The Current Understanding Of Asbestos-Induced Epigenetic Changes Associated With Lung Cancer

Yuen Yee Cheng, 1, 2 Emma M Rath, 3 Anthony Linton, 1, 2, 4 Man Lee Yuen, 1 Ken Takahashi, 1 Kenneth Lee 1, 2, 4 1Asbestos Disease Research Institute, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; 2Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia; 3Garvan Institute of Medical Research, Sydney, New South Wales, Australia; 4Concord Repatriation General Hospital, Sydney, New South Wales, AustraliaCorrespondence: Yuen Yee ChengAsbestos Disease Research Institute, PO Box 3628, Rhodes, New South Wales 2139, AustraliaTel +61 2 9767 9800Fax +61 2 9767 9860Email yycheng@adri.org.auAbstract: Asbestos is a naturally occurring mineral consisting of extremely fine fibres that can become trapped in the lungs after inhalation. Occupational and environmental exposures to asbestos are linked to development of lung cancer and malignant mesothelioma, a cancer of the lining surrounding the lung. This review discusses the factors that are making asbestos-induced lung cancer a continuing problem, including the extensive historic use of asbestos and decades long latency between exposure and disease development. Genomic mutations of DNA nucleotides and gene rearrangements driving lung cancer are well-studied, with biomarkers and targeted therapies already in clinical use for some of these mutations. The genes involved in these mutation biomarkers and targeted therapies are also involved in epigenetic mechanisms and are discussed in this review as it is hoped that identification of epigenetic aberrations in these genes will enable the same gene biomarkers and targeted therapies to be used. Currently, understanding of how asbestos fibres trapped in the lungs leads to epigenetic changes and lung cancer is incomplete. It has been shown that oxidoreduction reactions on fibre surfaces generate reactive oxygen species (ROS) which in turn damage DNA, leading to genetic and epigenetic alterations that reduce the activity of tumour suppressor genes. Epigenetic DNA methylation changes associated with lung cancer are summarised in this review, and some of these changes will be due to asbestos exposure. So far, little research has been carried out to separate the asbestos driven epigenetic changes from those due to non-asbestos causes of lung cancer. Asbestos-associated lung cancers exhibit less methylation variability than lung cancers in general, and in a large proportion of samples variability has been found to be restricted to promoter regions. Epigenetic aberrations in cancer are proving to be promising biomarkers for diagnosing cancers. It is hoped that further understanding of epigenetic changes in lung cancer can result in useful asbestos-associated lung cancer biomarkers to guide treatment. Research is ongoing into the detection of lung cancer epigenetic alterations using non-invasive samples of blood and sputum. These efforts hold the promise of non-invasive cancer diagnosis in the future. Efforts to reverse epigenetic aberrations in lung cancer by epigenetic therapies are ongoing but have not yet yielded success.Keywords: lung cancer, epigenetic biomarkers, microRNA, DNA methylation, immunohistochemistry, IHC, fluorescence in situ hybridization, FISH