Background

Colorectal carcinogenesis (CRC) is a multistep process, involving both genetic and epigenetic modifications of genes involved in diverse pathways ranging from tumor suppression to DNA mismatch repair.

Purpose

This study was undertaken to assess the role of promoter methylation of vitamin D receptor (VDR) gene, a transcription factor with myriad biological functions, in relation to its expression and clinicopathological parameters.

Methods

Tissue specimens were taken from a total of 75 colorectal cancer cases paired with their normal surrounding epithelium and analyzed by Real-time RT-PCR for assessing the expression profile and MS-PCR for analyzing the promoter methylation status of the VDR gene. Blood sample from the same patients was drawn for vitamin D estimation.

Results

The frequency of promoter methylation in cancerous tissue was 37.33% against 9.33% in normal tissues (p<0.001). The hypermethylated status of VDR promoter showed significantly inverse association with its expression (p=0.008). Furthermore, when compared with the clinical parameters, methylation status of VDR promoter was significantly associated with tumor staging (p=0.008), grading (p<0.001), depth of invasion (p=0.002) and lymph node metastases (p<0.001). Univariate and multivariate analysis indicated patients with increased VDR expression (p<0.001) and decreased methylation status (p=0.012) exhibited longer overall survival. Additionally, serum 25(OH)D₃ levels were not significantly associated with any of the patient characteristics.

Conclusion

Our study, first of its kind from Kashmir, indicated that VDR shows aberrant methylation pattern in CRC with consequent loss in its expression.

中文翻译：

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启动子高甲基化调节结直肠癌中维生素D受体（VDR）的表达-来自克什米尔山谷的一项研究

背景

大肠癌变（CRC）是一个多步骤过程，涉及基因的遗传和表观遗传修饰，涉及从肿瘤抑制到DNA错配修复的多种途径。

目的

这项研究旨在评估维生素D受体（VDR）基因（具有多种生物学功能的转录因子）的启动子甲基化与其表达和临床病理参数有关的作用。

方法

从总共75例结直肠癌患者的组织标本中与正常周围的上皮配对，并通过实时RT-PCR进行分析以评估表达谱，并通过MS-PCR进行分析以分析VDR基因的启动子甲基化状态。抽取来自同一患者的血液样本进行维生素D估算。

结果

癌组织中启动子甲基化的频率为37.33％，而正常组织中为9.33％（p < 0.001）。VDR启动子的高甲基化状态与其表达显着负相关（p = 0.008）。此外，与临床参数相比，VDR启动子的甲基化状态与肿瘤分期（p = 0.008），分级（p < 0.001），浸润深度（p = 0.002）和淋巴结转移（p < 0.001）显着相关。 。单因素和多因素分析表明患者的VDR表达增加（p < 0.001）和甲基化状态降低（p= 0.012）表现出更长的总生存期。另外，血清25（OH）D ₃水平与任何患者特征均无显着相关。

结论

我们的研究是来自克什米尔的首次此类研究，表明VDR在CRC中显示异常的甲基化模式，从而导致其表达损失。