title: The unfavorable effect of the A allele of the vitamin D receptor promoter polymorphism A-1012G has different mechanisms related to susceptibility and outcome of malignant melanoma.
abstract: The A allele of the A-1012G (rs4516035) vitamin D receptor (VDR) promoter polymorphism is associated with increased susceptibility and worsened outcome in malignant melanoma (MM). The A allele contains a GATA-3 binding site. There is a second polymorphism in the same promoter region, G-1520C (rs7139166), and there is potential for another GATA binding site in the G allele. Here, we tested the hypothesis that the G(-1520)A(-1012) haplotype might be a greater risk factor for MM than A-1012 alone. The A allele of A-1012G was preferentially linked to G of G-1520C and was more frequent in MM patients (p = 0.011) but G of G-1520C was not (p = 0.756). The CA haplotype was a very significant risk factor for MM (p = 0.0001) while the CG haplotype was protective (p = 0.014, combined model p = 0.00002). There was no effect of GA haplotype (p = 0.931), suggesting that that the difference in frequencies of the A allele between patients and controls was accounted for by the differences in frequencies of the CA haplotype. The A allele of A-1012G was more frequent in patients with metastasis (p = 0.054) than MM patients without metastasis, as was the G allele of G-1520C (p = 0.028). The GA haplotype was more frequent in patients with metastasis (p = 0.015), while frequencies of CA were similar. We suggest that the different roles of the A allele of A-1012G in susceptibility and metastasis risk may be a function of the availability of transcription factors in the differing cellular backgrounds related to susceptibility and progression of MM.
authors.affiliation: Department of Cancer Studies and Molecular Medicine; University of Leicester; Leicester, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Halsall
authors.forename: Joy E
authors.initials: JE
authors.lastname: Osborne
authors.forename: Michael P
authors.initials: MP
authors.lastname: Epstein
authors.forename: James H
authors.initials: JH
authors.lastname: Pringle
authors.forename: Peter E
authors.initials: PE
authors.lastname: Hutchinson