Hutchinson P E, Osborne J E, Lear J T, Smith A G, Bowers P W, Morris P N, Jones P W, York C, Strange R C, Fryer A A
Department of Dermatology, Leicester Royal Infirmary, United Kingdom.
Clin Cancer Res. 2000 Feb;6(2):498-504.
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. (> or = 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.
骨化三醇[1,25(OH)₂D₃]，即维生素D₃的激素衍生物，是包括培养的黑素细胞和恶性黑色素瘤（MM）细胞在内的多种细胞类型的抗增殖和促分化因子。维生素D受体（VDR）基因存在多种多态性，包括外显子2中的FokI限制性片段长度多态性（RFLP）、内含子8中的BsmI和ApaI多态性以及外显子9中相邻的TaqI RFLP。维生素D/1,25(OH)₂D₃水平的改变和VDR的多态性已被证明与多种系统性恶性肿瘤有关。我们推测该基因的多态性可能与MM患者易感性改变及预后相关。一项基于医院的病例对照研究，纳入316例MM患者和108例对照，用于评估与MM易感性的关联。Breslow厚度是MM中最重要的单一预后因素，用作结局指标。使用基于聚合酶链反应（PCR）的方法确定FokI和TaqI限制性位点的多态性。FokI RFLP而非TaqI RFLP的多态性与MM风险改变相关（P = 0.014）。更重要的是，变异等位基因与Breslow厚度增加相关。因此，两种RFLP（ttff基因型组合）的变异等位基因纯合性与更厚的肿瘤显著相关（≥3.5 mm；P = 0.001；优势比 = 31.5）。因此，预期会导致功能受损的VDR基因多态性与MM的易感性和预后相关。这些数据表明，VDR的配体1,25(OH)₂D₃可能对MM有保护作用，正如对其他恶性肿瘤所提出的那样。
