Roadmap for investigating epigenome deregulation and environmental origins of cancer

Abstract

The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene–environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor-specific (“fingerprints”) that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed and advances in epigenomics that may help in understanding the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed and how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment.

The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome

“…The heritability of epigenetic marks allows for faithful maintenance of cell identity (Lee et al 2014), whereas their reversibility allows for developmental plasticity, enabling the manifestation of different phenotypes in response to developmental cues and environmentally induced changes from a single unchanged genotype (Low and Gluckman 2018). Although some degree of stochastic epigenetic alterations, or epigenetic drift, can be observed in aging or as asymptomatic occurrences (Bjornsson et al 2008;Feil and Fraga 2012;Fraga 2009;Wong et al 2010), epigenetic aberrations have been described as important drivers of neurological diseases and cancer (Herceg et al 2018;Zoghbi and Beaudet 2016). Therefore, external stimuli that can cause shifts away from baseline rates of age-related epigenetic drift have been described as elements that cause "environmental deflection" (Kochmanski et al 2017).…”

“…Following the frequent inclusion of epigenetics as a parameter in environmental epidemiology studies, numerous reports have been made in recent years associating alterations in DNA methylation with various environmental factors, including biological agents, dietary habits, and air pollution (Ambatipudi et al 2016;Barouki et al 2018;de FC Lichtenfels et al 2018;Degli Esposti et al 2017;Fasanelli et al 2019;Feil and Fraga 2012;Hattori and Ushijima 2016;Herceg et al 2018;Martin and Fry 2018;Perrier et al 2019;Woo et al 2018). Similarly, many reports indicate that microRNA (miRNA) profiles are responsive to various environmental exposures, including air pollution ; Espín-Pérez et al (2018), both epidemiological studies], nanoparticles [Brzóska et al (2019), utilizing human liver cells], endocrine disruptors, such as bisphenol A (BPA) [Chou et al (2017), using human endometrial cells, and Martínez-Ibarra et al (2019), using human blood samples], and dichlorodiphenyltrichloroethane (DDT) [Krauskopf et al (2017), using human blood].…”

“…These include toxic elements (e.g., arsenic, cadmium, lead, mercury); naturally occurring animal, plant, and food allergens; pesticides, persistent organic pollutants (e.g., perfluorooctanoic acid, polychlorinated biphenyls); volatile organic compounds (e.g., benzene, formaldehyde, gasoline); plastic components (e.g., bisphenol A, phthalates); and air pollutants (e.g., asbestos, radon, tobacco smoke) (reviewed by Bijlsma and Cohen 2016;Sears and Genuis 2012). Biochemical effects commonly reported to be triggered by environmental toxicants include oxidative stress, endocrine disruption, genotoxicity, enzyme inhibition, epigenetic changes, and dysbiosis (reviewed by Herceg et al 2018;Sears and Genuis 2012). Evidently, there is a need for a concerted effort across all levels to understand and mitigate the impact of toxic exposures on human health and the environment.…”

Experimental identification of cancer driver alterations in the era of pan‐cancer genomics

“…Cancer‐related mutational and chromatin changes have been observed in cell‐based models of immortalization and transformation. This raises the possibility of taking advantage of these experimentally accessible systems to improve the functional understanding of alterations that drive the early events of cancer development . With the emergence of CRISPR‐Cas9 technology, the feasibility of correcting single point mutations or combinations in immortalized cell clones offers an intriguing opportunity for studying the contribution of mutations in putative cancer driver genes to the immortalized phenotype.…”

Genetic and Epigenetic Heterogeneity in Normal Liver Homeostasis and Its Implications for Liver Disease and Hepatocellular Cancer

“…As such, the epigenetic landscape has the potential for considerable plasticity relative to genetic alterations, making the epigenome more prone to change or adaptation. 33 Epigenetic modifications are a major potential source of phenotypic variation because of their ability to sense, react to, and integrate signals from multiple inputs including environmental stressors (including many of the HCC risk exposures such as alcohol and viral infection) and genetic alterations [34][35][36] The relative plasticity of epigenetic marks, coupled with established and emerging epigenetic pathwaytargeting therapies (including clinical trials involving HCC 37 ) make the epigenome a promising anticancer target. The potential significance of epigenetic heterogeneity to HCC treatment can be inferred from findings reported in other tumor types linking drug response 38,39 and resistance 29,40 to epigenetic mechanisms.…”