Cancer: The aging epigenome

  1. Brandon L Pierce  Is a corresponding author
  1. Departments of Public Health and Human Genetics, University of Chicago, United States
  2. Department of Human Genetics, University of Chicago, United States

Abstract

A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer.

Main text

Age is a prominent risk factor for most types of cancer, including breast, lung and colon cancers, which each have a large impact on public health (de Magalhães, 2013). Cancer risk increases with age, in part, because genetic mutations that arise from DNA replication errors and exposure to environmental carcinogens accumulate as we get older (Tomasetti et al., 2017).

Aging also alters the epigenome, the chemical marks spread across DNA that help switch genes on or off by altering how the genome is packaged. For instance, the addition of a methyl group to DNA can play a role in compressing the nearby DNA sequence so it can no longer be accessed by the cell’s machinery. Epigenetic modifications, including DNA methylation, have also been shown to contribute to the development of cancer (Flavahan et al., 2017; Saghafinia et al., 2018). However, the potential impact of age-related epigenetic changes on cancer development has not been fully characterized.

Previous studies have identified specific DNA methylation sites that are associated with age (Horvath and Raj, 2018). Researchers have developed algorithms, called ‘epigenetic clocks’, that use data from tens to hundreds of these methylation sites to estimate an individual’s ‘epigenetic age’. This includes the Horvath clock which predicts age using DNA methylation data from any tissue type (Horvath, 2013), and the Hannum clock which was designed to use data from blood cells (Hannum et al., 2013).

It has been hypothesized that people whose epigenetic age is greater than their age in years – a phenomenon known as accelerated aging – may be at higher risk of age-related diseases, including cancer (Yu et al., 2020). However, previous studies linking accelerated epigenetic aging and cancer have produced mixed results. Now, in eLife, Fernanda Morales Berstein from the University of Bristol and co-workers (who are based at various institutes in the United Kingdom, the United States, Greece and Australia) report how they tackled this question using a different approach to most prior studies called Mendelian randomization (Morales Berstein et al., 2022). Instead of associating a person’s risk of cancer with epigenetic clock estimates, they correlated it against genetic variations that are known to influence these algorithms.

First, the team examined results from a previously conducted genome-wide association study which had analyzed the DNA of over 34,000 individuals to identify genetic variations that influence epigenetic clocks (McCartney et al., 2021). They used these results to select specific variants that predict the epigenetic age values measured by four common clocks (Horvath, Hannum, PhenoAge and GrimAge).

Next, Morales Berstein et al. used the Mendelian randomization method to find out if the variants that predict accelerated aging also affect the risk of several different types of cancer (breast, prostate, ovarian, colorectal and lung cancer). To do this the team obtained data from several large genome-wide association studies that had searched the genome of individuals for differences that predict cancer status; genetic variations related to the aging clocks were then extracted to see if they were also associated with an increased risk of cancer.

The results of Morales Berstein et al. did not show many clear relationships between the epigenetic aging clocks and risk for the various types of cancer studied. The most promising finding was an association between the GrimAge clock and colorectal cancer. The GrimAge clock was not designed to predict age alone, but also reflects the effects of smoking and other mortality-related epigenetic features (Lu et al., 2019). Thus, the interpretation of this association is not straightforward, as this clock may capture the effects of environmental or lifestyle factors on the epigenome.

While the Morales Berstein et al. study did not show pervasive effects of epigenetic aging on cancer risk, their work is a critical contribution to cancer susceptibility research, as they have addressed an important question using rigorous methods, including Mendelian randomization. The primary strength of studies that use this approach is that they are less prone to certain types of biases that can affect observational research, such as confounding and reverse causation. Furthermore, it is important to acknowledge that epigenetic clocks have largely been developed based on how aging affects DNA methylation in blood cells. Much less is known regarding aging and epigenetics in other tissue types, including those prone to cancer, such as the ones examined by Morales Berstein et al.

Future studies will likely use Mendelian randomization to address similar hypotheses for additional cancer types and a wider variety of epigenetic aging algorithms. As the size of genome-wide association studies increase and more clock-related genetic variants are discovered, this approach will gain more power to detect the effects of epigenetic aging on cancer and other age-related diseases.

References

Article and author information

Author details

  1. Brandon L Pierce

    Brandon L Pierce is in the Departments of Public Health and Human Genetics, University of Chicago, Chicago, United States

    For correspondence
    brandonpierce@uchicago.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7829-952X

Publication history

  1. Version of Record published: April 28, 2022 (version 1)

Copyright

© 2022, Pierce

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 801
    Page views
  • 102
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Brandon L Pierce
(2022)
Cancer: The aging epigenome
eLife 11:e78693.
https://doi.org/10.7554/eLife.78693

Further reading

    1. Evolutionary Biology
    2. Genetics and Genomics
    Beatriz Navarro-Dominguez et al.
    Research Article Updated

    Meiotic drive supergenes are complexes of alleles at linked loci that together subvert Mendelian segregation resulting in preferential transmission. In males, the most common mechanism of drive involves the disruption of sperm bearing one of a pair of alternative alleles. While at least two loci are important for male drive—the driver and the target—linked modifiers can enhance drive, creating selection pressure to suppress recombination. In this work, we investigate the evolution and genomic consequences of an autosomal, multilocus, male meiotic drive system, Segregation Distorter (SD) in the fruit fly, Drosophila melanogaster. In African populations, the predominant SD chromosome variant, SD-Mal, is characterized by two overlapping, paracentric inversions on chromosome arm 2R and nearly perfect (~100%) transmission. We study the SD-Mal system in detail, exploring its components, chromosomal structure, and evolutionary history. Our findings reveal a recent chromosome-scale selective sweep mediated by strong epistatic selection for haplotypes carrying Sd, the main driving allele, and one or more factors within the double inversion. While most SD-Mal chromosomes are homozygous lethal, SD-Mal haplotypes can recombine with other, complementing haplotypes via crossing over, and with wildtype chromosomes via gene conversion. SD-Mal chromosomes have nevertheless accumulated lethal mutations, excess non-synonymous mutations, and excess transposable element insertions. Therefore, SD-Mal haplotypes evolve as a small, semi-isolated subpopulation with a history of strong selection. These results may explain the evolutionary turnover of SD haplotypes in different populations around the world and have implications for supergene evolution broadly.

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Noushin Hadadi et al.
    Tools and Resources

    Thermal adaptation is an extensively used intervention for enhancing or suppressing thermogenic and mitochondrial activity in adipose tissues. As such, it has been suggested as a potential lifestyle intervention for body weight maintenance. While the metabolic consequences of thermal acclimation are not limited to the adipose tissues, the impact on the rest of the tissues in context of their gene expression profile remains unclear. Here, we provide a systematic characterization of the effects in a comparative multi-tissue RNA sequencing approach following exposure of mice to 10 °C, 22 °C, or 34 °C in a panel of organs consisting of spleen, bone marrow, spinal cord, brain, hypothalamus, ileum, liver, quadriceps, subcutaneous-, visceral- and brown adipose tissues. We highlight that transcriptional responses to temperature alterations exhibit a high degree of tissue-specificity both at the gene level and at GO enrichment gene sets, and show that the tissue-specificity is not directed by the distinct basic gene expression pattern exhibited by the various organs. Our study places the adaptation of individual tissues to different temperatures in a whole-organism framework and provides integrative transcriptional analysis necessary for understanding the temperature-mediated biological programming.