The Exposome-Epigenome Nexus: Understanding Cancer Etiology through DNA methylation

This is the Third Prize Winner of the 2024 Molecular Oncology Writing Competition: Impact of the exposome on cancer risk.
The Exposome-Epigenome Nexus: Understanding Cancer Etiology through DNA methylation
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As part of World Cancer Day (4th Feb), the journal of Molecular Oncology invited researchers to take part in a writing competition aimed at highlighting the impact of the exposome on cancer risk. This entry, by Jose Jaime Diaz Larrosa (German Cancer Research Center (DKFZ), Germany), received the third prize.

The term exposome was formally coined by Christopher Wild in 2005 to define the multitude of exposures every person faces throughout their lifespan as well as the effect these factors have on health and development through different biological mechanisms. The exposome is a complex entity formed by an external component – divided into the natural (the elements we encounter), built (the human places we inhabit), social, policy and healthcare domains; and an internal one, which includes all the homeostatic responses to environmental stimuli, whose final outcome will influence the appearance of certain diseases, like cancer.

Cancer is a complex and multifactorial disease that arises from the interplay between genetic predispositions and environmental exposures. Despite these predispositions having been deeply researched, in so doing providing us with a massive corpus of knowledge and effective treatments, the environmental exposures have historically been more overlooked. Apart from a few extreme cases, little is known about how certain external stimuli can trigger or shape cancer development.

Epigenetic modifications are robust, stable and reversible chemical modifications by which the environment can impact cellular biology during development and disease onset. Interestingly, the last update of the Hallmarks of Cancer published by Hanahan in 2022 highlighted, among other factors, the importance of non-mutational epigenetic reprogramming in the appearance of this disease. The most studied epigenetic mark is DNA methylation, which consists of the addition of a methyl group to cytosine residues in CpG dinucleotides and plays a crucial role in regulating mammalian gene expression by modifying the chromatin structure and affecting transcriptional activity.

During tumourigenesis, the normal methylation landscape of a cell becomes aberrant leading to a global loss of DNA methylation (hypomethylation), which is thought to participate in genomic instability, activation of oncogenes and aneuploidy. On the other hand, there is also a focal gain of methylation (hypermethylation) associated with the silencing of promoters and distal enhancers, like those regulating tumor suppressor genes. Interestingly, these cancer-specific methylation landscapes can be used for diagnosis, for example with liquid biopsies. Liquid biopsies are a noninvasive diagnostic method, based on the analysis of the methylation patterns of cell-free DNA coming from cancer cells, that is present in the blood of patients.

Numerous studies have demonstrated the impact of environmental cues on DNA methylation and health issues. Lifestyle factors, such as smoking and nicotine exposure have been linked to methylation changes in genes related to obesity and cancer development already in adolescents born of smoking mothers, This conclusion shows the effect of the exposome already during gestational periods as well as its persistence over the years, even if the sampled donors were not smokers themselves. Additionally, exposure to lead has also been concluded to produce methylation specific modifications, this time, in several genes associated with brain development and neuronal function, as were detected in children who were prenatally exposed.

Strikingly, socioeconomic factors, such as the education level, have also been correlated to agedependent DNA methylation changes. This opens the door to analyzing the effect of many other exposures belonging to other domains of the external exposome and their relevance in cancer appearance. The built, policy and healthcare domains, despite being less explored and harder to correlate with a biological mechanism, could also affect cancer-related DNA methylation patterns.

Given the current economic inflation and the trend of most European countries reducing public healthcare investment, one might question whether factors such as a higher patient-to-doctor ratio, longer waiting times for specialized appointments, reduced access to public institutions, or insufficient hospital staffing have a measurable impact on cellular biology, and if DNA methylation can serve as a proxy for such effects.

These measurements could also be complemented by the work of several research groups who have already made substantial efforts such as the Public Health Exposome (PHE) framework created by Paul Juarez et al. (2014) in the USA, which aims to put together data coming from a variety of sources. These include hospitals and research centers, as well as public institutions like the US Department of Education, Agriculture, Post Office, Census, National Oceanic and Atmospheric Administration. All of these are publicly available, thus allowing researchers to organize and analyse all the different exposome variables.

This also highlights the importance of interdisciplinary collaboration in disease-fighting research and could potentially inspire other countries to undertake similar efforts to unravel the complex etiology of cancer.

Altogether, if we manage to put all these exposome-related data under the perspective of such a robust epigenetic mark as DNA methylation, we have the potential to understand the molecular effects of external stimuli in diseases like cancer and make policy makers understand the role that public administrations play in supporting personalised medicine and biological wellbeing.


Photo by Nareeta Martin on Unsplash

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