Abstract
BackgroundProstate cancer (PCa) has the highest incidence rates of cancers in men in western countries. Unlike several other types of cancer, PCa has few genetic drivers, which has led researchers to look for additional epigenetic and transcriptomic contributors to PCa development and progression. Especially datasets on DNA methylation, the most commonly studied epigenetic marker, have recently been measured and analysed in several PCa patient cohorts. DNA methylation is most commonly associated with downregulation of gene expression. However, positive associations of DNA methylation to gene expression have also been reported, suggesting a more diverse mechanism of epigenetic regulation. Such additional complexity could have important implications for understanding prostate cancer development but has not been studied at a genome-wide scale.ResultsIn this study, we have compared three sets of genome-wide single-site DNA methylation data from 870 PCa and normal tissue samples with multi-cohort gene expression data from 1117 samples, including 532 samples where DNA methylation and gene expression have been measured on the exact same samples. Genes were classified according to their corresponding methylation and expression profiles. A large group of hypermethylated genes was robustly associated with increased gene expression (UPUP group) in all three methylation datasets. These genes demonstrated distinct patterns of correlation between DNA methylation and gene expression compared to the genes showing the canonical negative association between methylation and expression (UPDOWN group). This indicates a more diversified role of DNA methylation in regulating gene expression than previously appreciated. Moreover, UPUP and UPDOWN genes were associated with different compartments — UPUP genes were related to the structures in nucleus, while UPDOWN genes were linked to extracellular features.ConclusionWe identified a robust association between hypermethylation and upregulation of gene expression when comparing samples from prostate cancer and normal tissue. These results challenge the classical view where DNA methylation is always associated with suppression of gene expression, which underlines the importance of considering corresponding expression data when assessing the downstream regulatory effect of DNA methylation.
Highlights
Prostate cancer (PCa) has the highest incidence rates of cancers in men in western countries
DNA hypermethylation and upregulated gene expression is a robust association pattern To initially limit the number of methylation sites, we first analysed the dataset from Absher (Table 1), which focuses on promoter regions
Of the 27,578 DNA methylation probes analysed in Absher, we identified 6110 probes that gained methylation and 2916 that lost methylation when PCa samples were compared to normal samples
Summary
Prostate cancer (PCa) has the highest incidence rates of cancers in men in western countries. Unlike several other types of cancer, PCa has few genetic drivers, which has led researchers to look for additional epigenetic and transcriptomic contributors to PCa development and progression. DNA methylation is most commonly associated with downregulation of gene expression. Positive associations of DNA methylation to gene expression have been reported, suggesting a more diverse mechanism of epigenetic regulation. Such additional complexity could have important implications for understanding prostate cancer development but has not been studied at a genome-wide scale. PCa demonstrates few distinct genetic drivers [5, 6], which has made it challenging to identify and study the mechanisms of PCa development and progression. CpGs tend to cluster into CpG islands (CGIs) — regions between 300 and 3000 bp in length with greater than 50% GC content and CpG/GpC ratio greater than 0.6 [8, 10, 11]
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