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

Abstract

Purpose: Melanoma 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 methods: Data 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.

Results: The 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%).

Conclusion: The 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.

Keywords: cutaneous melanoma; genetic epidemiology; melanocortin 1 receptor; pigmentation; pooled analysis.

Figure 1

Forest plot for NDE, NIE, and TE of any MC1R variant on melanoma risk. Notes: CDE estimates the direct effect of MC1R on melanoma when the mediator is controlled at level 0 (absent) or 1 (present) uniformly in the population, NDE essentially averages CDE over the population, NIE estimates the indirect effect of MC1R mediated by RH phenotype, and TE is the overall melanoma risk estimate for MC1R carriers and in each study is the product of NDE and NIE. Abbreviations: CDE, control direct effect; NDE, natural direct effect; NIE, natural indirect effect; PY, publication year; RH, red hair; SOR, summary OR; TE, total effect.

Figure 2

Forest plot for control direct effect of any MC1R variant on melanoma risk according to RH phenotype.* Notes: *Defined as presence of red hair, freckles, or skin type I/II. Control direct effect estimates the direct effect of MC1R on melanoma when the mediator is controlled at level 0 (absent) or 1 (present) uniformly in the population. Abbreviations: PY, publication year; RH, red hair; SOR, summary OR.

Figure 3

ROC curve comparison between base clinical model and the same model with inclusion of MC1R variants for patients with no RH phenotype.* Notes: (A) MC1R defined as the presence or absence of any MC1R variant and (B) as no MC1R variant, only r variants, and ≥1 R variants. *Non-RH patients defined as those without RH and freckles and with skin type III/IV. R and r alleles were respectively defined basing on their stronger or weaker association with the RH phenotype for the most common variants,– and on likely pathogenicity using the algorithm proposed by Davies et al for the less common variants. Abbreviations: RH, red hair; ROC, receiver-operating characteristic.