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. 2022 Feb 2;20(1):41.
doi: 10.1186/s12916-022-02246-y.

Systematic review of Mendelian randomization studies on risk of cancer

Georgios Markozannes  1   2 , Afroditi Kanellopoulou  1 , Olympia Dimopoulou  3 , Dimitrios Kosmidis  4 , Xiaomeng Zhang  5 , Lijuan Wang  5 , Evropi Theodoratou  5   6 , Dipender Gill  2 , Stephen Burgess  7   8 , Konstantinos K Tsilidis  9   10
Affiliations

Systematic review of Mendelian randomization studies on risk of cancer

Georgios Markozannes et al. BMC Med. .

Abstract

Background: 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.

Methods: 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 robust, probable, suggestive, and insufficient, 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.

Results: 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 robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust 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.

Conclusions: 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.

Keywords: Cancer; Evidence grading; Mendelian randomization; Risk factors; Systematic review.

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Conflict of interest statement

DG is employed part-time by Novo Nordisk, outside and unrelated to the current work; the rest of the authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Categorization of the evidence. * For the main analysis: statistically significant at the threshold set up by the study due to multiple testing or at 0.05 if no multiple testing threshold was defined. For the sensitivity analyses: statistically significant at 0.05
Fig. 2
Fig. 2
Study selection flowchart
Fig. 3
Fig. 3
Time trend of Mendelian randomization (MR) publications on cancer risk or mortality, by MR design
Fig. 4
Fig. 4
Evidence map
Fig. 5
Fig. 5
Network of the exposure–cancer associations of the Mendelian randomization analyses presenting robust evidence. Note: For circulating telomere length, the red arrows refer to longer while the green arrows refer to shorter genetically predicted telomere length. For HMG-GoA reductase, the green arrow to ovarian cancer refers to decreased genetically predicted levels of the exposure. Abbreviations: AC: adenocarcinoma; BMI: body mass index; ER−: estrogen receptor negative; ER+: estrogen receptor positive; FEV1: forced expiratory volume in one second; HDL: high-density lipoprotein; HMG-CoA: 3-Hydroxy-3-methylglutaryl coenzyme A; IGF-1: insulin-like growth factor 1; LDL: low-density lipoprotein; SCC: squamous cell carcinoma; SHBG: sex-hormone-binding globulin
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660. - DOI - PubMed
    1. Dwan K, Gamble C, Williamson PR, Kirkham JJ, Reporting Bias G. Systematic review of the empirical evidence of study publication bias and outcome reporting bias - an updated review. PloS one. 2013;8(7):e66844. - PMC - PubMed
    1. Hingorani A, Humphries S. Nature’s randomised trials. Lancet (London, England) 2005;366(9501):1906–1908. - PubMed
    1. Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–1163. - PubMed
    1. Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol. 2013;178(7):1177–1184. - PMC - PubMed

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