Investigating the causal effect of previously reported therapeutic agents for colorectal cancer prevention: protocol for a Mendelian randomization analysis.

ABSTRACT

Background: Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.9 million new cases in 2020 and a predicted rise to 3.2 million in 2040. Screening programmes are already in place to aid early detection and secondary prevention of CRC, but the rising prevalence means additional approaches are required in both primary and secondary prevention settings. Preventive therapy, whereby natural or synthetic agents are used to prevent, reverse or delay disease development, could be an effective strategy to further reduce cancer risk and potential agents have already been identified in conventional observational studies. However, as such studies are vulnerable to confounding and reverse causation, we aim to evaluate these observed relationships using Mendelian randomization (MR), an alternative causal inference approach which should be less susceptible to these biases. Methods and analysis: We will use two-sample MR, which uses two independent samples for the exposure and outcome data, to investigate previously reported observational associations of multiple potential preventive agents with CRC risk. We define preventive agents as any synthetic (e.g. approved medication) or natural (e.g. micronutrient, endogenous hormone) molecule used to reduce the risk of cancer. We will first extract potential preventive agents that have been previously linked to CRC risk in observational studies from reviews of the literature. We will then evaluate whether we can develop a genetic instrument for each preventive agent from previously published genome-wide association studies (GWASs) of direct measures of molecular traits (e.g. circulating levels of protein drug targets, blood-based biomarkers of dietary vitamins). The summary statistics from these GWASs, and a large GWAS of CRC, will be used in two-sample MR analyses to investigate the causal effect of putative preventive therapy agents on CRC risk. Sensitivity analyses will be conducted to evaluate the robustness of findings to potential violations of MR assumptions.

Colorectal cancer is the third most common cancer worldwide and the second most common cause of cancer-related death. An individual's chances of surviving the disease are increased if it is caught early or even prevented from developing in the first place. Currently, screening in the UK is offered to everyone over the age of 50 and whilst this can be effective in early cancer detection and secondary prevention, additional prevention strategies are needed to reduce cancer rates. Previous research has investigated whether intake of certain medications, dietary micronutrients or hormones can help prevent colorectal cancer development. There is some evidence to show that taking aspirin can reduce your risk of developing colorectal cancer, however, given potential adverse side effects to taking aspirin (e.g. gastrointestinal bleeding), this medication is not suitable for everyone. We wanted to assess whether other previously identified medications, micronutrients or hormones have any effect on reducing risk of cancer development. If we can identify a compound that could reduce an individual's risk of developing colorectal cancer, it could be used as an additional cancer prevention strategy. We curated a list of potential preventive compounds from previously conducted studies that used observational epidemiological (i.e. non-randomised) methods. Distinguishing statistical correlations from causal relationships when using observational methods can be difficult. This can be due to additional factors in the study affecting both the use of potential preventive compounds and an individual's risk of cancer development (e.g. those taking vitamin supplements having a healthier diet) or the observed relationship may be causal but in the opposite direction (e.g. a cancer diagnosis has a subsequent effect on dietary habits). We will use an alternative epidemiological method, called Mendelian randomization, which uses genetics to attempt to overcome this issue and enable us to determine if a specific compound is reducing cancer risk.