Discovery of a novel epigenetic cancer marker related to the oxidative status of human blood

Abstract

Long-lasting oxidative stress exposure may lead to relatively stable epigenetic modifications of the DNA in order to activate anti-oxidative defence mechanisms. Oxidative stress related DNA methylation may therefore be associated (causally or as a by-product) with cancer. We measured derivatives of reactive oxygen metabolites (D-ROM), total thiol levels (TTL) and DNA methylation with the Illumina Infinium 450K BeadChip in three samples of German individuals aged ≥50 years: n=1,000 ESTHER study baseline participants (DNA methylation only), n=99 ESTHER eight-year follow-up participants and n=142 participants of the BLITZ study. The correlation coefficient of methylation at cg10342304 and D-ROM in the ESTHER 8-year follow-up sample (r=-0.427; P=1 × 10-5) was replicated with a P-value indicating statistical significance after correction for multiple testing in the BLITZ sample (r=-0.192; P=0.022). The association was robust to adjusting for potential confounders. In the ESTHER baseline sample, the hazard ratio for cancer development in 11 years of follow-up comparing bottom and top quartile of DNA methylation at cg10342304 was 1.86 (95%-confidence-interval 1.01-3.43). In summary, this first epigenome-wide screening and replication study with oxidative status markers observed a negative correlation of D-ROM levels and DNA methylation at cg10342304 in two independent cohorts. This CpG site is located in the body region of the nucleoredoxin gene. The nucleoredoxin protein is a redox-dependent inhibitor of the Wnt/ß-catenin signaling pathway, a well-characterized cancer pathway. If the observed CpG-cancer association can be successfully replicated by other studies, this epigenetic marker could be an interesting biomarker of cancer risk.