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.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.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.We identified
a novel PDAC risk locus which modulates cancer risk by controlling gene expression
through DNA methylation.
