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Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk |
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| Authors: | Matteo Giaccherini Riccardo Farinella Manuel Gentiluomo Beatrice Mohelnikova-Duchonova Emanuele Federico Kauffmann Matteo Palmeri Faik Uzunoglu Pavel Soucek Dalius Petrauskas Giulia Martina Cavestro Romanas Zykus Silvia Carrara Raffaele Pezzilli Marta Puzzono Andrea Szentesi John Neoptolemos Livia Archibugi Orazio Palmieri Anna Caterina Milanetto Gabriele Capurso Casper H. J. van Eijck Hannah Stocker Rita T. Lawlor Pavel Vodicka Martin Lovecek Jakob R. Izbicki Francesco Perri Rita Kupcinskaite-Noreikiene Mara Götz Juozas Kupcinskas Tamás Hussein Péter Hegyi Olivier R. Busch Thilo Hackert Andrea Mambrini Hermann Brenner Maurizio Lucchesi Daniela Basso Francesca Tavano Ben Schöttker Giuseppe Vanella Stefania Bunduc Ágota Petrányi Stefano Landi Luca Morelli Federico Canzian Daniele Campa |
| Affiliation: | 1. Department of Biology, University of Pisa, Pisa, Italy;2. Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic;3. Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy;4. General Surgery Unit, Department of Translational Research and new Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy;5. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;6. Toxicogenomics Unit, Centre of Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic;7. Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania;8. Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy;9. Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy;10. Potenza Medical County Association, Potenza, Italy;11. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary János Szentágothai Research Center, University of Pécs, Pécs, Hungary Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary;12. Department of General Surgery, University of Heidelberg, Heidelberg, Germany;13. Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy Digestive and Liver Disease Unit, Sant' Andrea Hospital, Rome, Italy;14. Division of Gastroenterology and Research Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital, Foggia, Italy;15. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy;16. Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands;17. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany;18. ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy;19. Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic;20. Department of Surgery I, University Hospital Olomouc, Olomouc, Czech Republic;21. Center for Translational Medicine, Semmelweis University, Budapest, Hungary Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary;22. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary János Szentágothai Research Center, University of Pécs, Pécs, Hungary Center for Translational Medicine, Semmelweis University, Budapest, Hungary Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary;23. Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands;24. Oncological Department Massa Carrara, Azienda USL Toscana Nord Ovest, Carrara, Italy;25. Department of Medicine, University of Padova, Padova, Italy;26. Center for Translational Medicine, Semmelweis University, Budapest, Hungary Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary Carol Davila University of Medicine and Pharmacy, Bucharest, Romania;27. Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary;28. General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy;29. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany |
| Abstract: | Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10−9). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases. |
| Keywords: | association study genetic susceptibility pancreatic ductal adenocarcinoma single nucleotide polymorphisms |