Single-Nucleotide Polymorphisms in Pigment Genes and Nonmelanoma Skin Cancer Predisposition: A Systematic Review

M. Binstock, F. Hafeez, C. Metchnikoff and S.T. Arron


The British Journal of Dermatology. 2014;171(4):713-721. 

In This Article

Abstract and Introduction


Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A. The two most common NMSCs are basal cell carcinoma and squamous cell carcinoma. The associations of single-nucleotide polymorphisms (SNPs) in pigmentation pathway genes with NMSC are not well characterized. There is a series of epidemiological studies that have tested these relationships, but there is no recent summary of these findings. To explain overarching trends, we undertook a systematic review of published studies. The summarized data support the concept that specific SNPs in the pigmentation pathway are of importance for the pathogenesis of NMSC. The SNPs with the most promising evidence include MC1R rs1805007(T) (Arg151Cys) and rs1805008(T) (Arg160Trp), and ASIP AH haplotype [rs4911414(T) and rs1015362(G)]. There are a few other SNPs found in TYR,OCA2 and SLC45A2 that may show additional correlation after future research. With additional research there is potential for the translation of future findings to the clinic in the form of SNP screenings, where patients at high risk for NMSC can be identified beyond their phenotype by genotypically screening for predisposing SNPs.


Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A., accounting for more than 1 million new cases per year.[1–3] The two most common types of NMSC are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which occur in a ratio of 4·5 : 1 in the general population.[4] The primary risk factor for NMSC is ultraviolet (UV) radiation exposure, which causes DNA damage within the keratinocyte.[5,6] Melanin is proposed to serve as a filter to protect DNA from UV damage.[7,8] Patients with fair skin and a propensity to sunburn are at increased risk for NMSC, mediated by the interaction between the skin and UV.[9,10]

Epidermal pigmentation is a result of melanin synthesis in melanocytes[11] and transfer to surrounding keratinocytes for distribution throughout the epidermis of the skin.[12–15] Pigment formation falls into two categories, constitutive and facultative.[16] Constitutive pigmentation reflects the basal level of melanin production without additional environmental stimulus. Facultative pigmentation describes an enhanced level of melanin production due to exogenous or endogenous influences, such as exposure to sunlight or stress. This occurs in mature melanocytes and requires the same melanin-producing machinery involved in constitutive pigmentation.

The combination of constitutive pigmentation traits and the skin's facultative reaction to sunlight defines the clinical skin phenotype (CSP). Constitutive pigmentation is assessed through skin complexion, hair colour, eye colour and the presence of freckles. Facultative pigmentation is quantified through the Fitzpatrick skin type, a six-level scale based on a patient's self-reported tendency to burn or tan.[17] NMSC risk is directly associated with CSP,[18,19] where predisposing risk factors include fair complexion, light eyes, red or blond hair, propensity to freckle or burn, and inability to tan.[18–24] CSP is highly dependent on the production and distribution of melanin within the epidermis, all of which are determined by the proteins encoded by over 150 genes in the pigmentation pathway.[25,26]

Comparative genomics, positive selection evolution models and genome-wide/specific allele association studies have been used to identify genes and alleles associated with the pigmentation pathway.[27] A genome-wide association study (GWAS) utilizes an unbiased screen of 500 000 or more single-nucleotide polymorphisms (SNPs) to identify associations between SNPs and the outcome. If there is a positive correlation between a SNP and a designated trait, it does not necessarily mean that this SNP is responsible for that trait, but rather could imply that the causal variant is linked and may lie within the locus of interest. Because large populations must be screened in order to gain statistical power, an alternative is to analyse a preselected group of candidate SNPs. Multiple studies have applied locus-specific association studies and found that some SNPs in pigment genes are associated with an increased risk of NMSC, some of which remain significant even after controlling for CSP. This implies that these alleles may predispose to NMSC through cellular pathways separate from pigment production. The high-risk CSP traits may thus function as markers for predisposition to NMSC rather than as mediators of the causal mechanism. If this is the case, further research may show that it is more effective to screen patients genotypically using identified high-risk pigment SNPs rather than depending on CSP traits for NMSC prevention.

This is the first systematic review covering epidemiological studies of NMSC risk associated with polymorphisms of genes in the pigmentation pathway. The last review on this topic was performed in 2010.[28] We provide a basic overview of pigmentation pathway genetics to illustrate areas that have been thoroughly studied and identify areas that warrant further investigation. We summarize the impact of individual SNPs on the risk of NMSC through suspected pigmentary and nonpigmentary mechanisms. SNPs from genes that are correlated to pigmentation only through previous GWAS studies are excluded because there is no research showing their biochemical role in pigmentation. Melanoma review is beyond the scope of this paper and extensive reviews exist.[29,30] It is outside the scope of this paper to provide the comprehensive biochemistry of the pigmentation pathway. For more information on pigmentation genetics, a list of known loci is available online (; further information is available.[31]