DNA methylation of oxidative stress genes and cancer risk in the Normative Aging Study

Oxidative stress (OS) is a primary mechanism of carcinogenesis, and methylation of genes related to it may play a role in cancer development. In this study, we examined the prospective association between blood DNA methylation of four oxidative stress genes and cancer incidence. Our study population included a total of 582 participants in the Normative Aging Study (NAS) who had blood drawn during 1-4 visits from 1999-2012 (mean follow up 9.0 years). Promoter DNA methylation of CRAT, iNOS, OGG1 and GCR in blood leukocytes was measured using pyrosequencing. We used Cox regression models to examine prospective associations between cancer incidence and both methylation at the baseline visit and methylation rate of changes over time. Baseline OGG1 methylation was associated with higher risk of all-cancer (HR: 1.43, 95% CI: 1.15-1.78) and prostate cancer (HR: 1.52, 95% CI: 1.03-2.25) incidence. Compared with participants remaining cancer-free, those who eventually developed cancer had significantly accelerated CRAT methylation (p = 0.04) and decelerated iNOS methylation (p < 0.01) over time prior to cancer diagnosis. Accelerated CRAT methylation was associated with higher all-cancer incidence (HR: 3.88, 95% CI: 1.06-14.30), whereas accelerated iNOS methylation was associated with lower all-cancer incidence (HR: 0.08, 95% CI 0.02-0.38). Our results suggest that methylation and its dynamic change over time in OS-related genes, including OGG1, CRAT and iNOS, may play an important role in carcinogenesis. These results can potentially facilitate the development of early detection biomarkers and new treatments for a variety of cancers.