Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu metaanalýza, časopisecké články, práce podpořená grantem
PubMed
37130759
DOI
10.1136/jmg-2022-108910
PII: jmg-2022-108910
Knihovny.cz E-zdroje
- Klíčová slova
- DNA Methylation, Genetic Variation, Genetics, Germ-Line Mutation, Molecular Epidemiology,
- MeSH
- celogenomová asociační studie MeSH
- duktální karcinom slinivky břišní * genetika MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- nádory slinivky břišní * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
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.
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
Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Firenze Italy
Carol Davila University of Medicine and Pharmacy Bucarest Romania
Center for Traslational Medicine Semmelweis University Budapest Hungary
County Medical Association of Potenza Potenza Italy
Department of Biology University of Pisa Pisa Italy
Department of Biomedical Sciences Humanitas University Milan Italy
Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland
Department of General Surgery University of Heidelberg Heidelberg Germany
Department of Medicine DIMED Padua University Hospital Padova Italy
Department of Surgery DiSCOG Padua University Hospital Padova Italy
Department of Surgery Erasmus Medical Center Erasmus University Rotterdam Netherlands
Digestive and Liver Disease Unit Sant'Andrea Hospital Roma Italy
Division of Clinical Epidemiology and Aging Research Cancer Research Center Heidelberg Germany
Division of General and Transplant Surgery Pisa University Hospital Pisa Italy
Division of Pancreatic Disease Heart and Vascular Center Semmelweis University Budapest Hungary
Endoscopic Unit Department of Gastroenterology IRCCS Humanitas Research Hospital Rozzano Italy
Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany
German Cancer Consortium Heidelberg Germany
Institute for Translational Medicine Medical School University of Pécs Pecs Hungary
Janos Szentagothai Research Center University of Pecs Pecs Hungary
Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece
Network Aging Research Heidelberg University Heidelberg Germany
Oncology of Massa Carrara Oncological Department Azienda USL Toscana Nord Ovest Pisa Italy
Pancreatic Unit IRCCS Humanitas Research Hospital Rozzano Italy
Citace poskytuje Crossref.org
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