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Prediagnostic circulating markers of inflammation and risk of oesophageal adenocarcinoma: a study within the National Cancer Institute Cohort Consortium
  1. Michael B Cook1,
  2. Matthew J Barnett2,
  3. Cathryn H Bock3,
  4. Amanda J Cross4,
  5. Phyllis J Goodman5,
  6. Gary E Goodman2,6,
  7. Christopher A Haiman7,
  8. Kay-Tee Khaw8,
  9. Marjorie L McCullough9,
  10. Christine C Newton9,
  11. Marie-Christine Boutron-Ruault10,11,
  12. Eiliv Lund12,
  13. Martin Rutegård13,
  14. Mark D Thornquist2,
  15. Michael Spriggs14,
  16. Carol Giffen14,
  17. Neal D Freedman1,
  18. Troy Kemp15,
  19. Candyce H Kroenke16,
  20. Loïc Le Marchand17,
  21. Jin Young Park18,
  22. Michael Simon3,
  23. Lynne R Wilkens16,
  24. Ligia Pinto14,
  25. Allan Hildesheim1,
  26. Peter T Campbell9
  1. 1 Division of Cancer Epidemiology and Genetics, NIH, DHHS, National Cancer Institute, Rockville, Maryland, USA
  2. 2 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  3. 3 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA
  4. 4 Department of Epidemiology and Biostatistics, Imperial College London, London, UK
  5. 5 Southwest Oncology Group (SWOG) Statistics & Data Management Center (SDMC), Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  6. 6 Swedish Medical Center, Swedish Cancer Institute, Seattle, Washington, USA
  7. 7 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  8. 8 Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  9. 9 Department of Public Health and Primary Care, American Cancer Society Inc, Atlanta, Georgia, USA
  10. 10 CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, Paris, France
  11. 11 Generations and Health, Gustave Roussy, Villejuif, France
  12. 12 Department of Community Medicine, UiT The Arctic University of Norway, Tromso, Norway
  13. 13 Department of Surgical and Perioperative Sciences, Umea University, Umea, Sweden
  14. 14 Information Management Services (IMS), Rockville, Maryland, USA
  15. 15 Human Papilloma Virus (HPV) Immunology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
  16. 16 Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
  17. 17 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
  18. 18 Prevention and Implementation Group, International Agency for Research on Cancer, Lyon, France
  1. Correspondence to Dr Michael B Cook, Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH, DHHS, Bethesda, MD 9774, USA; cookmich{at}


Objective Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk.

Design This nested case–control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy.

Results Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker–cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity–oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk.

Conclusion This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.

  • oesophageal cancer
  • inflammation
  • inflammatory mediators
  • cancer epidemiology

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  • Contributors MBC and PTC contributed to the study concept, design and supervision. MBC had access to all of the data and takes responsibility for data integrity and data analysis. MBC obtained funding for the study. LP and TK conducted the laboratory analysis. All authors contributed to interpretation of data and critical revision of the manuscript for intellectual content.

  • Funding Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. CARET is funded by National Cancer Institute, National Institutes of Health grants U01- CA63673 and UM1-CA167462. CPS-II: The American Cancer Society funds the creation, maintenance and updating of the Cancer Prevention Study Nutritional Cohorts. The coordination of EPIC is financially supported by the European Commission (DG-SANCO), Imperial College London and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC – Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A11692 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). The MEC is funded by the National Cancer Institute National Institutes of Health, US Department of Health and Human Services U01 CA164973. PCPT is supported by the National Cancer Institute of the National Institutes of Health under Award Numbers 5UM1CA182883 and U10CA37429. The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C.

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval Multiple IRBs as it draws from seven distinct prospective cohort studies.

  • Provenance and peer review Not commissioned; externally peer reviewed.