Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.

1st Propaedeutic University Surgery Clinic Hippocratio General Hospital Medical School National and Kapodistrian University of Athens Athens Greece

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

Blood Transfusion Service Azienda Ospedaliera Universitaria Meyer Children's Hospital Florence Italy

Carol Davila University of Medicine and Pharmacy Bucharest Romania

Center for Translational Medicine Semmelweis University Budapest Hungary

Clinics of Institute of Endocrinology Lithuanian University of Health Sciences Kaunas Lithuania

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 DiSCOG University of Padova Padua Italy

Department of General Surgery University of Heidelberg Heidelberg Germany

Department of General Visceral and Thoracic Surgery University Hospital Hamburg Eppendorf Hamburg Germany

Department of Hematology Transplantation and Internal Medicine Medical University of Warsaw Warsaw Poland

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague 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 Lithuanian University of Health Sciences Kaunas Lithuania

Department of Surgery University Hospital Kralovske Vinohrady 3rd Faculty of Medicine Charles University Prague Czech Republic

Digestive and Liver Disease Unit Sant'Andrea Hospital Rome Italy

Digestive Diseases and Liver Transplantation Center Fundeni Clinical Institute Bucharest Romania

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

Endoscoopic Unit Gastroenterology Department IRCCS Humanitas Research Hospital Rozzano Milan Italy

Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

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

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

Gastroenterology Department Institute for Digestive Research Lithuanian University of Health Sciences Kaunas Lithuania

General Surgery 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

German Cancer Consortium Heidelberg Germany

Humanitas University Rozzano Milan Italy

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

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

Laboratory Medicine Department DIMED University of Padova Padua Italy

Oncology of Massa Carrara Oncological Department Azienda USL Toscana Nord Ovest Carrara Italy

Pancreatic Surgery Department IRCCS Humanitas Research Hospital Rozzano Milan Italy

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

Potenza County Medical Association Potenza Italy

Saarland Cancer Registry Saarbrücken Germany

University Hospital Olomouc Olomouc Czech Republic

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