Promoter Hypermethylation of Wnt/β-catenin Signaling Pathway Inhibitor Gene and its Association with MTHFR C677T Polymorphism in Patients with Colorectal Cancer.

OBJECTIVES

Colorectal cancer (CRC) is a common malignancy with a high rate of mortality. The dysregulation of genes involved in the Wnt/β-catenin signaling pathway is a common finding in cancers. Wnt-inhibitory factor-1 () suppresses the Wnt/β-catenin signaling pathway and its inactivation by genetics and epigenetic changes may cause cancer. We investigated the DNA methylation status of the gene in patients with CRC and its interaction with MTHFR C677T polymorphism, a known modifier of methylation reaction.

METHODS

We investigated 50 cancerous tissues and the adjacent non-cancerous tissue. Genomic DNA was extracted using a commercial kit and was treated by sodium bisulfite. Methylation-specific PCR was used for methylation analysis, and restriction fragment length polymorphism PCR to analyze the C677T polymorphism of the gene.

RESULTS

The frequency of WIF1 promoter DNA methylation was significantly higher in cancerous tissue than adjacent non-cancerous tissue (52.0% vs. 8.0%; < 0.001). WIF1 promoter DNA methylation status showed a significant association only with tumor location ( 0.009). Carriers of TT genotype and T allele of MTHFR C677T polymorphism had a significantly higher frequency of unmethylated WIF1 gene than methylated gene in cancerous tissue ( 0.025 and 0.001, respectively).

CONCLUSIONS

Promoter DNA hypermethylation of the gene is a significant risk factor for CRC development, which was significantly associated with tumor location only. The significant association of TT genotype and T allele of MTHFR C677T polymorphism with unmethylated gene suggests a protective role for this common polymorphism against methylation-induced development of CRC.