Gastroenterology

Gastroenterology

Volume 131, Issue 4, October 2006, Pages 1271-1283
Gastroenterology

Special report and review
Folate Intake, MTHFR Polymorphisms, and Risk of Esophageal, Gastric, and Pancreatic Cancer: A Meta-analysis

https://doi.org/10.1053/j.gastro.2006.08.010Get rights and content

Background & Aims: Increasing evidence suggests that a low folate intake and impaired folate metabolism may be implicated in the development of gastrointestinal cancers. We conducted a systematic review with meta-analysis of epidemiologic studies evaluating the association of folate intake or genetic polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, with risk of esophageal, gastric, or pancreatic cancer. Methods: A literature search was performed using MEDLINE for studies published through March 2006. Study-specific relative risks were weighted by the inverse of their variance to obtain random-effects summary estimates. Results: The summary relative risks for the highest versus the lowest category of dietary folate intake were 0.66 (95% confidence interval [CI], 0.53–0.83) for esophageal squamous cell carcinoma (4 case-control), 0.50 (95% CI, 0.39–0.65) for esophageal adenocarcinoma (3 case-control), and 0.49 (95% CI, 0.35–0.67) for pancreatic cancer (1 case-control, 4 cohort); there was no heterogeneity among studies. Results on dietary folate intake and risk of gastric cancer (9 case-control, 2 cohort) were inconsistent. In most studies, the MTHFR 677TT (variant) genotype, which is associated with reduced enzyme activity, was associated with an increased risk of esophageal squamous cell carcinoma, gastric cardia adenocarcinoma, noncardia gastric cancer, gastric cancer (all subsites), and pancreatic cancer; all but one of 22 odds ratios were >1, of which 13 estimates were statistically significant. Studies of the MTHFR A1298C polymorphism were limited and inconsistent. Conclusions: These findings support the hypothesis that folate may play a role in carcinogenesis of the esophagus, stomach, and pancreas.

Section snippets

Study Selection

A computerized literature search was conducted in MEDLINE for studies published in any language from 1966 to March 2006 using the key words folate, folic acid, or MTHFR in combination with cancer, neoplasm, or the individual cancer sites. We also reviewed the reference lists of the relevant articles to identify additional studies. Because folate intake frequently was only one of several dietary factors studied, reports that had fruit, vegetables, vitamins, or nutrients as key words were

Esophageal cancer

We identified 11 case-control studies20, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 that evaluated the association between dietary folate intake and risk of esophageal cancer. Four studies were excluded for the following reasons: no CIs,33, 34 duplicate publications,35 or the RR was not adjusted by age.36 The 7 remaining studies20, 27, 28, 29, 30, 31, 32 were included in the meta-analysis (Table 1). All studies adjusted for potential confounding by smoking and alcohol intake, and 5 studies also

Discussion

Results of this meta-analysis of observational studies support a significant inverse association of dietary folate intake with risk of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and pancreatic cancer. Summary results indicate that individuals with a high dietary folate intake are about 40%–50% less likely to develop these cancers compared with those with low intake. In support of a role of folate in the etiology of esophageal and pancreatic cancer, most but not all studies

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    Supported by the Swedish Research Council/Longitudinal Studies and the Swedish Cancer Foundation.

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