Polymorphisms in the One-Carbon Metabolic Pathway, and the Risk and Survival of Colorectal Cancer

Polymorphisms in one-carbon metabolizing genes cytosolic serine hydroxymethyltransferase (cSHMT), methylenetetrahydrofolate dehydrogenase (MTHFD1), glutamate carboxypeptidase II (GCPII), and thymidylate synthase (TS), have been identified. There is evidence implicating their functionality in modifying folate status and related CRC risk. Molecular and genetic epidemiologic approaches were used to investigate (1) whether dietary folate is a micronutrient that is protective against colorectal cancer; (2) whether the sub-population carrying genetic polymorphisms in folate-metabolizing genes is at increased risk of colorectal cancer; (3) how folate may interact with these polymorphisms to modify risk of colorectal cancer, and (4) how folate may interact with folate antagonists in contributing to the risk of colorectal cancer. The significance of this research lies not only in its potential to clarify etiology of colorectal cancer but also to guide the prevention of colorectal cancer through dietary modification. Interpretive Summary: Many genes have slight modifications in their structures which in part distinguishes people from each other. If a certain modification in a certain gene is frequently found in a population, this modification is called gene polymorphism. In the genes that control the function of the vitamin folic acid, there appear to be a number of polymorphisms. In this study the objective is to determine if these modifications in specific genes influence the risk of having colon cancer. In previous study we have shown that a modification in a gene called MTHFR, actually protect against the risk of colon cancer. In this study none of the three genes that we investigated influences the risk of having this 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.