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

BackgroundApart 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. MethodsWe 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. ResultsDuring 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). DiscussionThis 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.