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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #166586
Title: POLYMORPHISMS IN THE ONE-CARBON METABOLIC PATHWAY, SERUM FOLATE LEVELS AND COLORECTAL CANCER IN A PROSPECTIVE STUDY

Author
item CHEN, JIA - MOUNT SINAI SCH OF MED
item KYTE, CHARLES - MOUNT SINAI SCH OF MED
item VALCIN, MARTIN - MOUNT SINAI SCH OF MED
item CHAN, WENDY - MOUNT SINAI SCH OF MED
item WETMUR, JAMES - MOUNT SINAI SCH OF MED
item SELHUB, JACOB - TUFTS-HNRCA
item HUNTER, DAVID - BRIGHAM AND WOMEN'S HOSP
item MA, JING - BRIGHAM AND WOMEN'S HOSP

Submitted to: International Journal of Cancer
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/17/2003
Publication Date: 7/1/2004
Citation: Chen, J., Kyte, C., Valcin, M., Chan, W., Wetmur, J.G., Selhub, J., Hunter, D.J., Ma, J. 2004. Polymorphisms in the one-carbon metabolic pathway, serum folate levels and colorectal cancer in a prospective study. International Journal of Cancer. 110(4):617-20.

Interpretive Summary: Many genes have slight modifications in their structures which in part distinguish people from each other. If a modification in a certain gene is frequently found in a population, this modification is referred to as gene polymorphism. There appears to be a number of polymorphisms in the genes that control the function of the vitamin folic acid. In this study the objective was to determine if these modifications in specific genes influence the risk of colon cancer. In a previous study we have shown that MTHFR polymorphism protects against the risk of colon cancer. In this study none of the three genes that we investigated influenced the risk of colon cancer.

Technical Abstract: One-carbon (e.g., folate) metabolism plays a pivotal role in the etiology of colorectal cancer (CRC). Cytosolic serine hydroxymethyltransferase (cSHMT), methylenetetrahydrofolate dehydrogenase (MTHFD1) and glutamate carboxypeptidase II (GCPII) are key genes involved in this pathway. Several new polymorphisms have been identified and there is evidence implicating their functionality. We examined whether polymorphisms in these genes, i.e., cSHMT L474F, MTHFD1 R653Q and GCPII H475Y, modify the risk of CRC in the prospective Physicians' Health Study. Among the 270 incident CRC cases and 453 controls, none of the one-carbon polymorphisms were associated with risk of CRC. Compared to the wild-type genotype, the multivariate-adjusted relative risks and 95% confidence intervals were 1.14 [0.68, 1.93] for cSHMT 474FF, 1.04 [0.67, 1.62] for MTHFD1 653QQ and 1.00 [0.55, 1.82] for GCPII 474HY. Furthermore, we examined the associations between one-carbon polymorphisms and folate status in terms of plasma folate and homocysteine levels in this population. No independent gene effect was observed. Although compound homozygous variants at cSHMT and MTHFD1 loci had the lowest plasma folate levels compared to other compound genotypes, no significant gene-gene interactions were observed. Findings from our prospective investigation indicate that these newly identified polymorphisms in one-carbon metabolizing genes have limited functionality in modifying folate status and related CRC risk.