Previous studies have revealed a robust association between exposure to
asbestos and human
lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of
carcinogen-induced
malignancies. We examined the impact of
asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of
lung cancer tissue and paired normal lung from 28
asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91
non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in
lung cancer. DMRs in genes such as RARB (FDR 1.1 × 10-19 , mean change in beta [Δ] -0.09), GPR135 (FDR 1.87 × 10-8 , mean Δ -0.09) and TPO (FDR 8.58 × 10-5 , mean Δ -0.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with
asbestos exposure status in exposed versus non-exposed lung
tumors. Hypomethylation was characteristic to DVMCs in
lung cancer tissue from
asbestos-exposed subjects. When DVMCs related to
asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in
tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung
tumors and
asbestos exposure, suggesting that changes may be present in causal pathway from
asbestos exposure to
lung cancer.