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Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?

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Abstract

Dietary folate has been consistently associated with reduced risk of colorectal cancer (CRC). One of the known biochemical roles of folate is donation of methyl moieties. DNA hypomethylation is an early and almost ubiquitous occurrence in tumor tissue. Therefore, it was originally suggested that adequate folate intake contributed to reduced risk of CRC by facilitating methyl-mediated silencing of oncogenes. Methylene tetrahydrofolate reductase (MTHFR) metabolizes 5,10-MTHF (important in DNA synthesis) to 5-MTHF (contributes to downstream methylation reactions by regeneration of methionine from homocysteine). A common polymorphism in the MTHFR gene (C677T) results in a thermolabile phenotype associated with increased homocysteine levels and DNA hypomethylation. Consistent with the folate/methylation hypothesis, it was originally proposed that C677T may increase risk of CRC due to hypomethylation of oncogenes. However, most subsequent studies have reported a reduced risk associated with this polymorphism. This is inconsistent with methylation as the mechanism by which folate and MTHFR genotype mediate CRC risk. The hypothesis presented here proposes that localized folate depletion combined with the effect of the C677T polymorphism on enzyme stability, impacts on the DNA synthesis pathway and accounts for the observed variation in risk associated with genotype and folate status.

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Abbreviations

5,10-MTHF:

5,10-Methylene tetrahydrofolate

5-MTHF:

5-Methyl tetrahydrofolate

CI:

Confidence Interval

CRC:

Colorectal Cancer

DNA:

Deoxyribonucleic acid

dTMP:

Deoxythymidylate

dUMP:

Deoxyurydilate

FAD:

Flavin Adenine Dinucleotide

FAP:

Familial Adenomatous Polyposis

GC-MS:

Gas Chromatography-Mass Spectrometry

HNPCC:

Hereditary Non-Polyposis Colorectal Cancer

MTHFR:

Methylene tetrahydrofolate reductase

NSAIDs:

Non-Steroidal Anti-Inflammatory Drugs

OR:

Odds Ratio

SAH:

S-adenosylhomocysteine

SAM:

S-adenosylmethionine

tHcy:

Total Homocysteine

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Acknowledgments

The author would like to thank Dr. A. Molloy for valuable comments and suggestions during the early preparation of this manuscript.

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  1. University of Dundee, Maternal and Child Health Sciences, Ninewells Hospital, Dundee, DD1 9SY, UK

    N. T. Brockton

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Brockton, N.T. Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?. Cancer Causes Control 17, 1005–1016 (2006). https://doi.org/10.1007/s10552-006-0051-5

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