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Genotype-phenotype correlations
Original research
Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction
  1. Alice Alessandra Galeotti1,2,
  2. Manuel Gentiluomo1,
  3. Cosmeri Rizzato2,3,
  4. Ofure Obazee2,
  5. John P Neoptolemos4,
  6. Claudio Pasquali5,
  7. Michael Nentwich6,
  8. Giulia Martina Cavestro7,
  9. Raffaele Pezzilli8,
  10. William Greenhalf9,
  11. Bernd Holleczek10,11,
  12. Cornelia Schroeder6,
  13. Ben Schöttker11,12,
  14. Audrius Ivanauskas13,
  15. Laura Ginocchi14,
  16. Timothy J Key15,
  17. Péter Hegyi16,17,
  18. Livia Archibugi18,19,
  19. Erika Darvasi17,
  20. Daniela Basso20,
  21. Cosimo Sperti21,
  22. Maarten F Bijlsma22,23,
  23. Orazio Palmieri24,
  24. Viktor Hlavac25,
  25. Renata Talar-Wojnarowska26,
  26. Beatrice Mohelnikova-Duchonova27,
  27. Thilo Hackert4,
  28. Yogesh Vashist6,
  29. Ondrej Strouhal27,28,
  30. Hanneke van Laarhoven23,29,
  31. Francesca Tavano24,
  32. Martin Lovecek30,
  33. Christos Dervenis31,
  34. Ferenc Izbéki32,
  35. Andrea Padoan20,
  36. Ewa Małecka-Panas26,
  37. Evaristo Maiello24,
  38. Giuseppe Vanella18,
  39. Gabriele Capurso18,19,
  40. Jakob R Izbicki6,
  41. George E Theodoropoulos33,
  42. Krzysztof Jamroziak34,
  43. Verena Katzke35,
  44. Rudolf Kaaks35,
  45. Andrea Mambrini14,
  46. Ioannis S Papanikolaou36,
  47. Richárd Szmola37,
  48. Andrea Szentesi16,17,
  49. Juozas Kupcinskas13,
  50. Simona Bursi14,
  51. Eithne Costello9,
  52. Ugo Boggi38,
  53. Anna Caterina Milanetto5,
  54. Stefano Landi1,
  55. Maria Gazouli39,
  56. Ludmila Vodickova40,41,42,
  57. Pavel Soucek25,
  58. Domenica Gioffreda24,
  59. Federica Gemignani1,
  60. Hermann Brenner11,43,44,
  61. Oliver Strobel4,
  62. Markus Büchler4,
  63. Pavel Vodicka40,41,42,
  64. Salvatore Paiella45,
  65. Federico Canzian2,
  66. Daniele Campa1
  1. 1 Department of Biology, University of Pisa, Pisa, Italy
  2. 2 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  3. 3 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
  4. 4 Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
  5. 5 Pancreatic and Endocrine Surgical Unit, University of Padova, Padova, Italy
  6. 6 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  7. 7 Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milano, Italy
  8. 8 Department of Gastroenterology, Polyclinic of Sant’Orsola, Bologna, Italy
  9. 9 Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, UK
  10. 10 Saarland Cancer Registry, Saarbrücken, Germany
  11. 11 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  12. 12 Network Aging Research, University of Heidelberg, Heidelberg, Germany
  13. 13 Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
  14. 14 Oncological Department, Azienda USL Toscana Nord Ovest, Oncological Unit of Massa Carrara, Carrara, Italy
  15. 15 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  16. 16 Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
  17. 17 First Department of Medicine, University of Szeged, Szeged, Hungary
  18. 18 Digestive and Liver Disease Unit, S. Andrea Hospital, S. Andrea Hospital ‘Sapienza’ University of Rome, Rome, Italy
  19. 19 Pancreato-Biliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milano, Italy
  20. 20 Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
  21. 21 Third Surgical Clinic - Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, Padova, Italy
  22. 22 Laboratory for Experimental Oncology and Radiobiology Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
  23. 23 Cancer Center Amsterdam, Amsterdam, The Netherlands
  24. 24 Division of Gastroenterology and Research Laboratory, Department of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  25. 25 Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
  26. 26 Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
  27. 27 Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
  28. 28 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
  29. 29 Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
  30. 30 Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
  31. 31 Department of Surgical Oncology and HPB Surgery, University of Cyprus, Nicosia, Cyprus
  32. 32 Szent György University Teaching Hospital of Fejér County, Székesfehérvár, Hungary
  33. 33 First Propaedeutic University Surgery Clinic, Hippocratio General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  34. 34 Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
  35. 35 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  36. 36 Second Department of Internal Medicine and Research Unit, "Attikon" University General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  37. 37 Department of Interventional Gastroenterology, National Institute of Oncology, Budapest, Hungary
  38. 38 Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy
  39. 39 Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  40. 40 Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
  41. 41 Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
  42. 42 Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
  43. 43 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
  44. 44 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany
  45. 45 General and Pancreatic Surgery Department, Pancreas Institute, University of Verona, Verona, Italy
  1. Correspondence to Dr Federico Canzian, Genome Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; f.canzian{at}dkfz.de

Abstract

Background Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.

Objective We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.

Methods We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.

Results The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).

Conclusion We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

  • oncology
  • pancreas and biliary tract
  • genetic epidemiology

Data availability statement

Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. The data supporting the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Sharing data will be conditional to approval by the PANDoRA steering committee and, if needed, to additional approval of the competent Institutional Review Boards.

https://doi.org/10.1136/jmedgenet-2020-106961

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    Data availability statement

    Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. The data supporting the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Sharing data will be conditional to approval by the PANDoRA steering committee and, if needed, to additional approval of the competent Institutional Review Boards.

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    Footnotes

    • AAG and MG are joint first authors.

    • FC and DC are joint last authors.

    • AAG and MG contributed equally.

    • Contributors DC and FC conceived the study. MG, CR and AAG performed experimental work. DC, MG and AAG performed data analysis. All other authors contributed to the collection of samples and data. MG, AAG, CR, DC and FC drafted the manuscript, and all other authors took part in its critical revision. FC and DC share last authorship.

    • Funding This work was partially supported by Fondazione Arpa (www.fondazionearpa.it) and by Fondazione Tizzi (www.fondazionetizzi.it).

    • Competing interests MFB has received research funding from Celgene. HvL has acted as a consultant for Celgene, and Eli Lilly and Company, Nordic Pharma Group and Philips, and has received research grants from Amgen, Bayer Schering Pharma, Celgene, Eli Lilly and Company, GlaxoSmithKline Pharmaceuticals, MSD, Nordic Pharma Group, Philips and Roche Pharmaceuticals.

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