Human Genomics (Feb 2024)
Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk
- Pelin Ünal,
- Ye Lu,
- Bas Bueno-de-Mesquita,
- Casper H. J. van Eijck,
- Renata Talar-Wojnarowska,
- Andrea Szentesi,
- Maria Gazouli,
- Edita Kreivenaite,
- Francesca Tavano,
- Ewa Małecka-Wojciesko,
- Bálint Erőss,
- Martin Oliverius,
- Stefania Bunduc,
- Mateus Nóbrega Aoki,
- Ludmila Vodickova,
- Ugo Boggi,
- Matteo Giaccherini,
- Jurate Kondrackiene,
- Roger Chammas,
- Orazio Palmieri,
- George E. Theodoropoulos,
- Maarten F. Bijlsma,
- Daniela Basso,
- Beatrice Mohelnikova-Duchonova,
- Pavel Soucek,
- Jakob R. Izbicki,
- Vytautas Kiudelis,
- Giuseppe Vanella,
- Paolo Giorgio Arcidiacono,
- Barbara Włodarczyk,
- Thilo Hackert,
- Ben Schöttker,
- Faik G. Uzunoglu,
- Franco Bambi,
- Mara Goetz,
- Viktor Hlavac,
- Hermann Brenner,
- Francesco Perri,
- Silvia Carrara,
- Stefano Landi,
- Péter Hegyi,
- Frederike Dijk,
- Evaristo Maiello,
- Giovanni Capretti,
- Sabrina Gloria Giulia Testoni,
- Maria Chiara Petrone,
- Hannah Stocker,
- Stefano Ermini,
- Livia Archibugi,
- Manuel Gentiluomo,
- Giulia Martina Cavestro,
- Raffaele Pezzilli,
- Gregorio Di Franco,
- Anna Caterina Milanetto,
- Cosimo Sperti,
- John P. Neoptolemos,
- Luca Morelli,
- Klara Vokacova,
- Claudio Pasquali,
- Rita T. Lawlor,
- Francesca Bazzocchi,
- Juozas Kupcinskas,
- Gabriele Capurso,
- Daniele Campa,
- Federico Canzian
Affiliations
- Pelin Ünal
- Genomic Epidemiology Group, German Cancer Research Center
- Ye Lu
- Genomic Epidemiology Group, German Cancer Research Center
- Bas Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment
- Casper H. J. van Eijck
- Department of Surgery, Erasmus MC University Medical Center
- Renata Talar-Wojnarowska
- Department of Digestive Tract Diseases, Medical University of Lodz
- Andrea Szentesi
- Institute for Translational Medicine, Medical School, University of Pécs
- Maria Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens
- Edita Kreivenaite
- Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences
- Francesca Tavano
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital
- Ewa Małecka-Wojciesko
- Department of Digestive Tract Diseases, Medical University of Lodz
- Bálint Erőss
- Institute for Translational Medicine, Medical School, University of Pécs
- Martin Oliverius
- Department of Surgery, University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University
- Stefania Bunduc
- Center for Translational Medicine, Semmelweis University
- Mateus Nóbrega Aoki
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute
- Ludmila Vodickova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University
- Ugo Boggi
- Division of General and Transplant Surgery, Pisa University Hospital
- Matteo Giaccherini
- Department of Biology, University of Pisa
- Jurate Kondrackiene
- Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences
- Roger Chammas
- Department of Radiology and Oncology, Institute of Cancer of São Paulo
- Orazio Palmieri
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital
- George E. Theodoropoulos
- First Propaedeutic University Surgery Clinic, Hippocratio General Hospital, Medical School, National and Kapodistrian University of Athens
- Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center of Experimental Molecular Medicine, Amsterdam UMC Location University of Amsterdam
- Daniela Basso
- Department of Medicine, Laboratory Medicine, University of Padova
- Beatrice Mohelnikova-Duchonova
- Department of Oncology, Faculty of Medicine and Dentistry, Palacky University
- Pavel Soucek
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University
- Jakob R. Izbicki
- Department of General Visceral and Thoracic Surgery, University of Hamburg Medical Institutions
- Vytautas Kiudelis
- Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences
- Giuseppe Vanella
- PancreatoBiliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute
- Paolo Giorgio Arcidiacono
- PancreatoBiliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute
- Barbara Włodarczyk
- Department of Digestive Tract Diseases, Medical University of Lodz
- Thilo Hackert
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital
- Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center
- Faik G. Uzunoglu
- Department of General Visceral and Thoracic Surgery, University of Hamburg Medical Institutions
- Franco Bambi
- Blood Transfusion Service, Meyer Children’s Hospital
- Mara Goetz
- Department of General Visceral and Thoracic Surgery, University of Hamburg Medical Institutions
- Viktor Hlavac
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center
- Francesco Perri
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital
- Silvia Carrara
- Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital
- Stefano Landi
- Department of Biology, University of Pisa
- Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs
- Frederike Dijk
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam
- Evaristo Maiello
- Department of Oncology, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital
- Giovanni Capretti
- Pancreatic Unit, IRCCS Humanitas Research Hospital
- Sabrina Gloria Giulia Testoni
- PancreatoBiliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute
- Maria Chiara Petrone
- PancreatoBiliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute
- Hannah Stocker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center
- Stefano Ermini
- Blood Transfusion Service, Meyer Children’s Hospital
- Livia Archibugi
- PancreatoBiliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute
- Manuel Gentiluomo
- Department of Biology, University of Pisa
- Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University
- Raffaele Pezzilli
- Department of Gastroenterology, San Carlo Hospital
- Gregorio Di Franco
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa
- Anna Caterina Milanetto
- Department of Surgery, Oncology and Gastroenterology, University of Padova
- Cosimo Sperti
- Department of Surgery, Oncology and Gastroenterology, University of Padova
- John P. Neoptolemos
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital
- Luca Morelli
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa
- Klara Vokacova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences
- Claudio Pasquali
- Department of Surgery, Oncology and Gastroenterology, University of Padova
- Rita T. Lawlor
- Department of Diagnostics and Public Health, ARC-Net Centre for Applied Research on Cancer, University of Verona
- Francesca Bazzocchi
- Department of Surgery, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital
- Juozas Kupcinskas
- Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences
- Gabriele Capurso
- PancreatoBiliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute
- Daniele Campa
- Department of Biology, University of Pisa
- Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center
- DOI
- https://doi.org/10.1186/s40246-024-00576-x
- Journal volume & issue
-
Vol. 18,
no. 1
pp. 1 – 12
Abstract
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.
Keywords
- Association study
- Enhancer
- Pancreatic cancer
- Single nucleotide polymorphism
- Transcription factor binding site
