You are here

  • Home
  • Online First
  • Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

Article Text

Article menu
Download PDFPDF
Cancer genetics
Original research
Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma
  1. Chiara Corradi1,
  2. Giulia Lencioni1,
  3. Manuel Gentiluomo1,
  4. Alessio Felici1,
  5. Anna Latiano2,
  6. Gediminas Kiudelis3,
  7. Casper H J van Eijck4,
  8. Katalin Marta5,6,
  9. Rita T Lawlor7,
  10. Francesca Tavano2,
  11. Ugo Boggi8,
  12. Frederike Dijk9,
  13. Giulia Martina Cavestro10,
  14. Roel C H Vermeulen11,
  15. Thilo Hackert12,
  16. Maria Chiara Petrone13,
  17. Faik Güntac Uzunoğlu14,
  18. Livia Archibugi13,15,
  19. Jakob R Izbicki14,
  20. Luca Morelli16,
  21. Alessandro Zerbi17,18,
  22. Stefano Landi1,
  23. Hannah Stocker19,20,
  24. Renata Talar-Wojnarowska21,
  25. Gregorio Di Franco16,
  26. Péter Hegyi5,6,22,23,
  27. Cosimo Sperti24,
  28. Silvia Carrara25,
  29. Gabriele Capurso13,15,
  30. Maria Gazouli26,
  31. Hermann Brenner27,28,
  32. Stefania Bunduc5,6,29,
  33. Olivier Busch30,
  34. Francesco Perri2,
  35. Martin Oliverius31,
  36. Péter Jeno Hegyi5,6,
  37. Mara Goetz14,
  38. Pasquale Scognamiglio14,
  39. Andrea Mambrini32,
  40. Paolo Giorgio Arcidiacono13,
  41. Edita Kreivenaite3,
  42. Juozas Kupcinskas3,
  43. Tamas Hussein5,6,
  44. Stefano Ermini33,
  45. Anna Caterina Milanetto24,
  46. Pavel Vodicka34,35,36,
  47. Vytautas Kiudelis3,
  48. Viktor Hlaváč37,
  49. Pavel Soucek37,
  50. George E Theodoropoulos38,
  51. Daniela Basso39,
  52. John P Neoptolemos12,
  53. Mateus Nóbrega Aoki40,
  54. Raffaele Pezzilli41,
  55. Claudio Pasquali24,
  56. Roger Chammas40,
  57. Sabrina Gloria Giulia Testoni13,
  58. Beatrice Mohelnikova-Duchonova42,
  59. Maurizio Lucchesi32,
  60. Cosmeri Rizzato43,
  61. Federico Canzian44,
  62. Daniele Campa1
  1. 1Department of Biology, University of Pisa, Pisa, Italy
  2. 2Division of Gastroenterology and Research Laboratory, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  3. 3Department of Gastroenterology, Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
  4. 4Department of Surgery, Erasmus Medical Center, Erasmus University, Rotterdam, Netherlands
  5. 5Center for Traslational Medicine, Semmelweis University, Budapest, Hungary
  6. 6Division of Pancreatic Disease, Heart and Vascular Center, Semmelweis University, Budapest, Hungary
  7. 7ARC-NET, Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy
  8. 8Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy
  9. 9Department of Pathology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
  10. 10Division of Experimental Oncology, Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milano, Italy
  11. 11University of Utrect, Utrecht, Netherlands
  12. 12Department of General Surgery, University of Heidelberg, Heidelberg, Germany
  13. 13Pancreato-Biliary Endoscopy and Endoscopic Ultrasound, Pancreas Translational and Clinical Research Center, IRSSC San Raffaele Scientific Institute, Milan, Italy
  14. 14Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  15. 15Digestive and Liver Disease Unit, Sant’Andrea Hospital, Roma, Italy
  16. 16General Surgery, Department of Translational Research and New Technologies in Medicine and Surgery, Università di Pisa, Pisa, Italy
  17. 17Pancreatic Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy
  18. 18Department of Biomedical Sciences, Humanitas University, Milan, Italy
  19. 19Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  20. 20Network Aging Research (NAR), Heidelberg University, Heidelberg, Germany
  21. 21Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
  22. 22Institute for Translational Medicine, Medical School, University of Pécs, Pecs, Hungary
  23. 23Janos Szentagothai Research Center, University of Pecs, Pecs, Hungary
  24. 24Department of Surgery-DiSCOG, Padua University Hospital, Padova, Italy
  25. 25Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
  26. 26Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  27. 27Division of Clinical Epidemiology and Aging Research, Cancer Research Center (DKFZ), Heidelberg, Germany
  28. 28German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  29. 29Carol Davila University of Medicine and Pharmacy, Bucarest, Romania
  30. 30Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
  31. 31Department of Surgery, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Charles University, Prague, Czech Republic
  32. 32Oncology of Massa Carrara, Oncological Department, Azienda USL Toscana Nord Ovest, Pisa, Italy
  33. 33Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Firenze, Italy
  34. 34Department of Molecular Biology of Cancer, Institute of Experimental Medicine Czech Academy of Sciences, Prague, Czech Republic
  35. 35Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
  36. 36First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, Prague, Czech Republic
  37. 37Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
  38. 38First Propaedeutic University Surgery Clinic, Hippocratio General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  39. 39Department of Medicine-DIMED, Padua University Hospital, Padova, Italy
  40. 40Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba, Brazil
  41. 41County Medical Association of Potenza, Potenza, Italy
  42. 42Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
  43. 43Department of Translational Research and new Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
  44. 44Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  1. Correspondence to Professor Daniele Campa, Department of Biology, University of Pisa, Pisa, Italy; daniele.campa{at}unipi.it

Abstract

Introduction Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate.

Materials and methods We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case–Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase.

Results The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10−8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1.

Conclusion We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

  • DNA Methylation
  • Genetic Variation
  • Genetics
  • Molecular Epidemiology
  • Germ-Line Mutation

Data availability statement

Data are available upon reasonable request.

http://dx.doi.org/10.1136/jmg-2022-108910

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Data availability statement

    Data are available upon reasonable request.

    View Full Text

    Footnotes

    • Contributors CC and GL are joint first authors, contributed equally, and performed the lab work and the analysis of the data. FC and DC are joint last authors. DCacts as guarantor. DC conceived and designed the study. CC, DC, MG, CR and FC wrote the first draft of the manuscript. All authors contributed to the writing and approved the final version of the manuscript.

    • Funding This work was supported by intramural funding of DKFZ (to FC); Fondazione Tizzi (www.fondazionetizzi.it); Fondazione Arpa (www.fondazionearpa.it, to DC); and Associazione Italiana per la Ricerca sul Cancro (AIRC IG 2021-26201, to GC). This work was supported by Italian Ministry of Health grants (Ricerca Corrente 2022-2024) to Fondazione 'Casa Sollievo della Sofferenza' IRCCS Hospital, San Giovanni Rotondo (FGU), Italy and by the '5x1000' voluntary contribution.

    • Competing interests None declared.

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