Adiposity and endometrial cancer risk in postmenopausal women: a sequential causal mediation analysis

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • S Ghazaleh Dashti, The University of Melbourne, International Agency for Research on Cancer, Murdoch Children's Research Institute
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  • Dallas R English, The University of Melbourne, Cancer Council Victoria
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  • Julie A Simpson, The University of Melbourne
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  • Amalia Karahalios, The University of Melbourne, Monash University
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  • Margarita Moreno-Betancur, Murdoch Children's Research Institute, The University of Melbourne
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  • Carine Biessy, International Agency for Research on Cancer
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  • Sabina Rinaldi, International Agency for Research on Cancer
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  • Pietro Ferrari, International Agency for Research on Cancer
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  • Anne Tjonneland, Danish Cancer Society, Research Center, Copenhagen, Denmark.
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  • Jytte Halkjær, Danish Cancer Society, Research Center, Copenhagen, Denmark.
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  • Christina C Dahm
  • Helene Tilma Vistisen
  • Florence Menegaux, Universite Paris-Saclay
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  • Vittorio Perduca, Université de Paris
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  • Gianluca Severi, Universite Paris-Saclay, Gustave Roussy, University of Florence
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  • Krasimira Aleksandrova, German Institute of Human Nutrition, University of Potsdam
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  • Matthias B Schulze, University of Potsdam, German Institute of Human Nutrition
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  • Giovanna Masala, Institute for Cancer Research
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  • Sabina Sieri, Fondazione IRCCS Istituto Nazionale Tumori Milan
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  • Rosario Tumino, Cancer Registry and Histopathology Unit, Azienda Sanitaria Provinciale (ASP) Ragusa, Ragusa, Italy.
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  • Alessandra Macciotta, University of Turin
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  • Salvatore Panico, Federico II University, Naples, Italy.
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  • Anouk E Hiensch, Utrecht University
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  • Anne M May, Utrecht University
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  • J Ramón Quirós, Public Health Directorate
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  • Antonio Agudo, L'Hospitalet de Llobregat
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  • Maria-Jose Sánchez, Escuela Andaluza de Salud Pública (EASP), Granada, Instituto de Investigación Biosanitaria (ibs.GRANADA), CIBER Epidemiology and Public Health CIBERESP
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  • Pilar Amiano, Biodonostia Health Research Institute, CIBER Epidemiology and Public Health CIBERESP
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  • Sandra Colorado-Yohar, Murcia Regional Health Council, Murcia, Spain., CIBER Epidemiology and Public Health CIBERESP, University of Antioquia
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  • Eva Ardanaz, Navarra Public Health Institute, CIBER Epidemiology and Public Health CIBERESP, Navarra Institute for Health Research (IdiSNA)
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  • Naomi E Allen, University of Oxford
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  • Elisabete Weiderpass, International Agency for Research on Cancer
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  • Renée Turzanski Fortner, Deutsches Krebsforschungszentrum (DKFZ) Heidelberg
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  • Sofia Christakoudi, Imperial College, London, King's College London
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  • Konstantinos K Tsilidis, Imperial College London, University of Ioannina School of Medicine
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  • Elio Riboli, Imperial College London
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  • Rudolf Kaaks, Deutsches Krebsforschungszentrum (DKFZ) Heidelberg
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  • Marc J Gunter, International Agency for Research on Cancer
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  • Vivian Viallon, International Agency for Research on Cancer
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  • Laure Dossus, International Agency for Research on Cancer

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 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.

Original languageEnglish
JournalCancer Epidemiology, Biomarkers & Prevention
Volume30
Issue1
Pages (from-to)104-113
Number of pages11
ISSN1055-9965
DOIs
Publication statusPublished - Jan 2021

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