Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian randomization study based on 79,148 prostate cancer cases and 61,106 controls
BackgroundProstate cancer is the second most common male cancer worldwide, but there is substantial geographical variation suggesting a potential role for modifiable risk factors in prostate carcinogenesis.\n\nMethodsWe identified previously reported prostate cancer risk factors from the World Cancer Research Funds (WCRF) systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79,148 cases and 61,106 controls) or aggressive (15,167 cases and 58,308 controls) prostate cancer using Mendelian randomization (MR) based on genome wide association study (GWAS) summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7,844 prostate cancer cases and 204,001 controls).\n\nFindingsWCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms (SNPs). In MR analyses for overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical-activity, OR=0.49 (0.33-0.72; p=0.0003); serum iron, OR=0.92 (0.86-0.98; p=0.007); body mass index (BMI), OR=0.90 (0.84-0.97; p=0.003); and mono-unsaturated fat, OR=1.11 (1.02-1.20; p=0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive prostate cancer risk: OR=1.07 (1.01-1.15; p=0.03).\n\nInterpretationThe results for physical-activity, serum iron, BMI, mono-unsaturated fat and height are compatible with causality for prostate cancer but more research is needed to rule out violations of MR assumptions for some risk factors. The results suggest that interventions aimed at increasing physical activity may reduce prostate cancer risk, but the direction of effects of BMI, and iron are at odds with their effects on other diseases, so the overall public health impact of intervening on these need to be considered.\n\nFundingWorld Cancer Research Fund International (2015/1421), Cancer Research UK program grant (C18281/A19169), National Institute for Health Research, Bristol Biomedical Research Centre, and Victorian Cancer Agency (MCRF18005).