Folate Intake and the Risk of Upper Gastrointestinal Cancers

A Systematic Review and Meta-analysis

Martin Tio; Juliana Andrici; Michael R Cox; Guy D Eslick

Disclosures

J Gastroenterol Hepatol. 2014;29(2):250-258. 

In This Article

Abstract and Introduction

Abstract

Background and Aim There is conflicting evidence on the association between folate intake and the risk of upper gastrointestinal tract cancers. In order to further elucidate this relationship, we performed a systematic review and quantitative meta-analysis of folate intake and the risk of esophageal, gastric, and pancreatic cancer.

Methods Four electronic databases (Medline, PubMed, Embase, and Current Contents Connect) were searched to July 26, 2013, with no language restrictions for observational studies that measured folate intake and the risk of esophageal cancer, gastric cancer, or pancreatic cancer. Pooled odds ratios and 95% confidence intervals were calculated using a random effects model.

Results The meta-analysis of dietary folate and esophageal cancer risk comprising of nine retrospective studies showed a decreased risk of esophageal cancer (odds ratio [OR] 0.59; 95% confidence interval [95% CI] 0.51–0.69). The meta-analysis of dietary folate and gastric cancer risk comprising of 16 studies showed no association (OR 0.94; 95% CI 0.78–1.14). The meta-analysis of dietary folate and pancreatic cancer risk comprising of eight studies showed a decreased risk of pancreatic cancer (OR 0.66; 95% CI 0.49–0.89).

Conclusion Dietary folate intake is associated with a decreased risk of esophageal and pancreatic cancer, but not gastric cancer. Interpretation of these relationships is complicated by significant heterogeneity between studies when pooled, and by small numbers of studies available to analyze when stratification is performed to reduce heterogeneity.

Introduction

Folate is a naturally occurring nutrient that belongs to the B vitamin class that plays a central role in the one-carbon metabolism of DNA. Humans are unable to produce folate de novo, and instead rely upon folate derived from dietary intake. There is a significant body of research implicating folate in carcinogenesis, although there is evidence that folate may play a role in both promoting and preventing carcinogenesis.[1]

Mechanistic studies of folate have shown that low levels of folate can induce DNA strand breaks via uracil misincorporation into DNA,[2] and that both low and high levels of folate can alter DNA methylation levels.[3,4] These mechanisms of DNA damage, and of potential alterations to gene expression via DNA methylation, offer potential explanations of how folate may affect carcinogenesis.

The role of folate in colorectal carcinogenesis is probably the best studied, with a number of early observational studies suggesting that a high intake of folate decreases the risk of colorectal cancer.[5] On the basis of these early studies, a number of interventional chemoprevention clinical trials were performed, but both these and also later observational studies have provided conflicting evidence.[6,7]

The role of folate in upper gastrointestinal cancers is similarly unclear. Animal model evidence involving mice and dogs have suggested that high folate intake alters DNA methylation and can reduce gastric cancer risk.[8,9] In terms of epidemiological evidence, there are a number of studies indicating that polymorphisms of genes that function in the folate pathway can modulate the risk of esophageal and gastric cancer.[10,11] A 2006 systematic review found that high folate intake reduced the risk of esophageal and pancreatic cancers; however, the review was based on a small number of studies.[12] Many large-scale observational studies have been published during the last few years, and therefore, we performed a systematic review and quantitative meta-analysis of observational studies on folate intake and the risk of esophageal, gastric, and pancreatic cancers.

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