Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir 190006, India.
Division of Colorectal Surgery, SKIMS, Soura, Srinagar, Jammu and Kashmir 190011, India.
Cancer Genet. 2021 Apr;252-253:96-106. doi: 10.1016/j.cancergen.2021.01.002. Epub 2021 Jan 13.
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.
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.
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.
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)D levels were not significantly associated with any of the patient characteristics.
Our study, first of its kind from Kashmir, indicated that VDR shows aberrant methylation pattern in CRC with consequent loss in its expression.
结直肠癌（CRC）的发生是一个多步骤的过程，涉及参与从肿瘤抑制到 DNA 错配修复等多种途径的基因的遗传和表观遗传改变。
本研究旨在评估维生素 D 受体（VDR）基因启动子甲基化与其表达及临床病理参数的关系。VDR 是一种具有多种生物学功能的转录因子。
对总共 75 例结直肠癌病例及其正常周围上皮组织的组织标本进行了实时 RT-PCR 检测以评估其表达谱，MS-PCR 分析以评估 VDR 基因启动子的甲基化状态。从同一患者中抽取血液样本以评估维生素 D 水平。
癌症组织中 VDR 启动子的甲基化频率为 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呈显著负相关（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）显著相关。单因素和多因素分析表明，VDR 表达增加（p<0.001）和甲基化状态降低（p=0.012）的患者总生存时间更长。此外，血清 25(OH)D 水平与患者的任何特征均无显著相关性。
本研究首次来自克什米尔地区，表明 VDR 在 CRC 中表现出异常的甲基化模式，导致其表达缺失。
