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Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses
  1. Esther Molina-Montes1,2,
  2. Claudia Coscia1,2,
  3. Paulina Gómez-Rubio1,2,
  4. Alba Fernández1,
  5. Rianne Boenink1,
  6. Marta Rava1,
  7. Mirari Márquez1,2,
  8. Xavier Molero3,4,
  9. Matthias Löhr5,
  10. Linda Sharp6,7,
  11. Christoph W Michalski8,9,
  12. Antoni Farré10,
  13. José Perea11,12,
  14. Michael O’Rorke13,14,
  15. William Greenhalf15,
  16. Mar Iglesias2,16,
  17. Adonina Tardón17,18,
  18. Thomas M Gress19,
  19. Victor M Barberá20,
  20. Tatjana Crnogorac-Jurcevic21,
  21. Luis Muñoz-Bellvís22,
  22. J Enrique Dominguez-Muñoz23,
  23. Harald Renz24,
  24. Joaquim Balcells4,25,
  25. Eithne Costello15,
  26. Lucas Ilzarbe26,
  27. Jörg Kleeff8,9,
  28. Bo Kong8,
  29. Josefina Mora10,
  30. Damian O’Driscoll6,7,
  31. Ignasi Poves27,
  32. Aldo Scarpa28,
  33. Jingru Yu29,
  34. Manuel Hidalgo30,31,
  35. Rita T Lawlor28,
  36. Weimin Ye29,
  37. Alfredo Carrato2,32,
  38. Francisco X Real2,33,
  39. Núria Malats1,2
  40. On behalf of the PanGenEU Study Investigators
  1. 1 Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
  2. 2 CIBERONC, Madrid, Spain
  3. 3 Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Barcelona, Spain
  4. 4 Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain
  5. 5 Gastrocentrum, Karolinska Institutet and University Hospital, Stockholm, Sweden
  6. 6 National Cancer Registry Ireland, Cork, Ireland
  7. 7 HRB Clinical Research Facility, University College Cork, Cork, Ireland
  8. 8 Department of Surgery, Technical University of Munich, Munich, Germany
  9. 9 Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-Universitat Halle-Wittenberg, Halle, Germany
  10. 10 Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  11. 11 Department of Surgery, Hospital 12 de Octubre, Madrid, Spain
  12. 12 Department of Surgery, Health Research Institute, Fundación Jiménez Díaz, Madrid, Spain
  13. 13 Centre for Public Health, Queen's University Belfast, Belfast, UK
  14. 14 College of Public Health, University of Iowa, Iowa City, Iowa, USA
  15. 15 Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer Research-UK Centre, University of Liverpool, Liverpool, UK
  16. 16 Hospital del Mar—Parc de Salut Mar, Barcelona, Spain
  17. 17 Department of Medicine, Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
  18. 18 CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
  19. 19 Department of Gastroenterology, University Hospital of Giessen and Marburg, Marburg, Germany
  20. 20 Molecular Genetics Laboratory, University General Hospital of Elche, Elche, Spain
  21. 21 Barts Cancer Institute, Centre for Molecular Oncology, Queen Mary University of London, London, UK
  22. 22 Department of Surgery, Hospital Universitario de Salamanca, Salamanca, Spain
  23. 23 Department of Gastroenterology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
  24. 24 Institute of Laboratory Medicine and Pathobiochemistry, Phillips University of Marburg, Marburg, Germany
  25. 25 Exocrine Pancreas Research Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Barcelona, Spain
  26. 26 Department of Gastroenterology, Hospital del Mar - Parc de Salut Mar, Barcelona, Spain
  27. 27 Hospital del Mar - Parc de Salut Mar, Barcelona, Spain
  28. 28 ARC-Net Research Centre and Department of Diagnostics and Public Health-Section of Pathology, University of Verona, Verona, Italy
  29. 29 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and University Hospital, Stockholm, Sweden
  30. 30 Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
  31. 31 Hospital Universitario Madrid Sanchinarro, Madrid, Spain
  32. 32 Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Spain
  33. 33 Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, Madrid, Spain
  1. Correspondence to Dr Núria Malats, Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid E-28029, Spain; nuria{at}


Objectives To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI).

Design Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis.

Results T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55).

Conclusion Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.

  • pancreatic cancer
  • diabetes mellitus
  • obesity
  • cancer epidemiology

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  • Contributors All authors meet the criteria for authorship. They have read and approved the last version of the manuscript.

  • Funding The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (PI11/01542, PI0902102, PI12/01635, PI12/00815, PI15/01573); Red Temática de Investigación Cooperativa en Cáncer, Spain (RD12/0036/0034, RD12/0036/0050, RD12/0036/0073); WCR (15-0391); European Cooperation in Science and Technology - COST Action BM1204: EUPancreas. EU-6FP Integrated Project (018771-MOLDIAG-PACA), EU-FP7-HEALTH (259737- CANCERALIA, 256974-EPC-TM-Net); Associazione Italiana Ricerca sul Cancro (12182); Cancer Focus Northern Ireland and Department for Employment and Learning; and ALF (Agreement between the Swedish state and some county councils on cooperation on basic education of doctors, medical research, and the development of health care,SLL20130022), Sweden.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

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

  • Data availability statement No data are available.