1. Genetics and Genomics
  2. Medicine

Cancer: The aging epigenome

A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer.
https://doi.org/10.7554/eLife.78693
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  1. Brandon L Pierce
(2022)
Cancer: The aging epigenome
eLife 11:e78693.
https://doi.org/10.7554/eLife.78693
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  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

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.

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  1. Brandon L Pierce

    Brandon L Pierce is in the Departments of Public Health and Human Genetics, University of Chicago, Chicago, United States
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    brandonpierce@uchicago.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7829-952X

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

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Research organism

    1. Related to

    Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study

    Fernanda Morales Berstein, Daniel L McCartney ... Rebecca C Richmond

Further reading

    1. Genetics and Genomics
    2. Medicine

    Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study

    Fernanda Morales Berstein, Daniel L McCartney ... Rebecca C Richmond
    Research Article Updated

    Background:

    Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.

    Methods:

    We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671–13,879; N controls = 173,493–372,016), FinnGen (N cases = 719–8401; N controls = 74,685–174,006) and several international cancer genetic consortia (N cases = 11,348–122,977; N controls = 15,861–105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.

    Results:

    Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04–1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09–1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97–1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers.

    Conclusions:

    GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.

    Funding:

    FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic’s Operational Programme ‘Competitiveness, Entrepreneurship & Innovation’ (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer’s Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol.