David Timothy Bishop

Aspirin has been used to treat pain and fever for 120 years. Its uses expanded into treating arthritis and prevention of thrombotic events. Its anti‐cancer role emerged with observational studies in the 1980's and subsequent cancer review in those treated with aspirin in cardiovascular trials. Two randomised placebo‐controlled trials with cancer as an endpoint, the Women's Health Study and CAPP2 provided support. The latter involved 861 carriers of Lynch syndrome (LS) who received either 600 mg aspirin or placebo for 2–4 years. Aspirin recipients subsequently had 50% fewer colorectal cancers. CaPP3 randomised 1866 LS carriers to 600 mg, 300 mg or 100/75 mg daily for 2 years blinded then for 3 years open label. Lynch syndrome cancer and colorectal cancer rate mirrored that in the 600 mg limb of CAPP2. Those on the lowest dose had the fewest cancers in keeping with this being equivalent to 600 mg. The Intention to treat confidence intervals fell within the predefined upper limit of 1.5. A survey of primary care doctors revealed only 62% would agree to prescribe the 600 mg dose regardless of guidance. As a normal dietary component, salicylate is likely to influence multiple pathways. Most interesting is the recent demonstration that low dose aspirin blocks release of thromboxane A2, a product of activated platelets which suppresses T cell function. An international Delphi report has endorsed the daily use of 75–100 mg aspirin in adults with Lynch syndrome prior to old age when adverse effects become a greater concern.

Supplementary Table 5 shows effect estimates from pleiotropy-robust methods for all exposures with evidence from the initial MR analysis

Supplementary Table 11 shows multi-variable MR estimates for omega-3 on CRC risk including and excluding the FADS region, compared to the IVW estimate excluding the FADS region

Supplementary Table 9 shows results from CAUSE analysis, comparing a causal, sharing and null model

Background:Conventional observational studies have identified several potential therapeutic agents that may lower the risk of colorectal cancer development. However, these studies are susceptible to unmeasured and residual confounding and reverse causation, undermining robust causal inference.Methods:We used Mendelian randomization, a genetic epidemiologic method that can strengthen causal inference, to evaluate the effect of previously reported therapeutic agents on colorectal cancer risk, including medications, dietary micronutrients, and exogenous hormones. Genetic instruments were constructed using genome-wide association studies (GWAS) of molecular traits (e.g., circulating levels of protein drug targets, blood-based biomarkers of micronutrients, and circulating levels of endogenous hormones). Using summary statistics from these GWASs and a colorectal cancer risk GWAS (cases = 78,473; controls = 107,143), we employed Wald ratios and inverse-variance weighted models to estimate causal effects.Results:We found evidence for associations of genetically proxied elevated omega-3 fatty acids (OR = 1.10; 95% confidence interval, 1.03–1.18; P = 6.20 × 10−3) and reduced plasma angiotensin-converting enzyme (ACE) levels (OR = 1.08; 95% confidence interval, 1.03–1.13; P = 9.36 × 10−4) with colorectal cancer risk. Findings for ACE inhibition were consistent across sensitivity analyses.Conclusions:Reduced plasma ACE levels were robustly linked to increased colorectal cancer risk. Further work is required to better understand the mechanism behind this finding and whether this translates to adverse effects via medication use (i.e., ACE inhibitors).Impact:These findings provide updated evidence on the role of previously reported therapeutic agents in colorectal cancer risk, helping prioritize further evaluation of those agents with potential etiologic roles in cancer development.

Supplementary Table 8 shows results from z-test for heterogeneity between effect estimates for cancer restricted to subsites, sexes and early onset

Supplementary Table 3 contains genetic instruments used for each molecular trait including summary statistics and r2 and F-statistic

Supplementary Table 2 shows all preventive agents identified from literature search, their corresponding molecular trait and whether a genetic instrument was available