Mendelian randomisation study exploring the associations of serum folate with pan and site-specific cancers
Authors: Burrows Kimberley , Kazmi Nabila , Haycock Philip , Tsilidis Konstantinos K ,   The PRACTICAL consortium, CRUK, BPC3, CAPS and PEGASUS,   GECCO, CORECT and CCFR, Martin Richard M , Lewis Sarah J 
Published: September 2019

AbstractBackgroundEpidemiological studies report evidence for an association between folate and the risk of several common cancers. However, both protective and harmful effects have been reported, and effects may differ by cancer site. Using Mendelian randomisation (MR), we investigated the causal relationships of genetically predicted serum folate with pan-cancer risk (all cancers excluding non-melanoma skin cancers); breast, prostate, ovarian, lung, and colorectal cancers; and malignant melanoma.MethodsWe conducted a two-sample MR analysis, using genetic instruments for serum folate to appraise the possible causal role on risk of pan-cancer and six site-specific cancers using summary statistics available from large consortia and the population-based cohort study UK Biobank (UKBB).ResultsThere was little evidence that genetically elevated serum folate was causally associated with risk of pan-cancer or six site-specific cancers. Meta-analysis showed odds ratios (OR) per SD increase in log serum folate of 0.93 (95% CI 0.78-1.11) for breast cancer, 0.87 (95% CI 0.71-1.06) for prostate cancer, 0.84 (95% CI 0.59-1.20) for ovarian cancer, and 0.87 (95% CI 0.57-1.32) for lung cancer. The OR for colorectal cancer was 1.18 (95% CI 0.64-2.18) in large consortia analysis, while ORs for pan-cancers and malignant melanoma in UKBB were 0.88 (95% CI 0.73-1.06) and 0.56 (95% CI 0.29-1.08) respectively. The results were powered to detect modest effect sizes (>90% power (α 0.05) to detect ORs 1.2 (0.8) for the GWAS consortia) and were consistent between the two statistical approaches used (inverse variance weighted (IVW) and likelihood-based).ConclusionsThere is little evidence that genetically elevated 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.Key MessagesObservational studies have identified associations between folate (both intake and circulating levels) and risk of developing site-specific cancers. However, these studies are liable to biases such as confounding, measurement error, and reverse causation.Using Mendelian randomisation, we appraised the causal relationships between genetically influenced serum folate levels and pan-cancer risk (all cancers excluding non-melanoma skin cancers); breast, prostate, ovarian, lung, and colorectal cancers; and malignant melanoma.Overall findings suggest that there is little evidence for the causal associations between genetically influenced serum folate and risk of pan-cancer and six site-specific cancers.We 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.