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Systematic review of Mendelian randomization studies on risk of cancer

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Markozannes, Georgios 
Kanellopoulou, Afroditi 
Dimopoulou, Olympia 
Kosmidis, Dimitrios 
Zhang, Xiaomeng 


jats:titleAbstract</jats:title>jats:sec jats:titleBackground</jats:title> jats:pWe 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:titleMethods</jats:title> jats:pWe 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:italicrobust</jats:italic>, jats:italicprobable</jats:italic>, jats:italicsuggestive</jats:italic>, and jats:italicinsufficient</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:titleResults</jats:title> jats:pWe 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:italicrobust</jats:italic>, 275 (18.7%) by jats:italicprobable</jats:italic>, and 89 (6.1%) by jats:italicsuggestive</jats:italic> evidence. The most prominent jats:italicrobust</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:titleConclusions</jats:title> jats:pDespite 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>



Research Article, Mendelian randomization, Cancer, Risk factors, Systematic review, Evidence grading

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BMC Medicine

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Springer Science and Business Media LLC
Cancer research UK (C18281/A29019)
Wellcome Trust (204623/Z/16/Z)
NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)
Cancer Research UK Career Development Fellowship (C31250/A22804)