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Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

About this Publication
Title
Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.
Pubmed ID
38308339 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Hum Genomics. 2024 Feb 2; Volume 18 (Issue 1): Pages 12
Authors
Ünal P, Lu Y, Bueno-de-Mesquita B, van Eijck CHJ, Talar-Wojnarowska R, Szentesi A, Gazouli M, Kreivenaite E, Tavano F, Małecka-Wojciesko E, Erőss B, Oliverius M, Bunduc S, Nóbrega Aoki M, Vodickova L, Boggi U, Giaccherini M, Kondrackiene J, Chammas R, Palmieri O, ...show more Theodoropoulos GE, Bijlsma MF, Basso D, Mohelnikova-Duchonova B, Soucek P, Izbicki JR, Kiudelis V, Vanella G, Arcidiacono PG, Włodarczyk B, Hackert T, Schöttker B, Uzunoglu FG, Bambi F, Goetz M, Hlavac V, Brenner H, Perri F, Carrara S, Landi S, Hegyi P, Dijk F, Maiello E, Capretti G, Testoni SGG, Petrone MC, Stocker H, Ermini S, Archibugi L, Gentiluomo M, Cavestro GM, Pezzilli R, Di Franco G, Milanetto AC, Sperti C, Neoptolemos JP, Morelli L, Vokacova K, Pasquali C, Lawlor RT, Bazzocchi F, Kupcinskas J, Capurso G, Campa D, Canzian F
Affiliations
  • Genomic Epidemiology Group, German Cancer Research Center, In Neuenheimer Feld 280, 69120, Heidelberg, Germany.
  • Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
  • Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
  • Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland.
  • Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
  • Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
  • Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
  • Division of Gastroenterology and Research Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, FG, Italy.
  • Department of Surgery, University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
  • Center for Translational Medicine, Semmelweis University, Budapest, Hungary.
...show more
  • Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Curitiba, PR, Brazil.
  • Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Plzeň, Czech Republic.
  • Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy.
  • Department of Biology, University of Pisa, Pisa, Italy.
  • Department of Radiology and Oncology, Institute of Cancer of São Paulo, São Paulo, Brazil.
  • First Propaedeutic University Surgery Clinic, Hippocratio General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
  • Laboratory for Experimental Oncology and Radiobiology, Center of Experimental Molecular Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands.
  • Department of Medicine, Laboratory Medicine, University of Padova, Padua, Italy.
  • Department of Oncology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
  • Department of General Visceral and Thoracic Surgery, University of Hamburg Medical Institutions, Hamburg, Germany.
  • PancreatoBiliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy.
  • Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
  • Blood Transfusion Service, Meyer Children's Hospital, Florence, Italy.
  • Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy.
  • Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
  • Department of Oncology, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, FG, Italy.
  • Pancreatic Unit, IRCCS Humanitas Research Hospital, Milan, Italy.
  • Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
  • Department of Gastroenterology, San Carlo Hospital, Potenza, Italy.
  • General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
  • Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy.
  • Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
  • Department of Diagnostics and Public Health, ARC-Net Centre for Applied Research on Cancer, University of Verona, Verona, Italy.
  • Department of Surgery, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, FG, Italy.
  • Genomic Epidemiology Group, German Cancer Research Center, In Neuenheimer Feld 280, 69120, Heidelberg, Germany. f.canzian@dkfz.de.
Abstract

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

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