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.

ARC NET Centre for Applied Research on Cancer University and Hospital Trust of Verona Verona Italy

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

Carol Davila University of Medicine and Pharmacy Bucharest Romania

Center for Translational Medicine Semmelweis University Budapest Hungary

Centre for Translational Medicine Department of Medicine University of Szeged Szeged Hungary

Department of Biology University of Pisa Pisa Italy

Department of Gastroenterology Lithuanian University of Health Sciences Kaunas Lithuania

Department of General Surgery University of Heidelberg Heidelberg Germany

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

Department of Internal Medicine and Oncology Semmelweis University Budapest Hungary

Department of Medicine University of Padova Padova Italy

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

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

Department of Surgery 1 University Hospital Olomouc Olomouc Czech Republic

Department of Surgery Amsterdam UMC University of Amsterdam Cancer Center Amsterdam Amsterdam The Netherlands

Department of Surgery Erasmus MC University Medical Center Rotterdam The Netherlands

Department of Surgery Oncology and Gastroenterology University of Padova Padova Italy

Digestive and Liver Disease Unit Sant' Andrea Hospital Rome Italy

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Gastroenterology and Research Laboratory Fondazione IRCCS Casa Sollievo della Sofferenza Hospital Foggia Italy

Division of General and Transplant Surgery Pisa University Hospital Pisa Italy

Division of Pancreatic Diseases Heart and Vascular Center Semmelweis University Budapest Hungary

Endoscopic Unit Department of Gastroenterology IRCCS Humanitas Research Hospital Milan Italy

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

General Surgery Unit Department of Translational Research and new Technologies in Medicine and Surgery University of Pisa Pisa Italy

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

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

Institute for Translational Medicine Medical School University of Pécs Pécs Hungary

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

János Szentágothai Research Center University of Pécs Pécs Hungary

Oncological Department Massa Carrara Azienda USL Toscana Nord Ovest Carrara Italy

Pancreato Biliary Endoscopy and Endosonography Division Pancreas Translational and Clinical Research Center San Raffaele Scientific Institute Istituto di Ricovero e Cura a Carattere Scientifico Milan Italy

Potenza Medical County Association Potenza Italy

Toxicogenomics Unit Centre of Toxicology and Health Safety National Institute of Public Health Prague Czech Republic

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