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Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

2016; Impact Journals LLC; Volume: 7; Issue: 35 Linguagem: Inglês

10.18632/oncotarget.10935

1949-2553

Daniele Campa, Manuela Pastore, Manuel Gentiluomo, Renata Talar‐Wojnarowska, Juozas Kupčinskas, Ewa Małecka‐Panas, John P. Neoptolemos, Willem Niesen, Pavel Vodiĉka, Gianfranco Delle Fave, H. Bas Bueno-de-Mesquita, Maria Gazouli, Paola Pacetti, Milena Di Leo, Hidemi Ito, Harald Klüter, Pavel Souček, Vincenzo Corbo, Kenji Yamao, Satoyo Hosono, Rudolf Kaaks, Yogesh K. Vashist, Domenica Gioffreda, Oliver Strobel, Yasuhiro Shimizu, Frederike Dijk, Angelo Andriulli, Audrius Ivanauskas, Peter Bugert, Francesca Tavano, Ľudmila Vodičková, Carlo–Federico Zambon, Martin Loveček, Stefano Landi, Timothy J. Key, Ugo Boggi, Raffaele Pezzilli, Krzysztof Jamroziak, Beatrice Mohelníková-Duchoňová, Andrea Mambrini, Franco Bambi, Olivier R. Busch, Valerio Pazienza, Roberto Valente, George Theodoropoulos, Thilo Hackert, Gabriele Capurso, Giulia Martina Cavestro, Claudio Pasquali, Daniela Basso, Cosimo Sperti, Keitaro Matsuo, Markus W. Büchler, Kay‐Tee Khaw, Jakob R. Izbicki, Eithne Costello, Verena Katzke, Christoph Michalski, Anna Stępień, Cosmeri Rizzato, Federico Canzian,

Cancer-related Molecular Pathways

// Daniele Campa 1, 2 , Manuela Pastore 1, 2 , Manuel Gentiluomo 1, 2 , Renata Talar-Wojnarowska 3 , Juozas Kupcinskas 4 , Ewa Malecka-Panas 3 , John P. Neoptolemos 5 , Willem Niesen 6 , Pavel Vodicka 7, 8 , Gianfranco Delle Fave 9 , H. Bas Bueno-de-Mesquita 10, 11, 12 , Maria Gazouli 13 , Paola Pacetti 14 , Milena Di Leo 15 , Hidemi Ito 16 , Harald Klüter 17 , Pavel Soucek 18, 19 , Vincenzo Corbo 20 , Kenji Yamao 21 , Satoyo Hosono 16 , Rudolf Kaaks 22 , Yogesh Vashist 23 , Domenica Gioffreda 24 , Oliver Strobel 6 , Yasuhiro Shimizu 25 , Frederike Dijk 26 , Angelo Andriulli 24 , Audrius Ivanauskas 4 , Peter Bugert 17 , Francesca Tavano 24 , Ludmila Vodickova 8, 27 , Carlo Federico Zambon 28 , Martin Lovecek 29 , Stefano Landi 1 , Timothy J. Key 30 , Ugo Boggi 31 , Raffaele Pezzilli 32 , Krzysztof Jamroziak 33 , Beatrice Mohelnikova-Duchonova 18, 34 , Andrea Mambrini 14 , Franco Bambi 35 , Olivier Busch 36 , Valerio Pazienza 24 , Roberto Valente 9 , George E. Theodoropoulos 37 , Thilo Hackert 6 , Gabriele Capurso 9 , Giulia Martina Cavestro 15 , Claudio Pasquali 38 , Daniela Basso 39 , Cosimo Sperti 38 , Keitaro Matsuo 40 , Markus Büchler 6 , Kay-Tee Khaw 41 , Jakob Izbicki 23 , Eithne Costello 5 , Verena Katzke 22 , Christoph Michalski 6 , Anna Stepien 42 , Cosmeri Rizzato 43 , Federico Canzian 2 1 Department of Biology, University of Pisa, Pisa, Italy 2 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland 4 Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania 5 Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom 6 Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany 7 Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic 8 Institute of Biology and Medical Genetics, 1 st Medical Faculty, Charles University, Prague, Czech Republic 9 Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy 10 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 11 Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom 12 Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 13 Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece 14 Oncological Department Massa Carrara Azienda USL Toscana Nord Ovest, Carrara, Italy 15 Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy 16 Division Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan 17 Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service Baden-Württemberg – Hessen gGmbH, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany 18 Laboratory of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic 19 Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic 20 ARC-Net Research Centre, and Department of Diagnostics and Public Health University and Hospital Trust of Verona, Verona, Italy 21 Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan 22 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 23 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 24 Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy 25 Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan 26 Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands 27 Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Prague, Czech Republic 28 Department of Medicine - DIMED, University of Padova, Padova, Italy 29 Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic 30 Epidemiology Unit Nuffield Department of Population Health University of Oxford, Oxford, UK 31 Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy 32 Pancreas Unit, Department of Digestive System, Dant'Orsola-Malpighi Hospital, Bologna, Italy 33 Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland 34 Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic 35 Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy 36 Department of Surgery, Academic Medical Centre, Amsterdam, The Netherlands 37 Colorectal Unit, First Department of Propaedeutic Surgery, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece 38 Department of Surgery, Oncology and Gastroenterology-DiSCOG, University of Padova, Padova, Italy 39 Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy 40 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan 41 Clinical Gerontology Unit, Addenbrooke's Hospital, School of Clinical Medicine, University of Cambridge, Cambridge, UK 42 Laboratory of Clinical, Transplant Immunology and Genetics, Copernicus Memorial Hospital, Lodz, Poland 43 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy Correspondence to: Federico Canzian, email: f.canzian@dkfz.de Keywords: pancreatic cancer, CDKN2A, single nucleotide polymorphisms, miRSNP, association study Received: May 09, 2016 Accepted: July 13, 2016 Published: July 29, 2016 ABSTRACT The CDKN2A ( p16 ) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (OR het =1.14, 95% CI 1.01-1.27, p=0.026, OR hom =1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.