Diet-wide analyses for risk of colorectal cancer: prospective study of 12,250 incident cases among 543,000 women in the UK

Background: Apart from alcohol and processed meat, uncertainty remains regarding the role of diet in the aetiology of colorectal cancer. We conducted a large diet-wide association study of colorectal cancer risk, together with a targeted genetic analysis. Methods: We examined associations of 97 foods and nutrients with risk of colorectal cancer in 542,778 women enrolled in the Million Women Study using multivariable-adjusted Cox regression models. We also assessed the association between genetically predicted milk intake (as a proxy of dairy and/or calcium intake) and colorectal cancer risk in the ColoRectal Transdisciplinary Study, the Colon Cancer Family Registry, and the Genetics and Epidemiology of Colorectal Cancer consortium (GECCO) using a two-sample Mendelian randomisation (MR) analysis. Results: During a mean (SD) 16.6 (4.8) years of follow-up, 12,251 women were diagnosed with colorectal cancer. Seventeen dietary factors were associated with risk of colorectal cancer (False Discovery Rate <0.05). Of these associations, alcohol and calcium intakes had the strongest associations with colorectal cancer risk; a positive association for alcohol (relative risk [RR] per 20 g/day=1.15, 95% confidence interval [CI] 1.09-1.20, p<0.0000001) and an inverse association for calcium (RR per 300 mg/day=0.83, 95% CI 0.77-0.89, p<0.000001). Other dairy-related factors including dairy milk, yogurt, riboflavin, magnesium, phosphorus, and potassium were also inversely associated with colorectal cancer risk, though further analysis showed that calcium intake was likely to account for these associations. Of the remaining dietary factors that were associated with colorectal cancer risk, only red and processed meat intake was associated with increased risk. Breakfast cereal, fruit, wholegrains, carbohydrates, fibre, total sugars, folate, and vitamin C were inversely associated with risk, though these associations may have been influenced by residual confounding by lifestyle and other dietary factors. In MR analyses, genetically predicted milk consumption was inversely associated with risk of colorectal cancer (RR per 200 g/day=0.60, 95% CI 0.46-0.74), colon cancer (RR per 200 g/day=0.60, 95% CI 0.43-0.77), and rectal cancer (RR per 200 g/day=0.49, 95% CI 0.31-0.67). Discussion: This comprehensive diet-wide study provides robust evidence for the protective role of dairy milk and dairy products in colorectal cancer incidence, which is likely to be driven largely if not wholly by calcium. More research is needed to understand the potential health impacts of increasing calcium intake in some populations. ### Competing Interest Statement Ulrike Peters was a consultant with AbbVie and her husband is holding individual stocks for the following companies: BioNTech SE ADR, Amazon, CureVac BV, NanoString Technologies, Google Alphabet Inc Class C, NVIDIA Corp, Microsoft Corp. ### Funding Statement This work was funded by Cancer Research UK and the UK Medical Research Council. KEBs work on this project was funded by a Girdlers Health Research Council Fellowship. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. For the purpose of open access, the authors have applied a Creative Commons Attribution CC BY licence to any Author Accepted Manuscript version arising. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Oxford and Anglia Multi-Centre Research Ethics Committee and all participants gave written consent for follow-up through medical records. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Information on data access is available at www.millionwomenstudy.org/data_access/.