<em>MC1R</em> variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project

Abstract

PurposeMelanoma represents an important public health problem, due to its high case-fatality rate. Identification of individuals at high risk would be of major interest to improve early diagnosis and ultimately survival. The aim of this study was to evaluate whether MC1R variants predicted melanoma risk independently of at-risk phenotypic characteristics.Materials and methodsData were collected within an international collaboration – the M-SKIP project. The present pooled analysis included data on 3,830 single, primary, sporadic, cutaneous melanoma cases and 2,619 controls from seven previously published case–control studies. All the studies had information on MC1R gene variants by sequencing analysis and on hair color, skin phototype, and freckles, ie, the phenotypic characteristics used to define the red hair phenotype.ResultsThe presence of any MC1R variant was associated with melanoma risk independently of phenotypic characteristics (OR 1.60; 95% CI 1.36–1.88). Inclusion of MC1R variants in a risk prediction model increased melanoma predictive accuracy (area under the receiver-operating characteristic curve) by 0.7% over a base clinical model (P=0.002), and 24% of participants were better assessed (net reclassification index 95% CI 20%–30%). Subgroup analysis suggested a possibly stronger role of MC1R in melanoma prediction for participants without the red hair phenotype (net reclassification index: 28%) compared to paler skinned participants (15%).ConclusionThe authors suggest that measuring the MC1R genotype might result in a benefit for melanoma prediction. The results could be a valid starting point to guide the development of scientific protocols assessing melanoma risk prediction tools incorporating the MC1R genotype.

High naevus count and MC 1R red hair alleles contribute synergistically to increased melanoma risk

“…However, most of the increase in genetic predictive value was explained by variation within the MC1R gene, which has a major influence on melanogenesis (RHC phenotype) and DNA repair. MC1R variants are particularly useful in explaining the higher melanoma risk evident in some individuals who do not have an obvious high‐risk pigmentation phenotype …”

Comprehensive genetic testing combined with citizen science reveals a recently characterized ancient MC1R mutation is associated with partial recessive red phenotypes in dog

“…MC1R signaling activates antioxidant, DNA repair and anti-in ammatory pathways (27)(28)(29). MC1R genotype affects the probability of developing malignant melanoma (30), nonmelanoma skin cancer (30)(31)(32), risk for developing complicated sepsis after trauma (33) and development of Parkinson's disease (26,34,35) in humans. Loss-or reduced-function variants in human MC1R have also been investigated in the response to pain, analgesia and anesthetics (36)(37)(38)(39).…”

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort

“…24 MC1R variants confer a significant increased risk in darkly pigmented individuals, highlighting the impact of MC1R through non-pigmentary pathways. 25,26 Moreover, MC1R genotype is associated with phenotypic characteristics of melanoma 27 and melanocytic nevi 28 and seems to influence the somatic mutational load in adult CM. 29 Childhood/adolescent CM patients have an elevated prevalence of MC1R variants, but the limited number of available studies coupled to the small number of cases per study makes challenging to draw clear conclusions.…”