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

0580684 - ÚEM 2024 RIV GB eng J - Článek v odborném periodiku
Corradi, Ch. - Lencioni, G. - Gentiluomo, M. - Felici, A. - Latiano, A. - Kiudelis, G. - van Eijck, C.H.J. - Marta, K. - Lawlor, R.T. - Tavano, F. - Boggi, U. - Dijk, F. - Cavestro, G.M. - Vermeulen, R.C.H. - Hackert, T. - Petrone, M.Ch. - Uzunoglu, F.G. - Archibugi, L. - Izbicki, J.R. - Morelli, L. - Zerbi, A. - Landi, S. - Stocker, H. - Talar-Wojnarowska, R. - Di Franco, G. - Vodička, Pavel … celkem 62 autorů
Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.
Journal of Medical Genetics. Roč. 60, č. 10 (2023), s. 980-986. ISSN 0022-2593. E-ISSN 1468-6244
Institucionální podpora: RVO:68378041
Klíčová slova: DNA methylation * genetic variation * genetics * molecular epidemiology * germ-line mutation
Obor OECD: Human genetics
Impakt faktor: 4, rok: 2022
Způsob publikování: Omezený přístup
https://jmg.bmj.com/content/60/10/980

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=4.93x10(-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.
Trvalý link: https://hdl.handle.net/11104/0350868