Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms

Abstract

Background: Age-related epigenetic dysregulations were associated with several diseases, including cancer. The individual number of stochastic epigenetic mutations (SEMs) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated. Methods:A SEM, at a given CpG site, was defined as an extreme outlier of blood DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case-control pairs nested in three prospective cohorts. Further, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions. Results:In the three-study meta-analysis the estimated odds ratios (ORs) per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% CI 1.11-1.41 for breast cancer, and 1.23; 95% CI 1.07-1.42 for lung cancer. In MCCS, the OR for mature B-cell neoplasm was 1.46; 95% CI 1.25-1.71. Enrichment analyses indicated that SEMs more likely occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (p<0.0001 and p=0.0005 respectively): two components of the Polycomb-Repressive-Complex-2 (PCR2). Finally, using longitudinal DNA methylation data, we showed that PCR2-specific SEMs are generally more stable in time compared with SEMs occurring in the whole-genome. Conclusions:The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples. Enrichment analyses indicate key enzymatic pathways possibly involved in carcinogenesis mechanisms. Impact:We provide the first evidence of the prospective association between epimutations and a higher risk of different cancers. We hypothesized a possible mechanism of carcinogenesis involving PCR2 complex proteins worthy of further investigation.

DNA methylation‐based biomarkers of aging were slowed down in a two‐year diet and physical activity intervention trial: the DAMA study

“…Functional characterization of PArSEMs CpGs highlights an enrichment of reversible epimutations in TFBS of two members of the Polycomb Repressive Complex 2 (PRC2) proteins: EZH2 and SUZ12. Interestingly, previous studies indicate that a lower number of SEMs in genes targeted by these two proteins, mostly tumor suppressor genes, is associated with a lower risk of future cancer development (Gagliardi et al, 2020 ). Additionally, KEGG pathway gene ontology enrichment analysis shows that PArSEMs are enriched in several cancer‐related pathways such as hsa05205 (“Proteoglycans in cancer”), hsa05224 (“Breast cancer”), hsa04310 (“Wnt signaling pathway”), and hsa04024 (“cAMP signaling pathway”).…”

“…The total number of SEMs per individual, also known as epigenetic mutation load (EML) (Yan et al, 2020 ), is defined as the sum of extreme (outliers) DNAm values per sample. Recently, (Gentilini et al, 2015 ) provided evidence of the exponential relationship between age and SEMs, which occurs naturally during aging as a consequence of the “epigenetic drift.” A higher EML has been associated with age‐related pathological conditions like X chromosome activation skewing (Gentilini et al, 2015 ) and risk factors for non‐communicable diseases like cigarette smoking, alcohol intake, exposure to toxicants, and low socioeconomic status (Curtis et al, 2019 ; Fiorito et al, 2019 ), and it is associated with increased risk of different types of cancer in prospective studies (Gagliardi et al, 2020 ; Wang et al, 2019 ). Interestingly, DNAm epigenetic clocks and EML are weakly correlated, suggesting they describe different aspects of epigenetic aging processes (Yan et al, 2020 ).…”

DNA methylation age as a biomarker for cancer

“…34 The number of stochastic epigenetic mutations, sites of extreme levels of high or low methylation that accumulate with age in a random manner, has recently been shown to be associated with a higher cancer risk in prediagnostic blood samples. 35 In addition to randomly distributed changes, DNA methylation at certain sites changes with age in a predictable manner. These changes follow specific patterns, with age-associated hypermethylated CpG sites targeting bivalent chromatin promotors or polycomb group proteins, and age-associated hypomethylated CpG sites found enriched in gene enhancers.…”

“…This divergence over time in DNA methylation patterns within twin pairs was referred to as “epigenetic drift” 34 . The number of stochastic epigenetic mutations, sites of extreme levels of high or low methylation that accumulate with age in a random manner, has recently been shown to be associated with a higher cancer risk in prediagnostic blood samples 35 …”

Deregulation of Transcriptional Enhancers in Cancer

“…It is important to note that enhancers operate as platforms for the epigenetic machinery. Thus, in addition to genetic variations in cis-regulatory elements, mutations in enhancer-associated proteins can also influence cell state, tumour formation and progression, via altered epi-decoration of enhancers [ 118 , 119 ].…”