Exploring the causal role of the human gut microbiome in endometrial cancer: a Mendelian randomization approach

Endometrial cancer presents a major public health issue, particularly in post-menopausal women. Whilst there are known risk factors for the disease, including oestrogen and obesity, these factors do not fully explain risk variability in cancer outcomes. The identification of novel risk factors may aid in better understanding of endometrial cancer development and, given the link with oestrogen metabolism, obesity and the risk of various cancers, the gut microbiome could be one such risk factor. Mendelian randomization (MR), a method that reduces biases of conventional epidemiological studies (namely, confounding and reverse causation) by using genetic variants to proxy exposures, was used to investigate the effect of gut microbial traits on endometrial cancer risk. Whilst our initial analyses showed that the presence of an unclassified group of bacteria in the Erysipelotrichaceae family increased the risk of oestrogen-dependent endometrial cancer (odds ratio (OR) per approximate doubling of the genetic liability to presence vs absence: 1.13; 95% CI: 1.01, 1.26; P=0.03), subsequent sensitivity analyses, including colocalisation, suggested these findings were unlikely reflective of causality. This work highlights the importance of using a robust MR analysis pipeline, including sensitivity analyses to assess the validity of causal effect estimates obtained using MR. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement EF and RK are supported by Wellcome Trust PhD studentships (grant numbers: 228277/Z/23/Z and 228278/Z/23/Z respectively) on the Molecular, Genetic, Lifecourse Epidemiology programme (218495/Z/19/Z). KHW is supported by the University of Bristol and both KHW and CH were supported by Cancer Research UK [grant number RCCPDF\100007] for this paper. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The data used was openly available for use in this study, endometrial cancer summary data was accessed at https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST006464/, https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST006465/ and https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST006466/ The microbiome summary data was accessed at https://data.bris.ac.uk/data/dataset/22bqn399f9i432q56gt3wfhzlc I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes GWAS summary-level data used in this study were publicly available for microbiome GWAS (mGWAS) conducted by Hughes et al (10) (available here: https://data.bris.ac.uk/data/dataset/22bqn399f9i432q56gt3wfhzlc). We used the full meta-analysis results (i.e., listed as sub-level method\_em) for the main analysis and FGFP-only analysis (i.e., listed as sub-level method\_score) for the sensitivity analyses, including reverse MR and colocalisation analyses. Summary-level data for overall and subtype specific endometrial cancer was publically available on the IEU OpenGWAS (GWAS IDs: ebi-a-GCST006464-6).