Systematic review of Mendelian randomization studies on risk of cancer

Abstract

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely <jats:italic>robust</jats:italic>, <jats:italic>probable</jats:italic>, <jats:italic>suggestive</jats:italic>, and <jats:italic>insufficient</jats:italic>, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by <jats:italic>robust</jats:italic>, 275 (18.7%) by <jats:italic>probable</jats:italic>, and 89 (6.1%) by <jats:italic>suggestive</jats:italic> evidence. The most prominent <jats:italic>robust</jats:italic> associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.</jats:p> </jats:sec>