{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:49:50Z","timestamp":1778626190144,"version":"3.51.4"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Numerous studies have reported that metformin can reduce the risk of tumor development. However, some of the results of these studies are conflicting, necessitating a more reliable evaluation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) of tumors to explore the causal relationship between metformin and tumors. Two cohorts of patients taking metformin were obtained from the UK Biobank. Complete phenotype data of the tumors were obtained from FinnGen_R10. We elucidated the causal relationship using a two-sample Mendelian randomization (MR) analysis. More importantly, we conducted a meta-analysis to ensure relatively unbiased results. In the MR analysis, we used the inverse-variance weighted (IVW) method as the main outcome indicator. Subsequently, two cohorts were integrated for the meta-analysis. Finally, we investigated the mechanisms through mediational MR analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MR analysis revealed that metformin might have a causal relationship with 13 tumor-associated phenotypes in the training cohort. Four phenotypes were validated in the testing cohort. In the training and testing cohorts, metformin exhibited a protective effect against brain meningiomas and malignant neoplasms of the breast (HER-positive), oral cavity, tonsils, and the base of the tongue. Intriguingly, after integrating the results of the two cohorts for the meta-analysis, 12 results were statistically significant. Mediational MR analysis suggested that the effects of metformin on brain meningiomas may be weakened by the presence of the family Oxalobacteraceae.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Metformin exhibits potential preventive and therapeutic effects on four types of tumors: brain meningioma, malignant neoplasms of the breast (HER-positive), oral cavity and tonsils, and the base of the tongue. Large randomized controlled trials are required to confirm these findings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2024.1397390","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:59:37Z","timestamp":1718758777000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Bridging the gap: exploring the causal relationship between metformin and tumors"],"prefix":"10.3389","volume":"15","author":[{"given":"Zexin","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenfeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zexia","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihan","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuesong","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shenyuan","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yadong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haibo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S41","DOI":"10.2337\/dc15-S010","article-title":"(7) Approaches to glycemic treatment","volume":"38","year":"2015","journal-title":"Diabetes Care"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1002\/cncr.26439","article-title":"Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer","volume":"118","author":"Bayraktar","year":"2012","journal-title":"Cancer"},{"key":"B3","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false Discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1002\/ijc.29274","article-title":"Menopausal hormone therapy and central nervous system tumor risk: large UK prospective study and meta-analysis","volume":"136","author":"Benson","year":"2015","journal-title":"Int. J. Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1093\/ije\/dyy258","article-title":"Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption","volume":"48","author":"Bowden","year":"2019","journal-title":"Int. J. Epidemiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet. Epidemiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1007\/s10654-015-0011-z","article-title":"Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors","volume":"30","author":"Burgess","year":"2015","journal-title":"Eur. J. Epidemiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.clbc.2013.08.012","article-title":"Metformin decreases circulating androgen and estrogen levels in nondiabetic women with breast cancer","volume":"13","author":"Campagnoli","year":"2013","journal-title":"Clin. Breast Cancer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1002\/ijc.34198","article-title":"Incidence and survival of benign, borderline, and malignant meningioma patients in the United States from 2004 to 2018","volume":"151","author":"Cao","year":"2022","journal-title":"Int. J. Cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1038\/s41598-017-01353-8","article-title":"Metformin disrupts malignant behavior of oral squamous cell carcinoma via a novel signaling involving Late SV40 factor\/Aurora-A","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1227\/01.neu.0000188281.91351.b9","article-title":"Epidemiology of intracranial meningioma","volume":"57","author":"Claus","year":"2005","journal-title":"Neurosurgery"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1004679","DOI":"10.3389\/fmicb.2022.1004679","article-title":"Wholegrain fermentation affects gut microbiota composition, phenolic acid metabolism and pancreatic beta cell function in a rodent model of type 2 diabetes","volume":"13","author":"Costabile","year":"2022","journal-title":"Front. Microbiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.1002\/cncr.10410","article-title":"The association between breast carcinoma and meningioma in women","volume":"94","author":"Custer","year":"2002","journal-title":"Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"k601","DOI":"10.1136\/bmj.k601","article-title":"Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians","volume":"362","author":"Davies","year":"2018","journal-title":"Bmj"},{"key":"B16","doi-asserted-by":"publisher","first-page":"10804","DOI":"10.1158\/0008-5472.CAN-07-2310","article-title":"Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells","volume":"67","author":"Dowling","year":"2007","journal-title":"Cancer Res."},{"key":"B17","volume-title":"MRC IEU UK Biobank GWAS pipeline version 1","author":"Elsworth","year":"2023"},{"key":"B18","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1002\/dmrr.2276","article-title":"Avoiding the slippery slope: preventing the development of diabetes in women with a history of gestational diabetes","volume":"28","author":"Feig","year":"2012","journal-title":"Diabetes Metab. Res. Rev."},{"key":"B19","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/nature22318","article-title":"Corrigendum: disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota","volume":"545","author":"Forslund","year":"2017","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/s41392-022-00947-7","article-title":"Antibody drug conjugate: the \"biological missile\" for targeted cancer therapy","volume":"7","author":"Fu","year":"2022","journal-title":"Signal Transduct. Target Ther."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1001\/jama.2022.6147","article-title":"Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: the MA.32 randomized clinical trial","volume":"327","author":"Goodwin","year":"2022","journal-title":"Jama"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e147096","DOI":"10.1172\/jci.insight.147096","article-title":"Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions","volume":"6","author":"Gutkind","year":"2021","journal-title":"JCI Insight"},{"key":"B23","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"Bmj"},{"key":"B24","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1007\/s10549-012-2404-y","article-title":"Clinical pathological characteristics and prognostic analysis of 1,013 breast cancer patients with diabetes","volume":"137","author":"Hou","year":"2013","journal-title":"Breast Cancer Res. Treat."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4726","DOI":"10.1038\/s41467-022-32183-6","article-title":"The causes and consequences of Alzheimer's disease: phenome-wide evidence from Mendelian randomization","volume":"13","author":"Korologou-Linden","year":"2022","journal-title":"Nat. Commun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41588-020-00763-1","article-title":"Large-scale association analyses identify host factors influencing human gut microbiome composition","volume":"53","author":"Kurilshikov","year":"2021","journal-title":"Nat. Genet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature."},{"key":"B28","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s12935-023-02902-0","article-title":"Cancer immunotherapy with immune checkpoint inhibitors (ICIs): potential, mechanisms of resistance, and strategies for reinvigorating T cell responsiveness when resistance is acquired","volume":"23","author":"Marei","year":"2023","journal-title":"Cancer Cell Int."},{"key":"B29","doi-asserted-by":"publisher","first-page":"4478","DOI":"10.1158\/1078-0432.CCR-20-4557","article-title":"FDA approval summary: fam-trastuzumab deruxtecan-nxki for the treatment of unresectable or metastatic HER2-positive breast cancer","volume":"27","author":"Narayan","year":"2021","journal-title":"Breast Cancer"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1038\/s41588-020-0684-4","article-title":"Complex genetic signatures in immune cells underlie autoimmunity and inform therapy","volume":"52","author":"Orr\u00f9","year":"2020","journal-title":"Nat. Genet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"6934","DOI":"10.1038\/s41467-023-42532-8","article-title":"Genome-wide association analysis of plasma lipidome identifies 495 genetic associations","volume":"14","author":"Ottensmann","year":"2023","journal-title":"Nat. Commun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1001\/jamainternmed.2017.3601","article-title":"Research and development spending to bring a single cancer drug to market and revenues after approval","volume":"177","author":"Prasad","year":"2017","journal-title":"JAMA Intern Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"a040501","DOI":"10.1101\/cshperspect.a040501","article-title":"Mendelian randomization: concepts and scope","volume":"12","author":"Richmond","year":"2022","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3801","DOI":"10.1038\/s41467-020-17670-y","article-title":"A decade of immune-checkpoint inhibitors in cancer therapy","volume":"11","author":"Robert","year":"2020","journal-title":"Nat. Commun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0181089","DOI":"10.1371\/journal.pone.0181089","article-title":"Diabetes, use of metformin, and the risk of meningioma","volume":"12","author":"Seliger","year":"2017","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1001\/jamaoncol.2021.2318","article-title":"Addition of metformin to concurrent chemoradiation in patients with locally advanced non-small cell lung cancer: the NRG-lu001 phase 2 randomized clinical trial","volume":"7","author":"Skinner","year":"2021","journal-title":"JAMA Oncol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.3892\/ijo.2018.4343","article-title":"Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation","volume":"52","author":"Tang","year":"2018","journal-title":"Int. J. Oncol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3480","DOI":"10.3892\/ol.2017.6632","article-title":"Lack of chemopreventive efficacy of metformin in rodent models of urinary bladder, head and neck, and colon\/intestine cancer","volume":"14","author":"Thompson","year":"2017","journal-title":"Oncol. Lett."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1001\/jamaoncol.2021.2328","article-title":"Metformin in combination with chemoradiotherapy in locally advanced non-small cell lung cancer: the OCOG-ALMERA randomized clinical trial","volume":"7","author":"Tsakiridis","year":"2021","journal-title":"JAMA Oncol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.2337\/diacare.27.7.1605","article-title":"Mortality and causes of death in a national sample of diabetic patients in Taiwan","volume":"27","author":"Tseng","year":"2004","journal-title":"Diabetes Care"},{"key":"B41","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1007\/s10549-014-2985-8","article-title":"Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes","volume":"145","author":"Tseng","year":"2014","journal-title":"Breast Cancer Res. Treat."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.18632\/aging.101019","article-title":"Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus","volume":"8","author":"Tseng","year":"","journal-title":"Aging (Albany NY)"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.18632\/oncotarget.6626","article-title":"Metformin may reduce oral cancer risk in patients with type 2 diabetes","volume":"7","author":"Tseng","year":"","journal-title":"Oncotarget"},{"key":"B44","doi-asserted-by":"publisher","first-page":"41132","DOI":"10.18632\/oncotarget.17066","article-title":"Metformin and lung cancer risk in patients with type 2 diabetes mellitus","volume":"8","author":"Tseng","year":"2017","journal-title":"Oncotarget"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1111\/liv.13872","article-title":"Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes","volume":"38","author":"Tseng","year":"","journal-title":"Liver Int."},{"key":"B46","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.metabol.2018.04.009","article-title":"Metformin and risk of developing nasopharyngeal cancer in patients with type 2 diabetes mellitus","volume":"85","author":"Tseng","year":"","journal-title":"Metabolism"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.3390\/biom11101405","article-title":"Metformin is associated with a lower incidence of benign brain tumors: a retrospective cohort study in patients with type 2 diabetes mellitus","volume":"11","author":"Tseng","year":"2021","journal-title":"Biomolecules"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.3389\/fimmu.2018.01236","article-title":"Metformin and autoimmunity: a \"new deal\" of an old drug","volume":"9","author":"Ursini","year":"2018","journal-title":"Front. Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1093\/nsr\/nwaa034","article-title":"Strategies for engineering advanced nanomedicines for gas therapy of cancer","volume":"7","author":"Wang","year":"2020","journal-title":"Natl. Sci. Rev."},{"key":"B51","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/s11060-010-0386-3","article-title":"Epidemiology and etiology of meningioma","volume":"99","author":"Wiemels","year":"2010","journal-title":"J. Neurooncol"},{"key":"B52","volume-title":"World cancer report: cancer research for cancer prevention","author":"Wild","year":"2020"},{"key":"B53","volume-title":"Cancer","year":""},{"key":"B54","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1038\/nm.4345","article-title":"Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug","volume":"23","author":"Wu","year":"2017","journal-title":"Nat. Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"413","DOI":"10.21037\/tlcr.2019.08.09","article-title":"The association of PD-L1 expression with the efficacy of anti-PD-1\/PD-L1 immunotherapy and survival of non-small cell lung cancer patients: a meta-analysis of randomized controlled trials","volume":"8","author":"Xu","year":"2019","journal-title":"Transl. Lung Cancer Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"376","DOI":"10.7150\/ijms.92131","article-title":"Altered gut microbiota as a potential risk factor for coronary artery disease in diabetes: a two-sample Bi-directional mendelian randomization study","volume":"21","author":"Zeng","year":"2024","journal-title":"Int. J. Med. Sci."},{"key":"B57","doi-asserted-by":"publisher","first-page":"5674","DOI":"10.3892\/ol.2019.10237","article-title":"Effect of adriamycin combined with metformin on biological function of human tongue cancer SSC-15 cells","volume":"17","author":"Zhang","year":"2019","journal-title":"Oncol. Lett."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1291699","DOI":"10.3389\/fmicb.2023.1291699","article-title":"The cause-and-effect relationship between gut microbiota abundance and carcinoid syndrome: a bidirectional Mendelian randomization study","volume":"14","author":"Zhang","year":"2023","journal-title":"Front. Microbiol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1397390\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:59:45Z","timestamp":1718758785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1397390\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,19]]},"references-count":58,"alternative-id":["10.3389\/fgene.2024.1397390"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2024.1397390","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3910448\/v1","asserted-by":"object"}]},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,19]]},"article-number":"1397390"}}