Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

1st Department of Medicine University of Szeged Szeged Hungary

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

CIBERONC Madrid Spain

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

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 Łodz Łodz Poland

Department of Gastroenterology and Institute for Digestive Research 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 Hematology Transplantation and Internal Medicine Medical University of Warsaw Warsaw Poland

Department of Laboratory Medicine University Hospital of Padova Padua Italy

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

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

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

Department of Surgery The Pancreas Institute University and Hospital Trust of Verona Verona Italy

Digestive Endoscopy Unit Division of Gastroenterology Humanitas Research Hospital Milan Italy

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

Division of Experimental Oncology Gastroenterology and Gastrointestinal Endoscopy Unit Vita Salute San Raffaele University IRCCS Ospedale San Raffaele Scientific Institute Milan Italy

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

Division of Gastroenterology San Carlo Hospital Potenza Italy

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Division of Surgical Pathology Department of Surgical Medical Molecular Pathology and Critical Area University of Pisa Pisa Italy

Fundeni Clinical Institute Bucharest Romania

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 Translational Medicine Medical School University of Pécs Pécs Hungary

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

Institute of Experimental Medicine Czech Academy of Sciences Prague Czech Republic

Pancreato Biliary Endoscopy and Endosonography Division Pancreas Translational and Clinical Research Center Vita Salute San Raffaele University IRCCS San Raffaele Scientific Institute Milan Italy

Sant'Andrea Hospital Faculty of Medicine and Psychology Sapienza University of Rome Rome Italy

Szent György University Teaching Hospital of Fejér County Székesfehérvár Hungary

Unità Operativa Chirurgia Generale e dei Trapianti University of Pisa Pisa Italy

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