BACKGROUND AND METHODS: Seven genetic biomarkers previously associated with 
melanoma were analysed in a meta-analysis conducted in three South European 
populations: five red hair colour (RHC) MC1R alleles, one SLC45A2 variant 
(p.Phe374Leu) and one thermosensitive TYR variant (p.Arg402Gln). The study 
included 1639 melanoma patients and 1342 control subjects.
RESULTS: The estimated odds ratio (OR) associated with carrying at least one 
MC1R RHC variant was 2.18 (95% confidence interval (CI): 1.86-2.55; 
p-value=1.02×10(-21)), with an additive effect for carrying two RHC variants 
(OR: 5.02, 95% CI: 2.88-8.94, p-value=3.91×10(-8)). The SLC45A2 variant, 
p.Phe374Leu, was significantly and strongly protective for melanoma in the three 
South European populations studied, with an overall OR value of 0.41 (95% CI: 
0.33-0.50; p-value=3.50×10(-17)). The association with melanoma of the TYR 
variant p.Arg402Gln was also statistically significant (OR: 1.50; 95% CI: 
1.11-2.04; p-value=0.0089). Adjustment for all clinical potential confounders 
showed that melanoma risks attributable to MC1R and SLC45A2 variants strongly 
persisted (OR: 2.01 95% CI: 1.49-2.72 and OR: 0.50, 95% CI: 0.31-0.80, 
respectively), while the association of TYR p.Arg402Gln was no longer 
significant. In addition, stratification of clinical melanoma risk factors 
showed that the risk of melanoma was strong in those individuals who did not 
have clinical risk factors.
CONCLUSION: In conclusion, our results show without ambiguity that in South 
European populations, MC1R RHC and SCL45A2 p.Phe374Leu variants are strong 
melanoma risk predictors, notably in those individuals who would not be 
identified as high risk based on their phenotypes or exposures alone. The use of 
these biomarkers in clinical practice could be promising and warrants further 
discussion.