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 (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=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.

ARC Net Research Centre and Department of Diagnostics and Public Health University and Hospital Trust of Verona Verona Italy

Biomedical Center Faculty of Medicine in Pilsen Charles University Prague Prague Czech Republic

Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Florence Italy

Clinical Gerontology Unit Addenbrooke’s Hospital School of Clinical Medicine University of Cambridge Cambridge UK

Colorectal Unit 1st Department of Propaedeutic Surgery Athens Medical School National and Kapodistrian University of Athens Athens Greece

Department for Determinants of Chronic Diseases Bilthoven The Netherlands

Department of Basic Medical Sciences Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece

Department of Biology University of Pisa Pisa Italy

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

Department of Epidemiology and Biostatistics The School of Public Health Imperial College London London United Kingdom

Department of Gastroenterological Surgery Aichi Cancer Center Hospital Nagoya Japan

Department of Gastroenterology Aichi Cancer Center Hospital Nagoya Japan

Department of Gastroenterology Lithuanian University of Health Sciences Kaunas Lithuania

Department of General Visceral and Thoracic Surgery University Medical Center Hamburg Eppendorf Hamburg Germany

Department of General Visceral and Transplantation Surgery Heidelberg University Hospital Heidelberg Germany

Department of Hematology Institute of Hematology and Transfusion Medicine Warsaw Poland

Department of Laboratory Medicine University Hospital of Padova Padova Italy

Department of Medicine DIMED University of Padova Padova Italy

Department of Oncology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czech Republic

Department of Pathology Academic Medical Centre Amsterdam The Netherlands

Department of Social and Preventive Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Department of Surgery 1 Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czech Republic

Department of Surgery Academic Medical Centre Amsterdam The Netherlands

Department of Surgery Oncology and Gastroenterology DiSCOG University of Padova Padova Italy

Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa Pisa Italy

Digestive and Liver Disease Unit S Andrea Hospital 'Sapienza' University of Rome Rome Italy

Division Epidemiology and Prevention Aichi Cancer Center Research Institute Nagoya Japan

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Gastroenterology and Research Laboratory IRCCS Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

Division of General and Transplant Surgery Pisa University Hospital Pisa Italy

Division of Molecular Medicine Aichi Cancer Center Research Institute Nagoya Japan

Epidemiology Unit Nuffield Department of Population Health University of Oxford Oxford UK

Gastroenterology and Gastrointestinal Endoscopy Unit Vita Salute San Raffaele University IRCCS San Raffaele Scientific Institute Milan Italy

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

Institute for Health Research Liverpool Pancreas Biomedical Research Unit University of Liverpool Liverpool United Kingdom

Institute of Biology and Medical Genetics 1st Medical Faculty Charles University Prague Czech Republic

Institute of Experimental Medicine Czech Academy of Science Prague Czech Republic

Institute of Transfusion Medicine and Immunology German Red Cross Blood Service Baden Württemberg Hessen gGmbH Medical Faculty Mannheim Heidelberg University Mannheim Germany

Laboratory of Clinical Transplant Immunology and Genetics Copernicus Memorial Hospital Lodz Poland

Laboratory of Pharmacogenomics Biomedical Center Faculty of Medicine in Pilsen Charles University Prague Pilsen Czech Republic

Laboratory of Toxicogenomics National Institute of Public Health Prague Czech Republic

Oncological Department Massa Carrara Azienda USL Toscana Nord Ovest Carrara Italy

Pancreas Unit Department of Digestive System Dant'Orsola Malpighi Hospital Bologna Italy

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Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

Genetic Susceptibility in Understanding of Pancreatic Ductal Adenocarcinoma Risk: A Decade-Long Effort of the PANDORA Consortium

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival