Folate exposures and risk of colorectal cancer: an umbrella review of meta-analyses of observational studies and randomised controlled trials.

Abstract

To systematically summarise and evaluate the existing evidence of the associations between diverse folate exposures and the risk of colorectal cancer (CRC), while identifying evidence quality. Umbrella review of meta-analyses. PubMed, Web of Science, Cochrane and Embase were searched from the database inception to March 2024, with an update to 12 October 2025. We included meta-analyses of randomised controlled trials or observational studies that investigated the associations between folate exposures and CRC or precancerous lesions (ie, adenoma and polyps). For each association, we recalculated the summary effect size with 95% CI using the DerSimonian and Laird random-effects model, heterogeneity (<i>I</i>² statistic), 95% prediction interval, small-study effect (Egger's test) and excess significance bias (χ² test). This umbrella review included five meta-analyses describing 10 associations between folate exposures and CRC risk. In the general population, moderate-quality evidence supported an inverse association between total folate intake (from foods and supplements) and CRC risk (RR 0.84; 95% CI 0.80 to 0.90), while low-quality evidence suggested inverse associations of dietary folate intake (from foods alone) (RR 0.88; 95% CI 0.81 to 0.96) and folic acid supplement intake (RR 0.83; 95% CI 0.77 to 0.90) with CRC risk. Among patients with inflammatory bowel disease, low-quality evidence suggested an inverse association between folic acid supplement intake and CRC incidence (HR 0.71; 95% CI 0.53 to 0.96). Additionally, elevated circulating folate levels were observed to have a provoking effect on advanced-stage tumours (OR 1.95; 95% CI 1.18 to 3.22; Grading of Recommendations Assessment, Development and Evaluation (GRADE): very low). Sensitivity analysis revealed a potential increased risk of adenoma recurrence associated with folic acid supplement use among patients with a history of adenoma (RR 1.05; 95% CI 0.86 to 1.29; GRADE: high). These findings suggest that consuming dietary folate and total folate intake may be beneficial in CRC primary prevention. Specifically, folic acid supplements may inhibit colorectal carcinogenesis in normal tissues while promoting cancer in the established neoplastic foci. CRD42024537550.