Promoter hypermethylation regulates vitamin D receptor (VDR) expression in colorectal cancer-A study from Kashmir valley.

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)D 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.