Abstract
BackgroundRecent studies have identified age-related changes in DNA methylation patterns in normal and cancer tissues in a process that is called epigenetic drift. However, the evolving patterns, functional consequences, and dynamics of epigenetic drift during carcinogenesis remain largely unexplored. Here we analyze the evolution of epigenetic drift patterns during progression from normal squamous esophagus tissue to Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) using 173 tissue samples from 100 (nonfamilial) BE patients, along with publically available datasets including The Cancer Genome Atlas (TCGA).ResultsOur analysis reveals extensive methylomic drift between normal squamous esophagus and BE tissues in nonprogressed BE patients, with differential drift affecting 4024 (24%) of 16,984 normally hypomethylated cytosine-guanine dinucleotides (CpGs) occurring in CpG islands. The majority (63%) of islands that include drift CpGs are associated with gene promoter regions. Island CpGs that drift have stronger pairwise correlations than static islands, reflecting collective drift consistent with processive DNA methylation maintenance. Individual BE tissues are extremely heterogeneous in their distribution of methylomic drift and encompass unimodal low-drift to bimodal high-drift patterns, reflective of differences in BE tissue age. Further analysis of longitudinally collected biopsy samples from 20 BE patients confirm the time-dependent evolution of these drift patterns. Drift patterns in EAC are similar to those in BE, but frequently exhibit enhanced bimodality and advanced mode drift. To better understand the observed drift patterns, we developed a multicellular stochastic model at the CpG island level. Importantly, we find that nonlinear feedback in the model between mean island methylation and CpG methylation rates is able to explain the widely heterogeneous collective drift patterns. Using matched gene expression and DNA methylation data in EAC from TCGA and other publically available data, we also find that advanced methylomic drift is correlated with significant transcriptional repression of ~ 200 genes in important regulatory and developmental pathways, including several checkpoint and tumor suppressor-like genes.ConclusionsTaken together, our findings suggest that epigenetic drift evolution acts to significantly reduce the expression of developmental genes that may alter tissue characteristics and improve functional adaptation during BE to EAC progression.
Highlights
Recent studies have identified age-related changes in DNA methylation patterns in normal and cancer tissues in a process that is called epigenetic drift
Using data from the HumanMethylation450 BeadChip (HM450) methylation arrays, we aimed to better characterize the full extent of epigenetic drift occurring in Barrett’s esophagus (BE) and the temporal dynamics of epigenetic drift and to explore the impact of advanced drift on gene expression in esophageal adenocarcinoma (EAC) for which we have both gene expression and methylation data
Genomic scope of drift Out of 146,029 hypomethylated CpG dinucleotides (CpGs) probes in normal squamous (NS) tissue, we identified 18,013 (12%) probes that have significant positive correlation and 560 (0.4%) that have a significant negative correlation (q < 0.01) with the mean differential drift of 67 previously validated drift CpGs in 64 BE samples from patients without a diagnosis of dysplasia or cancer
Summary
Recent studies have identified age-related changes in DNA methylation patterns in normal and cancer tissues in a process that is called epigenetic drift. The first is based on the discovery (of sets) of CpG dinucleotides (CpGs) in the genome that are subject to age-dependent, possibly complex changes in methylation levels that, in aggregate, correlate strongly with chronological age [2,3,4] We refer to these types of CpGs as clock-CpGs. A second and simpler concept is based on the observation of gradual age-related changes in methylation levels at specific CpG sites or CpG-rich regions, a process commonly referred to as epigenetic or methylomic drift [5,6,7,8,9,10,11]. Some CpG islands show very low methylation levels early in life but are known to become gradually methylated over time as a result of sporadic de novo methylation events during DNA replication We identify these as drift CpGs. It is worth pointing out that data supporting these concepts come mainly from cross-sectional studies that include individuals of different age. Individual-level (longitudinal) drift, unless studied directly in select individuals over time as we have collected for this study, is typically inferred from population drift
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