Folate Intake,<i>MTHFR</i>Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis

Kennedy, Deborah; Stern, Seth; Matok, Ilan; Moretti, Myla E; Sarkar, Moumita; Adams‐Webber, Thomasin; Koren, Gideon

doi:10.1155/2012/952508

Cited by 53 publications

(45 citation statements)

References 76 publications

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“…Previous meta-analyses have suggested inverse associations between higher folate intake and a reduced risk of cancer of the lung, pancreas, colon and other parts of the gastrointestinal tract (Dai et al, 2013;Kennedy et al, 2011;Larsson et al, 2006;Lin et al, 2013). In addition, genetic polymorphisms in folate metabolism have been associated with these malignancies (Kennedy et al, 2012;Larsson et al, 2006;Liu et al, 2012). However, some studies report that very high folate intakes, attributable to supplement use, may increase cancer risk.…”

Section: Discussionmentioning

confidence: 99%

Folate intake and risk of bladder cancer: a meta-analysis of epidemiological studies

Shui

2013

International Journal of Food Sciences and Nutrition

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Epidemiological studies have reported conflicting results between folate intake and bladder cancer risk. We conducted a meta-analysis of epidemiological studies published between 1996 and June 2013 on the relationship between folate intake and bladder cancer. We quantified associations with bladder cancer using meta-analysis of risk estimates (REs) associated to the highest versus the lowest category of folate intake using random effect models. Seven cohort and six case-control studies were eligible for inclusion. A significantly decreased risk with bladder cancer was observed in overall folate intake group (RE = 0.84; 95% CI, 0.72-0.96) and subgroup of case-control studies (RE = 0.73; 95% CI, 0.57-0.89), but not in cohort studies (RE = 0.96; 95% CI, 0.81-1.10) when comparing the highest with the lowest category of folate intake. No heterogeneity and publication bias were observed across studies. Although the current evidence, mainly based on data from case-control studies, supports an inverse association between folate intake and bladder cancer, additional large and well-designed cohort studies are needed before definitive conclusions can be drawn.

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Section: Discussionmentioning

confidence: 99%

Folate intake and risk of bladder cancer: a meta-analysis of epidemiological studies

Shui

2013

International Journal of Food Sciences and Nutrition

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“…Indeed, folate deficiency has been shown to suppress DNA synthesis in neoplastic cells (102, 104). Epidemiological data on folate, however, have suggested that a high level of folate is associated with a reduction in risk of colorectal cancer (73, 97–99, 179). Some clinical studies have also demonstrated efficacy (93, 154, 221), although other clinical studies have shown no or even detrimental effects of folate supplementation on colorectal cancer (37, 58, 124, 214).…”

Section: Introductionmentioning

confidence: 99%

Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology

et al. 2016

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The International Agency for Research on Cancer recently released an assessment classifying red and processed meat as “carcinogenic to humans” on the basis of the positive association between increased consumption and risk for colorectal cancer. Diet, however, can also decrease the risk for colorectal cancer and be used as a chemopreventive strategy. Bioactive dietary molecules, such as n-3 polyunsaturated fatty acids, curcumin, and fermentable fiber, have been proposed to exert chemoprotective effects, and their molecular mechanisms have been the focus of research in the dietary/chemoprevention field. Using these bioactives as examples, this review surveys the proposed mechanisms by which they exert their effects, from the nucleus to the cellular membrane. In addition, we discuss emerging technologies involving the culturing of colonic organoids to study the physiological effects of dietary bioactives. Finally, we address future challenges to the field regarding the identification of additional molecular mechanisms and other bioactive dietary molecules that can be utilized in our fight to reduce the incidence of colorectal cancer.

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“…A large, recent meta-analysis (24,816 cases) reported a reduced colorectal cancer risk when comparing highest (median, > 441 μg/day) with lowest (median, 212 μg/day) folate intake (RR 0.88; 95% CI 0.81-0.95)[17]. Using genetic studies, a meta-analysis of 67 studies reported strong evidence of association between the MTHFR 677TT genotype (which results in lower serum folate) and lower colorectal cancer risk under conditions of high folate intake[53].…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomisation study exploring the associations of serum folate with pan and site-specific cancers

Burrows¹,

Kazmi²,

Haycock³

et al. 2019

Preprint

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Background: Epidemiological studies report evidence for an association between folate, an essential B vitamin, and the risk of several common cancers. However, both protective and harmful effects have been reported, and effects may differ by cancer site. These associations suggest that modulating dietary folate, or its synthetic form folic acid, could be used to modify population-wide cancer risk. However, observational studies are liable to biases, including residual confounding and reverse causation, thus limiting causal inference. Using Mendelian randomisation (MR), we investigated the causal relationships of genetically determined serum folate with pan-cancer risk (all cancers excluding non-melanoma skin cancers); breast, prostate, ovarian, lung, and colorectal cancers; and malignant melanoma. Methods:Using publicly available genome-wide association study (GWAS) summary data, we identified genetic instruments to proxy serum folate levels and analysed these using GWAS summary statistics of risk of pan-cancer and six site-specific cancers available from large consortia and the population-based cohort study UK Biobank (UKBB) within a two-sample Mendelian randomisation framework. We conducted MR using the inverse variance weighted (IVW) method and the likelihood-based approach. We performed sensitivity analyses to assess potential violations of MR assumptions. Results:We identified three SNPs (rs1801133, rs1999594, rs7545014) robustly associated with serum folate in a healthy, young adult Irish population using publicly available GWAS summary data. There was little evidence that genetically increased serum folate was associated with risk of pan-cancer or six site-specific cancers. Meta-analysis showed odds ratios (OR) per standard deviation (SD) increase in log10 serum folate of 0.92 (95% confidence interval 0.78-1.07) for breast cancer, 0.87 (95% confidence interval 0.71-1.06) for prostate cancer, 0.87 (95% confidence interval 0.61-1.25) for ovarian cancer, 0.87 (95% confidence interval 0.57-1.34) for lung cancer, and 1.26 (95% confidence interval 0.84-1.88) for colorectal cancer. ORs for pan-cancers and malignant melanoma in UKBB were 0.86 (95% confidence interval 0.71-1.03) and 0.57 (95% confidence interval 0.30-1.10) respectively. The results were powered to detect modest effect sizes (>80% power [α=0.05] to detect ORs 1.1 (or its inverse 0.9) for the cancer GWAS consortia) and were consistent between the two statistical approaches used (IVW and likelihood-based). Conclusions:There is little evidence that genetically increased serum folate may affect the risk of pan-cancer and six site-specific cancers. However, we may still be underpowered to detect clinically relevant but smaller magnitude effects. Our results provide some evidence that increasing levels of circulating folate through widespread supplementation or deregulation of fortification of foods with folic acid is unlikely to lead to moderate unintended population-wide increase in cancer risk.

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Folate Intake,MTHFRPolymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis

Cited by 53 publications

References 76 publications

Folate intake and risk of bladder cancer: a meta-analysis of epidemiological studies

Folate intake and risk of bladder cancer: a meta-analysis of epidemiological studies

Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology

Mendelian randomisation study exploring the associations of serum folate with pan and site-specific cancers

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