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Int J Cancer. 2017 Nov 15;141(10):2014-2029. doi: 10.1002/ijc.30897. Epub 2017 Aug 2.

Asbestos-associated genome-wide DNA methylation changes in lung cancer.

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Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, Helsinki, Finland.
Epigenetics Group, Section of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer, Lyon, France.
Division of Human Genome Research Centre, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
Laboratory of Genetic Diagnostics, National Cancer Institute, Vilnius, Lithuania.
Department of Pathology, University of Helsinki, and HUSLAB, Helsinki University Hospital, Finland.


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.


DNA methylation arrays; asbestos exposure; lung cancer; pyrosequencing; smoking

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