Risk Factors for Colon Cancer in Northeastern Thailand: Interaction of MTHFR Codon 677 and 1298 Genotypes with Environmental Factors

Abstract

BackgroundPolymorphisms in methylenetetrahydrofolate reductase (MTHFR), such as MTHFR C677T and A1298C, are associated with several cancers. This study aimed to evaluate the effects of MTHFR polymorphisms on colon cancer risk and possible interactions with environmental factors in a population from northeastern Thailand.MethodsThis hospital-based case–control study was conducted during 2002–2006; 130 colon cancer cases and 130 age- and sex-matched controls were enrolled. Information was collected and blood samples were obtained for assay of MTHFR C677T and A1298C polymorphisms by polymerase chain reaction with restriction fragment length polymorphism techniques. Associations between variables of interest and colon cancer were assessed using conditional logistic regression.ResultsIncreased risk of colon cancer was associated with alcohol consumption and bowel habits. Alcohol drinkers who consumed ≤0.50 or >0.50 units of alcohol per day had elevated risks (ORadj = 3.5; 95% CI: 1.19–10.25 and ORadj = 1.71; 95% CI: 0.74–3.96, respectively). The risk was also higher in subjects with frequent constipation (11.69; 2.18–62.79) and occasional constipation (3.43; 1.72–6.82). An interaction was observed between the MTHFR C677T polymorphism and freshwater fish consumption on colon cancer risk (P value for interaction = 0.031). Interactions were observed between the MTHFR A1298C polymorphism and bowel habits, family history of cancer, alcohol consumption, and beef consumption on colon cancer risk (P-value for interaction = 0.0005, 0.007, 0.067, 0.003, respectively).ConclusionsIn a Thai population, colon cancer risk was associated with alcohol and beef consumption, bowel habits, and family history of cancer. Interactions between MTHFR polymorphisms and environmental factors were also observed.

Interactions Between MTHFR C677T - A1298C Variants and Folic Acid Deficiency Affect Breast Cancer Risk in a Chinese Population

“…The more dynamic effect of C677T is due to its location within the catalytic region. The A1298C polymorphism may affect enzyme regulation possibly by influencing S-adenosylmethionine, which is an allosteric inhibitor of MTHFR and is known to bind in the C-terminal region (Yi et al, 2002;Promthet et al, 2010). Consequently, effects on MTHFR activity may become significant when an individual carries both mutations.…”

“…However, individuals that were heterozygous for both the 1298AgC and 677CgT mutation had somewhat lower activities in lymphocytes (50% to 60% of controls) than single 677CgT heterozygotes (Weisberg et al, 1998). Low enzyme activity may reduce the capacity of DNA methylation and possibly reduce uracil misincorporation into DNA (Weisberg et al, 1998;Skibola et al, 1999;Crott et al, 2001;Huang et al, 2008;Dhillon et al, 2009;Promthet et al, 2010;Rodrigues et al, 2010). One puzzling result of the present study is that there was no trend toward a reduction of MNBN levels in single mutant (TTAA) cells compared with wild-type (CCAA) cells.…”

“…This mutation causes an alanine to valine substitution and reduces the enzyme's catalytic activity Rodrigues et al, 2010). An additional polymorphism, MTHFRA1298C, results in the change from a glutamic acid to an alanine residue and decreases the enzyme's activity (Weisberg et al, 1998;Promthet et al, 2010). Reduced MTHFR activity increases the 5, 10-methylenetetrahydrofolate concentration, whereas it decreases the 5-methyltetrahydrofolate concentration.…”

“…Such a situation is expected to favor the synthesis of dTMP over methylation of CpG, and to minimize both the uracil incorporation into DNA and also the chromosomal breaks caused by uracil. Two common polymorphisms have been reported that are linked to an increased risk of a wide range of adverse health conditions (such as birth defects, slow growth, anemia, weight loss, digestive disorders, some behavioral issues, cardiovascular disease and several cancers) (Weisberg et al, 1998;Huang et al, 2008;Dhillon et al, 2009;Promthet et al, 2010;Rodrigues et al, 2010).…”

“…Epidemiological studies indicate that the 677TT genotype is associated with a lower risk of acute lymphocytic leukemia (Skibola et al, 1999) and colon carcinoma (Promthet et al, 2010), especially in lowrisk subjects who consume a diet high in folate (Crott et al, 2001). In contrast, under FA deficiency, the 677TT variant genotype has been associated with an increased risk of cancer at various sites (breast, gastric, cervical and prostate) (Beilbya et al, 2004;Zoodsma et al, 2005;Bistulfi et al, 2010).…”