Mendelian randomization studies of cancer risk: a literature review

In this paper, we summarize prior studies that have used Mendelian Randomization (MR) methods to study the effects of exposures, lifestyle factors, physical traits, and/or biomarkers on cancer risk in humans. Many such risk factors have been associated with cancer risk in observational studies, and the MR approach can be used to provide evidence as to whether these associations represent causal relationships. MR methods require a risk factor of interest to have known genetic determinants that can be used as proxies for the risk factor (i.e., "instrumental variables" or IVs), and these can be used to obtain an effect estimate that, under certain assumptions, is not prone to bias caused by unobserved confounding or reverse causality. This review seeks to describe how MR studies have contributed to our understanding of cancer causation.

We searched the published literature and identified 76 MR studies of cancer risk published prior to October 31, 2017. Risk factors commonly studied included alcohol consumption, Vitamin D, anthropometric traits, telomere length, lipid traits, glycemic traits, and markers of inflammation. Risk factors showing compelling evidence of a causal association with risk for at least one cancer type include alcohol consumption (for head/neck and colorectal), adult body mass index (increases risk for multiple cancers, but decreases risk for breast), height (increases risk for breast, colorectal, and lung; decreases risk for esophageal), telomere length (increases risk for lung adenocarcinoma, melanoma, renal cell carcinoma, glioma, B-cell lymphoma subtypes, chronic lymphocytic leukemia, and neuroblastoma), and hormonal factors (affects risk for sex-steroid sensitive cancers).

This review highlights alcohol consumption, body mass index, height, telomere length, and the hormonal exposures as factors likely to contribute to cancer causation. This review also highlights the need to study specific cancer types, ideally subtypes, as the effects of risk factors can be heterogeneous across cancer types. As consortia-based genome-wide association studies increase in sample size and analytical methods for MR continue to become more sophisticated, MR will become an increasingly powerful tool for understanding cancer causation.