Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood

Background: DNA methylation markers have been associated with lung cancer risk and may identify aetiologically relevant genomic regions, or alternatively, be markers of disease risk factors or biological processes associated with disease development. Methods: In a nested case–control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 participants (208 cases; 222 controls) in the 1989 CLUE II cohort. We compared DNA methylation levels with case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years-based smoking methylation score. Stratification analyses were conducted over time from blood draw to diagnosis, histology, and smoking status. Results: We identified 16 single CpG sites and 40 DMRs significantly associated with lung cancer risk (q Conclusion: The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing potential biomarkers for lung cancer risk stratification. Future studies will need to examine whether these regions are causally related to lung cancer.