DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

Abstract

Aberrant DNA hypermethylation of tumor suppressor genes is thought to be an early event in tumorigenesis. Many studies have reported the methylation status of individual genes with known involvement in cancer, but an unbiased assessment of the biological function of the collective of hypermethylated genes has not been conducted so far. Based on the observation that a variety of human cancers recapitulate developmental gene expression patterns (that is activate genes normally expressed in early development and suppress late developmental genes), we hypothesized that the silencing of differentiation-associated genes in cancer could be attributed in part to DNA hypermethylation. To this end, we investigated the developmental expression patterns of genes with hypermethylated CpG islands in primary human lung carcinomas and lung cancer cell lines. We found that DNA hypermethylation primarily affects genes that are expressed in late stages of murine lung development. Gene ontology characterization of these genes shows that they are almost exclusively involved in morphogenetic differentiation processes. Our results indicate that DNA hypermethylation in cancer functions as a selective silencing mechanism of genes that are required for the maintenance of a differentiated state. The process of cellular de-differentiation that is evident on both the microscopic and transcriptional level in cancer might at least partly be mediated by these epigenetic events. Our observations provide a mechanistic explanation for induction of differentiation upon treatment with DNA methyltransferase inhibitors.

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

“…Hypermethylated genes were enriched for developmental and differentiation-associated processes and polycomb targets premarked by histone H3K27 trimethylation in embryonic cells (24,25). These results are consistent with a hypothesis that DNA methylation in lung cancer preferentially targets genes involved in morphogenetic processes and late stage differentiation of the lung epithelium, potentially contributing to establishment of an early undifferentiated cancer phenotype (24).…”

“…1A). Correlation analyses of DNA methylation and gene expression revealed a pattern of negative correlations at transcription start sites and more positive correlations in Functional annotation analysis of genes with hypermethylated CpGs in the 4136 CpG set showed enrichment of biologic processes such as regulation of transcription, neural development, and cell morphogenesis corroborating previous studies (24,25), whereas hypomethylated genes showed a much less clear functional enrichment (Supplementary Table S2). …”

DNA Methylation Signatures Identify Biologically Distinct Thyroid Cancer Subtypes

“…Hypermethylated genes were mainly found to be related to developmental processes along the lines of/similar to those found in previous studies of other cancer types (45,46). However, hypomethylated genes were enriched for GO terms associated with the immune system.…”

High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq

“…Gene ontology analysis of the genes associated with these DMRs revealed that the aberrantly hypermethylated genes primarily belonged to categories related to nucleic acid binding, DNA binding, and activation of transcription factors, suggesting that the methylation of these affected genes coupled with the downregulation of RNA expression resulted in the decreased expression of other genes. Studies of non-small-cell lung carcinoma by Helman et al [14] and Zhao et al . [15] demonstrated that methylation-enriched genes displayed aberrant methylation and RNA expression in multiple tumor types; these genes were referred to as tumor suppressor genes.…”