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Vitamin D Receptor Polymorphisms Are Associated with Altered Prognosis in Patients with Malignant Melanoma¹

Departments of Dermatology [P. E. H., J. E. O.] and Plastic Surgery [P. N. M.], Leicester Royal Infirmary, Leicester LE1 5WW; Department of Dermatology [J. T. L., A. G. S.], North Staffordshire Hospital, Stoke-on-Trent, Staffordshire ST4 7PA; Department of Dermatology, Royal Cornwall Hospitals, Truro, Cornwall TR1 3LJ [P. W. B.]; and Department of Mathematics [P. W. J.] and Centre for Pathology and Molecular Medicine, School of Postgraduate Medicine [R. C. S., A. A. F], University of Keele, Staffordshire ST5 5BG, United Kingdom

Calcitriol [1,25(OH)₂D₃], the hormonal derivative of vitamin D₃, is an antiproliferative and prodifferentiation factor for several cell types, including cultured melanocytes and malignant melanoma (MM) cells. Several polymorphisms of the vitamin D receptor (VDR) gene have been described including a FokI RFLP in exon 2, BsmI, and ApaI polymorphisms in intron 8 and an adjacent TaqI RFLP in exon 9. Alterations in vitamin D/1,25(OH)₂D₃ levels and polymorphisms of the VDR have been shown to be associated with several systemic malignancies. We hypothesize that polymorphism in this gene may be associated with altered susceptibility and outcome in patients with MM. A hospital-based case-control study, using 316 MM cases and 108 controls, was used to assess associations with MM susceptibility. Breslow thickness, the most important single prognostic factor in MM, was used as the outcome measure. Polymorphisms at the FokI and TaqI restriction sites were determined using PCR-based methods. Polymorphism at the FokI, but not TaqI, RFLP was associated with an altered risk of MM (P = 0.014). More importantly, variant alleles were associated with increased Breslow thickness. Thus, homozygosity for variant alleles at both RFLP (ttff genotype combination) was significantly associated with thicker tumors. (3.5 mm; P = 0.001; odds ratio = 31.5). Thus, polymorphisms of the VDR gene, which would be expected to result in impaired function, are associated with susceptibility and prognosis in MM. These data suggest that 1,25(OH)₂D₃, the ligand of the VDR, may have a protective influence in MM, as has been proposed for other malignancies.

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