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Article

PubMed

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

Journal of medical genetics. 2023 Oct ; 60 (10) : 980-986. [epub] 20230502

J Med Genet
ISSN 1468-6244 | 0022-2593
Source

Language English Country England, Great Britain Media print-electronic

Document type Meta-Analysis, Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid37130759

PubMed 37130759
DOI 10.1136/jmg-2022-108910
PII: jmg-2022-108910
Knihovny.cz E-resources

Keywords
DNA Methylation, Genetic Variation, Genetics, Germ-Line Mutation, Molecular Epidemiology,
MeSH
Genome-Wide Association Study MeSH
Carcinoma, Pancreatic Ductal * genetics MeSH
Humans MeSH
DNA Methylation genetics MeSH
Pancreatic Neoplasms * genetics MeSH
Check Tag
Humans MeSH
Publication type
Journal Article MeSH
Meta-Analysis MeSH
Research Support, Non-U.S. Gov't 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.

1st Faculty of Medicine Institute of Biology and Medical Genetics Charles University Prague Czech Republic

1st Propaedeutic University Surgery Clinic Hippocratio General Hospital Medical School National and Kapodistrian University of Athens Athens Greece

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

Biomedical Centre and Department of Surgery 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