Adiposity and endometrial cancer risk in postmenopausal women: a sequential causal mediation analysis
Dashti, S Ghazaleh; English, Dallas R; Simpson, Julie A; Karahalios, Amalia; Moreno-Betancur, Margarita; Biessy, Carine; Rinaldi, Sabina; Ferrari, Pietro; Tjonneland, Anne; Halkjær, Jytte; Dahm, Christina C; Vistisen, Helene Tilma; Menegaux, Florence; Perduca, Vittorio; Severi, Gianluca; Aleksandrova, Krasimira; Schulze, Matthias B; Masala, Giovanna; Sieri, Sabina; Tumino, Rosario; Macciotta, Alessandra; Panico, Salvatore; Hiensch, Anouk E; May, Anne M; Quirós, J Ramón; Agudo, Antonio; Sánchez, Maria-Jose; Amiano, Pilar; Colorado-Yohar, Sandra; Ardanaz, Eva; Allen, Naomi E; Weiderpass, Elisabete; Fortner, Renée Turzanski; Christakoudi, Sofia; Tsilidis, Konstantinos K; Riboli, Elio; Kaaks, Rudolf; Gunter, Marc J; Viallon, Vivian; Dossus, Laure
(2021) Cancer Epidemiology Biomarkers & Prevention, volume 30, issue 1, pp. 104 - 113
(Article)
Abstract
Background: Adiposity increases endometrial cancer risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); IL6, IL1-receptor antagonist, TNF receptor 1 and 2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); and free estradiol and estrone (estrogen biomarkers) in the
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adiposity. endometrial cancer link in postmenopausal women. Methods: We used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Eligible women did not have cancer, hysterectomy, and diabetes; did not use oral contraceptives or hormone therapy; and were postmenopausal at recruitment. Mediating pathways from adiposity to endometrial cancer were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis. Results: The study included 163 cases and 306 controls. The adjusted OR for endometrial cancer for body mass index (BMI) ≥30 versus ≥18.5-<25 kg/m2 was 2.51 (95% confidence interval, 1.26-5.02). The ORsNIE were 1.95 (1.01-3.74) through all biomarkers [72% proportion mediated (PM)] decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33% PM); 1.13 (0.71-1.80) through inflammation beyond (the potential influence of) adiponectin (13% PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5% PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21% PM). The ORNDE not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results. Conclusions: Reduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated approximately 70% of increased odds of endometrial cancer in women with obesity versus normal weight. Impact: If replicated, these results could have implications for identifying targets for intervention to reduce endometrial cancer risk in women with obesity.
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Keywords: Oncology, Epidemiology, Journal Article
ISSN: 1055-9965
Publisher: American Association for Cancer Research Inc.
Note: Funding Information: This work was supported by the World Cancer Research Fund (grants 2003/18 and 2007/13), Australian National Health and Medical Research Council grants (1150591 to S.G. Dashti and 1104975 to J.A. Simpson), and Melbourne Research Scholarship (to S.G. Dashti). M. Moreno-Betancur is the recipient of an Australian Research Council Discovery Early Career Award (project number DE190101326) funded by the Australian Government. The work reported in this article was undertaken by S.G. Dashti while hosted by the IARC and funded partially by a PhD scholarship by IARC. The coordination of EPIC is financially supported by the European Commission and the IARC. The national cohorts are supported by the following: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, and Institut National de la Santéet de la Recherche Médicale (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Funding Information: S.G. Dashti reports grants from World Cancer Research Fund [this work was supported by the World Cancer Research Fund (grants 2003/18 and 2007/13)] and Australian National Health and Medical Research Council [grant 1150591 (postgraduate PhD scholarship)], personal fees from International Agency for Research on Cancer [IARC; the work reported in this article was undertaken by S.G. Dashti while hosted by the IARC and funded partially by a PhD scholarship by IARC], and other from several (the coordination of EPIC is financially supported by the European Commission and the International Agency for Research on Cancer) during the conduct of the study, as well as grants from Australian National Health and Medical Research Council [grant 1150591 (postgraduate PhD scholarship)] and personal fees from IARC (PhD scholarship by IARC) and Melbourne Research Scholarship (PhD scholarship from the University of Melbourne) outside the submitted work. S. Rinaldi reports grants from World Cancer Research Fund during the conduct of the study. M.B. Schulze reports grants from German Federal Ministry of Science, European Union, German Cancer Aid, and European Community during the conduct of the study. L. Dossus reports grants from World Cancer Research Fund during the conduct of the study. No disclosures were reported by the other authors. Funding Information: The authors thank thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC Study. This study also made use of data from the EPIC-Norfolk cohort. This work was supported by the World Cancer Research Fund (grants 2003/18 and 2007/13), Australian National Health and Medical Research Council grants (1150591 to S.G. Dashti and 1104975 to J.A. Simpson), and Melbourne Research Scholarship (to S.G. Dashti). M. Moreno-Betancur is the recipient of an Australian Research Council Discovery Early Career Award (project number DE190101326) funded by the Australian Government. The work reported in this article was undertaken by S.G. Dashti while hosted by the IARC and funded partially by a PhD scholarship by IARC. The coordination of EPIC is financially supported by the European Commission and the IARC. The national cohorts are supported by the following: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, and Institut National de la Santé et de la Recherche Médicale (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sport, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund, and Statistics Netherlands (the Netherlands); European Research Council and Nordforsk, Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund, Regional Governments of Andalucía, Asturias, Basque Country, Murcia, andNavarra, and Instituto de Salud Carlos III Red Temática de Investigación Cooperativa en Salud (Spain); Swedish Cancer Society, Swedish Scientific Council, and Regional Governments of Skåne and Västerbotten (Sweden); and Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (United Kingdom). Publisher Copyright: © 2020 American Association for Cancer Research.
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