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.

Keywords: biomarkers; cancer; environment; epigenetics; molecular mechanisms; perspectives; research gaps.

Figure 1.

Exposures arising from external sources (environmental chemicals, air pollution, infectious agents, diet, tobacco, alcohol, endocrine disruptors) and internal processes (metabolism, hormones, inflammation, gut microflora, aging) may induce stable and potentially reversible changes in the epigenome. The patterns (“signatures”) and persistence of these alterations depend on multiple factors, including the type of epigenetic changes (some genomic regions remain methylated for longer periods than others), the dosage and duration of the exposure (longer and more intense exposures could minimize reversibility of DNA methylation), the tissue type and the developmental stage (in utero life or puberty may be particularly sensitive periods to some exposure). Thus, epigenetic mechanisms may represent “sensors” of exposure and “mediators” of the outcomes, including cancer development. Epigenome alterations should prove instrumental in discovery of new biomarkers for risk stratification and early detection and attractive targets for novel therapies and preventive strategies.

Figure 2.

An integrated approach for the production and integration of epigenetic data in carcinogen identification and evaluation. This approach implies the use of cutting edge epigenomics, population-based cohorts, and innovative bioinformatics tools for the identification, quantification, mapping of changes in the epigenome induced by known and suspected carcinogens. Human tumor samples from case– control and population-based cohorts are used in combination with in vitro cell systems and mouse models to perform epigenomic profiling to identify signatures, genes and pathways that are deregulated by specific risk exposure. This is followed by validation in population-based cohorts and where appropriate the data are crossed with the epigenomic databases. Identification of genes and pathways is followed by functional studies to provide biological plausibility to associations that are observed. The outcome is providing evidence base for studies directly relevant to cancer causation and prevention and identification of markers for early detection and cancer risk stratification.

Figure 3.

Constitutional epimutations and epigenetic mosaicism as a mechanism of cancer causality and targets for biomarker discovery. Although epigenetic patterns are tissue specific, interrogating the epigenome in tissues that are not the target tissue (surrogates) may be informative of exposure history and cancer risk. Environmental exposure, stochastic event, or even germline epimutation may be propagated over life course and result in epigenetic mosaicism or germline epimutations across tissues which may constitute an increased susceptibility to cancer.