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The Folate Pool in Colorectal Cancers Is Associated with DNA Hypermethylation and with a Polymorphism in Methylenetetrahydrofolate Reductase

¹ Department of Surgery, Kanazawa University School of Medicine, Kanazawa, Japan;
² Divisions of Tissue Pathology and
³ Molecular Pathology, Institute of Medical and Veterinary Science, Adelaide, Australia;
⁴ Colorectal Surgery Unit, Royal Adelaide Hospital, Adelaide, Australia; and
⁵ Department of Surgery, University of Western Australia, Nedlands, Australia

ABSTRACT

Purpose: Aberrant DNA methylation occurs in a subset of colorectal cancers and is characterized by regional areas of hypermethylation at CpG islands. The aims of this study were firstly to evaluate the levels of folate intermediates (FIs) in tumors with aberrant DNA methylation and secondly to determine whether these levels are affected by polymorphisms in key genes involved in folate metabolism.

Experimental Design: The concentrations of two major intracellular FIs, 5,10-methylenetetrahydrofolate and tetrahydrofolate (FH₄), were measured in 103 surgically resected colorectal cancers. DNA hypermethylation at seven different CpG islands was measured using the MethylLight assay. Genotyping for polymorphisms in the thymidylate synthase, cystathionine ß-synthase, methionine synthase, and methylenetetrahydrofolate reductase (MTHFR) genes was carried out using PCR and PCR-RFLP.

Results: Significantly higher levels of FH₄ were found in tumors from the proximal colon compared with those originating in the distal colon and rectum. Tumors with aberrant DNA methylation of CpG islands within promoter regions of the hMLH1, TIMP3, and ARF genes also contained higher levels of both 5,10-methylenetetrahydrofolate and FH₄. In contrast, patients who were homozygous for the C667T polymorphism of the MTHFR gene had significantly lower concentrations of both these FIs in their tumor tissue.

Conclusions: The concentrations of FIs in colorectal tumors are directly related to the presence of frequent DNA hypermethylation and inversely related to the presence of a common polymorphism in the MTHFR gene. FIs could serve as biochemical markers for the risk of developing this disease, as well as for the prediction of toxicity and efficacy of fluorouracil-based treatments.

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