control Observational Study

“…Age at first sun exposure and history of sunburn in childhood/adolescence appear to have a large influence [2]. Recognized clinical findings associated with neoplasia development include pigmentation characteristics, such as light skin, eyes, and hair, and the presence of ephelides [3][4][5][6][7][8][9]. Melanocytic nevi, especially atypical, multiple, or congenital nevi, are also important risk factors [10,11].…”