Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

Autor:	Corradi C; Department of Biology, University of Pisa, Pisa, Italy., Lencioni G; Department of Biology, University of Pisa, Pisa, Italy., Gentiluomo M; Department of Biology, University of Pisa, Pisa, Italy., Felici A; Department of Biology, University of Pisa, Pisa, Italy., Latiano A; Division of Gastroenterology and Research Laboratory, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Kiudelis G; Department of Gastroenterology, Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania., van Eijck CHJ; Department of Surgery, Erasmus Medical Center, Erasmus University, Rotterdam, Netherlands., Marta K; Center for Traslational Medicine, Semmelweis University, Budapest, Hungary.; Division of Pancreatic Disease, Heart and Vascular Center, Semmelweis University, Budapest, Hungary., Lawlor RT; ARC-NET, Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy., Tavano F; Division of Gastroenterology and Research Laboratory, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Boggi U; Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy., Dijk F; Department of Pathology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands., Cavestro GM; Division of Experimental Oncology, Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milano, Italy., Vermeulen RCH; University of Utrect, Utrecht, Netherlands., Hackert T; Department of General Surgery, University of Heidelberg, Heidelberg, Germany., Petrone MC; Pancreato-Biliary Endoscopy and Endoscopic Ultrasound, Pancreas Translational and Clinical Research Center, IRSSC San Raffaele Scientific Institute, Milan, Italy., Uzunoğlu FG; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Archibugi L; Pancreato-Biliary Endoscopy and Endoscopic Ultrasound, Pancreas Translational and Clinical Research Center, IRSSC San Raffaele Scientific Institute, Milan, Italy.; Digestive and Liver Disease Unit, Sant'Andrea Hospital, Roma, Italy., Izbicki JR; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Morelli L; General Surgery, Department of Translational Research and New Technologies in Medicine and Surgery, Università di Pisa, Pisa, Italy., Zerbi A; Pancreatic Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy.; Department of Biomedical Sciences, Humanitas University, Milan, Italy., Landi S; Department of Biology, University of Pisa, Pisa, Italy., Stocker H; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Network Aging Research (NAR), Heidelberg University, Heidelberg, Germany., Talar-Wojnarowska R; Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland., Di Franco G; General Surgery, Department of Translational Research and New Technologies in Medicine and Surgery, Università di Pisa, Pisa, Italy., Hegyi P; Center for Traslational Medicine, Semmelweis University, Budapest, Hungary.; Division of Pancreatic Disease, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.; Institute for Translational Medicine, Medical School, University of Pécs, Pecs, Hungary.; Janos Szentagothai Research Center, University of Pecs, Pecs, Hungary., Sperti C; Department of Surgery-DiSCOG, Padua University Hospital, Padova, Italy., Carrara S; Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy., Capurso G; Pancreato-Biliary Endoscopy and Endoscopic Ultrasound, Pancreas Translational and Clinical Research Center, IRSSC San Raffaele Scientific Institute, Milan, Italy.; Digestive and Liver Disease Unit, Sant'Andrea Hospital, Roma, Italy., Gazouli M; Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Brenner H; Division of Clinical Epidemiology and Aging Research, Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Bunduc S; Center for Traslational Medicine, Semmelweis University, Budapest, Hungary.; Division of Pancreatic Disease, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.; Carol Davila University of Medicine and Pharmacy, Bucarest, Romania., Busch O; Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands., Perri F; Division of Gastroenterology and Research Laboratory, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Oliverius M; Department of Surgery, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Charles University, Prague, Czech Republic., Hegyi PJ; Center for Traslational Medicine, Semmelweis University, Budapest, Hungary.; Division of Pancreatic Disease, Heart and Vascular Center, Semmelweis University, Budapest, Hungary., Goetz M; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Scognamiglio P; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Mambrini A; Oncology of Massa Carrara, Oncological Department, Azienda USL Toscana Nord Ovest, Pisa, Italy., Arcidiacono PG; Pancreato-Biliary Endoscopy and Endoscopic Ultrasound, Pancreas Translational and Clinical Research Center, IRSSC San Raffaele Scientific Institute, Milan, Italy., Kreivenaite E; Department of Gastroenterology, Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania., Kupcinskas J; Department of Gastroenterology, Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania., Hussein T; Center for Traslational Medicine, Semmelweis University, Budapest, Hungary.; Division of Pancreatic Disease, Heart and Vascular Center, Semmelweis University, Budapest, Hungary., Ermini S; Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Firenze, Italy., Milanetto AC; Department of Surgery-DiSCOG, Padua University Hospital, Padova, Italy., Vodicka P; Department of Molecular Biology of Cancer, Institute of Experimental Medicine Czech Academy of Sciences, Prague, Czech Republic.; Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.; First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, Prague, Czech Republic., Kiudelis V; Department of Gastroenterology, Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania., Hlaváč V; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic., Soucek P; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic., Theodoropoulos GE; First Propaedeutic University Surgery Clinic, Hippocratio General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Basso D; Department of Medicine-DIMED, Padua University Hospital, Padova, Italy., Neoptolemos JP; Department of General Surgery, University of Heidelberg, Heidelberg, Germany., Nóbrega Aoki M; Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba, Brazil., Pezzilli R; County Medical Association of Potenza, Potenza, Italy., Pasquali C; Department of Surgery-DiSCOG, Padua University Hospital, Padova, Italy., Chammas R; Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba, Brazil., Testoni SGG; Pancreato-Biliary Endoscopy and Endoscopic Ultrasound, Pancreas Translational and Clinical Research Center, IRSSC San Raffaele Scientific Institute, Milan, Italy., Mohelnikova-Duchonova B; Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic., Lucchesi M; Oncology of Massa Carrara, Oncological Department, Azienda USL Toscana Nord Ovest, Pisa, Italy., Rizzato C; Department of Translational Research and new Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Canzian F; Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany., Campa D; Department of Biology, University of Pisa, Pisa, Italy daniele.campa@unipi.it.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2023 Oct; Vol. 60 (10), pp. 980-986. Date of Electronic Publication: 2023 May 02.
DOI:	10.1136/jmg-2022-108910
Abstrakt:	Introduction: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. Materials and Methods: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. Results: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10 -8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense ( RCCD1-AS1 ) gene which, when expressed, decreases the expression of the RCC1 domain-containing ( RCCD1 ) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1 . Conclusion: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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