<p>The Current Understanding Of Asbestos-Induced Epigenetic Changes Associated With Lung Cancer</p>

Abstract

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.

The evolving landscape of sex-based differences in lung cancer: a distinct disease in women

“…Asbestos was widely used in building, textiles and insulation materials until the late 1900s, and exposures have been described both in occupational and non-occupational settings, with often a long latency period (30 years or more) between exposure and development of cancer [22]. While the occupational risk of lung cancer from asbestos has been described with higher frequency in men, one meta-analysis found that women were at slightly higher risk compared to men of developing lung cancer from a non-occupational exposure to asbestos [23]. There is a paucity of cohort studies evaluating the risk of non-occupational asbestos exposure with the development of lung cancer; thus the severity of this risk, particularly in women, may be underrepresented currently.…”

Role of microRNAs in Lung Carcinogenesis Induced by Asbestos

“…A link between the hypermethylation of promotor DNA and inflammation has been shown in many forms of cancer, including asbestos-related lung cancer [ 133 , 134 ]. Molecular genetic analysis have shown changes in the number of DNA copies, changes in the profiles of many microRNAs, and dysregulation of the expression of certain genes in asbestos-associated lung cancer [ 130 , 133 , 134 ]. However, how asbestos fibers directly or indirectly affect cells in lung cancer and how they interact with cells at the molecular level is currently not known [ 17 ].…”

Bridging the gap between toxicity and carcinogenicity of mineral fibres by connecting the fibre crystal-chemical and physical parameters to the key characteristics of cancer

“…Although DNA damage-inducible genes, such as TP53 and GADD153, are up-regulated in asbestos treated cells ( Johnson and Jaramillo, 1997 ), accumulation of fibres in the lung and the continuous production of ROS/RNS causes repeated DNA damage, leading to increased genetic instability, a hallmark of neoplastic development ( Nymark et al, 2008 ). Although the mechanism by which asbestos induces epigenetic changes is not fully understood, several studies have shown that both phagocytosis of fibres by AM and oxido-reduction reactions on fibre surfaces are known to generate ROS that result in DNA damage and oxidative stress, leading to genetic alterations ( Cheng et al, 2020 ). High iron content of amphibole asbestos explains how iron-induced Fenton reactions also contribute to increased ROS ( Cheng et al, 2020 ) and it was observed that iron-rich amphibole asbestos species induce phosphorylated histone γ-H2AX ( Msiska et al, 2010 ) marker of epigenetic alteration and gene-specific DNA methylation ( Mossman, 2017 , Öner et al, 2018 , Mossman and Gualtieri, 2020 ).…”