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.
- DNA Methylation
- Genetic Variation
- Molecular Epidemiology
- Germ-Line Mutation
Data availability statement
Data are available upon reasonable request.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Contributors CC and GL are joint first authors, contributed equally, and performed the lab work and the analysis of the data. FC and DC are joint last authors. DCacts as guarantor. DC conceived and designed the study. CC, DC, MG, CR and FC wrote the first draft of the manuscript. All authors contributed to the writing and approved the final version of the manuscript.
Funding This work was supported by intramural funding of DKFZ (to FC); Fondazione Tizzi (www.fondazionetizzi.it); Fondazione Arpa (www.fondazionearpa.it, to DC); and Associazione Italiana per la Ricerca sul Cancro (AIRC IG 2021-26201, to GC). This work was supported by Italian Ministry of Health grants (Ricerca Corrente 2022-2024) to Fondazione 'Casa Sollievo della Sofferenza' IRCCS Hospital, San Giovanni Rotondo (FGU), Italy and by the '5x1000' voluntary contribution.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.