Skin Pigmentation Genetics for the Clinic

Abstract

Human pigmentation characteristics play an important role in the effects of sun exposure, skin cancer induction and disease outcomes. Several of the genes most important for this diversity are involved in the regulation and distribution of melanin pigmentation or enzymes involved in melanogenesis itself within the melanocyte cell present in the skin, hair and eyes. The single nucleotide polymorphisms and extended haplotypes within or surrounding these genes have been identified as risk factors for skin cancer, in particular, melanoma. These same polymorphisms have been under selective pressure leading towards lighter pigmentation in Europeans in the last 5,000-20,000 years that have driven the increase in frequency in modern populations. Although pigmentation is a polygenic trait, due to interactive and quantitative gene effects, strong phenotypic associations are readily apparent for these major genes. However, predictive value and utility are increased when considering gene polymorphism interactions. In melanoma, an increased penetrance is found in cases when pigmentation gene risk alleles such as MC1R variants are coincident with mutation of higher-risk melanoma genes including CDKN2A, CDK4 and MITF E318K, demonstrating an interface between the pathways for pigmentation, naevogenesis and melanoma. The clinical phenotypes associated with germline changes in pigmentation and naevogenic genes must be understood by clinicians, and will be of increasing relevance to dermatologists, as genomics is incorporated into the delivery of personalised medicine.

Phenotypic and genotypic analysis of amelanotic and hypomelanotic melanoma patients

“…The three SNPs in the MTAP and PLA2G6 loci that were assayed as part of this study have been reported to be linked on extended haplotypes . The MTAP rs4636294*G melanoma protective allele was more common in the AHM group than the pigmented lesion group (53.4% vs. 41.7%; P = 0.02) whereas the PLA2G6 rs11570734*G protective allele was less common in the AHM group (23.9% vs. 36.6%; P = 0.02).…”

“…Tables and present the allelic and genotype frequencies of seven candidate genes with polymorphisms known to influence skin colour, naevi and melanoma . MC1R R alleles were more prevalent in AHM patients (51.1%) than the pigmented melanoma cohort (34.5%) or controls (22.3%; P = 0.002).…”

“…426 of 436 case samples and all 692 controls were of sufficient quality for genotyping. We specifically looked at seven candidate pigmentation SNPs with known effects on phenotype and melanoma‐associated genes with common tagging SNPs for risk haplotypes . Approximately half of the genomic DNA was subject to automated DNA sequence analysis of PCR amplified fragments covering the MC1R coding region .…”

“…The MC1R coding variants V60L, R163Q and D294H, not included on the Illumina array, were genotyped by TaqMan assay C_7519054_10, C_7519060_20 and C_1010501_30, respectively. MC1R allele classification as WT, R (D84E, R142H, R151C, R160W, D294H) and r (V60L, V92M, I155T, R163Q) were as described . Secondary to this, a genome‐wide association study (GWAS) was performed.…”

Are melanocortin peptides future therapeutics for cutaneous wound healing?

“…It may be fascinating to explore if there is any association between natural loss‐of‐function variants of human MC1R and the efficacy of wound healing and extracellular matrix remodelling in men. Physiologically, hypomorphic variants of MC1R lead to reduced intracellular cAMP synthesis and are associated with the red hair pale skin phenotype in humans . In the context of wound healing, it is puzzling to note a recent a prospective cohort study of burned adult Black/African American and native American race that were independently associated with severe postburn hypertrophic scarring .…”