Pleiotropic variants (i.e. genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted 10 years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61 052 variants reported to be associated by at least one genome-wide association study with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16 055 pancreatic ductal adenocarcinoma (PDAC) cases and 212 149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P = 6.52 × 10-5) and 7q36.3-rs288762 (P = 3.03 × 10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell-differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.

1st Department of Propaedeutic Surgery Hippocration General Hospital National and Kapodistrian University of Athens Athens Greece

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

Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Florence Italy

Carol Davila University of Medicine and Pharmacy Bucharest Romania

Center for Translational Medicine Semmelweis University Budapest Hungary

Center for Translational Research in Oncology São Paulo Brazil

Centre for Nutrition Prevention and Health Services National Institute for Public Health and the Environment Bilthoven The Netherlands

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

County Medical Association of Potenza Potenza Italy

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 Biomedical Sciences Humanitas University Milan Italy

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

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 Transplantology and Internal Medicine Medical University of Warsaw Warsaw Poland

Department of Oncology Fondazione IRCCS 'Casa Sollievo della Sofferenza' Hospital San Giovanni Rotondo Italy

Department of Oncology Palacky University Olomouc Olomouc Czech Republic

Department of Surgery 1 University Hospital Olomouc Olomouc Czech Republic

Department of Surgery Erasmus MC University Medical Center Rotterdam The Netherlands

Department of Surgery Fondazione IRCCS 'Casa Sollievo della Sofferenza' Hospital San Giovanni Rotondo Italy

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

Digestive and Liver Disease Unit Sant'Andrea Hospital Rome Italy

Digestive Endoscopy Unit Division of Gastroenterology Humanitas Clinical and Research Center IRCCS Milan Italy

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

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 San Giovanni Rotondo Italy

Division of General and Transplant Surgery Pisa University Hospital Pisa Italy

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

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Fundeni Clinical Institute Bucharest Romania

Gastroenterology Department Lithuanian University of Health Sciences Kaunas Lithuania

Gastrointestinal Endoscopy Unit Vita Salute San Raffaele University IRCCS San Raffaele Milan Italy

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

Genetic and Molecular Epidemiology Group Spanish National Cancer Research Centre Madrid Spain

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

German Cancer Consortium 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 Prague Czech Republic

Institute of Experimental Medicine Czech Academy of Science Prague Czech Republic

János Szentágothai Research Center University of Pécs Pécs Hungary

Laboratory for Applied Science and Technology in Health Carlos Chagas Institute Oswaldo Cruz Foundation Curitiba Brazil

Laboratory for Experimental Oncology and Radiobiology Center for Experimental and Molecular Medicine Amsterdam UMC and Cancer Center Amsterdam Amsterdam The Netherlands

Medical Faculty Heidelberg Heidelberg University Heidelberg Germany

Medical School Institute for Translational Medicine University of Pécs Pécs Hungary

Network Aging Research Heidelberg University Heidelberg Germany

Oncode Institute Amsterdam The Netherlands

Oncological Department Massa Carrara Azienda USL Toscana Nord Ovest Carrara Italy

Pancreatic Unit Humanitas Clinical and Research Center IRCCS Milan Italy

Pancreato Biliary Endoscopy and Endosonography Division Pancreas Translational and Clinical Research Center IRSSC San Raffaele Scientific Institute Milan Italy

Surgery Clinic 3rd Faculty of Medicine Charles University Prague Czech Republic

Surgery Department Lithuanian University of Health Sciences Kaunas Lithuania

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Commentary: Special Issue: Current Understanding of Colorectal and Pancreatic Cancers