Association of functional, inherited vitamin D-binding protein variants with melanoma-specific death.

BACKGROUND: It is unclear whether genetic variants affecting vitamin D metabolism are associated with melanoma prognosis. Two functional missense variants in the vitamin D-binding protein gene (GC), rs7041 and rs4588, determine three common haplotypes Gc1s, Gc1f, and Gc2. Gc1f may be associated with decreased all-cause death among melanoma patients, based on results of a prior study, but its association with melanoma-specific death is unclear.

METHODS: We investigated the association of the Gc1s, Gc1f, and Gc2 haplotypes with melanoma-specific and all-cause death among 4,490 individuals with incident, invasive primary melanoma in two population-based studies using multivariable Cox-proportional hazards regression.

RESULTS: In the pooled analysis of both datasets, those with the Gc1f haplotype had a 37% lower risk of melanoma-specific death compared to those without Gc1f (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.47 to 0.83, P = 0.001) adjusting for age, sex, study center, first or higher-order primary melanoma, tumor site, pigmentary phenotypes, and Breslow thickness. Associations were similar in both studies. In pooled analyses stratified by Breslow thickness, the corresponding melanoma-specific death HRs for those with the Gc1f haplotype compared to those without Gc1f were 0.89 (95% CI = 0.63 to 1.27) among participants with tumors ≤2.0 mm and 0.40 (95% CI = 0.25 to 0.63) among participants with tumors >2.0 mm (Pinteraction= 0.003).

CONCLUSIONS: Our findings suggest that individuals with the GC haplotype Gc1f may have a lower risk of dying from melanoma-specifically from thicker, higher-risk melanoma-compared to those without Gc1f.