Methylene Tetrahydrofolate Reductase Genotype Modifies the Chemopreventive Effect of Folate in Colorectal Adenoma, but not Colorectal Cancer

Abstract

Epidemiologic evidence suggests a role for folate, a critical component of the 1-carbon cycle, in colorectal adenoma and cancer pathogenesis. Low folate levels, along with genetic polymorphisms in key enzymes such as methylene tetrahydrofolate reductase (MTHFR), can cause DNA hypomethylation and aberrant CpG methylation, which have been associated with colorectal tumor development. We investigated self-reported folate and alcohol intake alongside possible modifying effects of MTHFR 677 C>T and 1298 A>C polymorphisms in UK case-control studies of colorectal adenoma (317 cases, 296 controls) and cancer (500 cases, 742 controls). A significant association between MTHFR 1298 and colorectal cancer risk was observed [odds ratio, 1.57; 95% confidence interval (95% CI), 1.05-2.37], which was more pronounced in males (odds ratio, 3.02; 95% CI, 1.63-5.62). Although we found no association between MTHFR 677 and colorectal cancer, when data were stratified by sex, an increased risk was seen in females (odds ratio, 1.96; 95% CI, 1.11-3.46) but not in males. High folate intake was associated with a decreased risk for colorectal adenoma (odds ratio, 0.47; 95% CI, 0.30-0.73; P trend , <0.001), which was modified by MTHFR 1298 genotype (P interaction = 0.006). However, we found no evidence to support the hypothesis that a high-folate diet protects against colorectal cancer development. Consistent with previous studies, high alcohol intake (z14 U/wk) was associated with a significantly increased cancer risk (odds ratio, 2.57; 95% CI, 1.81-3.64). Our data suggest that dietary folate intake may be an important determinant for premalignant colorectal disease development but not colorectal cancer, an association that is modified by MTHFR genotype. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2421 -30)

Genetic Variants of Methyl Metabolizing Enzymes and Epigenetic Regulators: Associations with Promoter CpG Island Hypermethylation in Colorectal Cancer

“…Analyses were stratified by sex in some studies, and positive associations with colorectal cancer were reported among men for MTHFR C677T (47) and A1298C (48,50). In addition, similar to our study, the rare T allele of the MTHFR C677T polymorphism has been observed to be associated with increased colorectal cancer risk among women but not among men (48). MTHFR polymorphisms may reduce enzymatic activity and thereby decrease the pool of 5-methyltetrahydrofolate.…”

“…Rare variants of these polymorphisms were generally inversely associated with colorectal cancer risk (4,5,12,44,45) or with colorectal adenoma recurrence (46). Conversely, associations with increased colorectal cancer risk (47)(48)(49), colorectal adenoma risk (50), or increased risk for colorectal adenoma recurrence (51,52) have been observed as well. Analyses were stratified by sex in some studies, and positive associations with colorectal cancer were reported among men for MTHFR C677T (47) and A1298C (48,50).…”

“…Conversely, associations with increased colorectal cancer risk (47)(48)(49), colorectal adenoma risk (50), or increased risk for colorectal adenoma recurrence (51,52) have been observed as well. Analyses were stratified by sex in some studies, and positive associations with colorectal cancer were reported among men for MTHFR C677T (47) and A1298C (48,50). In addition, similar to our study, the rare T allele of the MTHFR C677T polymorphism has been observed to be associated with increased colorectal cancer risk among women but not among men (48).…”

Genetic variation in the folate metabolic pathway and risk of childhood leukemia

“…An alternative explanation, suggested in relation to colorectal cancer, 46 relates to differences in circulating folate levels between populations. In the mid to late 1990s fortification of foods with folic acid became mandatory in several countries, including the United States, but not the United Kingdom, resulting in marked increases in folate intake.…”

The Recessive model of 677C>T Polymorphism in MTHFR gene increase moderately the risk of Colorectal Cancer in Moroccan patients

“…Our study show a similar results of the meta-analysis for 11 studies representing over 7,000 case-control study participants published by Deborah et al [17]. In contrast only one reported a significant OR based on gender and genotype Lightfoot and al. found that the men with 677CT genotype had a reduced risk of CRC, and women with 677TT genotype had increased risk [18].…”