Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

ARC Net Centre for Applied Research on Cancer University of Verona Verona Italy

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

Cancer Center Amsterdam Imaging and Biomarkers Amsterdam The Netherlands

Carol Davila University of Medicine and Pharmacy Bucharest Romania

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria

Center for Translational Medicine Semmelweis University Budapest Hungary

Centre for Individualised Infection Medicine Hannover Germany

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

Consortium for Biomedical Research in Epidemiology and Public Health Barcelona Spain

Department for Immunology and Metabolism Life and Medical Sciences Institute University of Bonn Bonn Germany

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

Department of Biochemistry and Molecular Biology 1 University of Granada Granada Spain

Department of Biology University of Pisa Pisa Italy

Department of Biomedical Sciences Humanitas University Milan Italy

Department of Diagnostics and Public Health Section of Pathology University of Verona Verona Italy

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

Department of DIMED Laboratory Medicine University of Padova Padova Italy

Department of DISCOG University of Padova Padova Italy

Department of Engineering for Innovation in Medicine University of Verona Verona Italy

Department of Gastroenterology IRCCS Humanitas Research Hospital Endoscopic Unit Milan Italy

Department of General Surgery University of Heidelberg Heidelberg Baden Württemberg Germany

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

Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center Nijmegen The Netherlands

Department of Medical Oncology Amsterdam UMC location University of Amsterdam Amsterdam The Netherlands

Department of Medical Oncology Amsterdam UMC Location University of Amsterdam Amsterdam The Netherlands

Department of Medical Oncology Complejo Hospitalario de Jaén Jaén Spain

Department of Molecular Biology of Cancer Institute of Experimental Medicine Czech Academy of Sciences Prague 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 University Hospital Kralovske Vinohrady 3rd Faculty of Medicine Charles University Prague Czech Republic

Digestive and Liver Disease Unit S Andrea Hospital Rome Italy

Digestive Diseases and Liver Transplantation Center Fundeni Clinical Institute Bucharest Romania

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 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

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

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

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

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

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

Genomic Oncology Area GENYO Centre for Genomics and Oncological Research Pfizer University of Granada Andalusian Regional Government PTS Granada Spain

German Cancer Consortium Heidelberg Germany

Institute for Health Research Liverpool Pancreas Biomedical Research Unit University of Liverpool Liverpool UK

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

Instituto de Investigación Biosanataria Ibs Granada Granada Spain

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

National Institute for Public Health and the Environment Bilthoven The Netherlands

Oncologia Massa Carrara Azienda USL Toscana Nord Ovest Carrara Italy

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

Pancreatic Unit IRCCS Humanitas Research Hospital Milan Italy

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

Potenza County Medical Association Potenza Italy

Saarland Cancer Registry Saarbrücken Germany

Toxicogenomics Unit National Institute of Public Health Prague Czech Republic

University of Utrecht Utrecht The Netherlands

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