Defining Driver DNA Methylation Changes in Human Cancer

Abstract

Human malignant tumors are characterized by pervasive changes in the patterns of DNA methylation. These changes include a globally hypomethylated tumor cell genome and the focal hypermethylation of numerous 5'-cytosine-phosphate-guanine-3' (CpG) islands, many of them associated with gene promoters. It has been challenging to link specific DNA methylation changes with tumorigenesis in a cause-and-effect relationship. Some evidence suggests that cancer-associated DNA hypomethylation may increase genomic instability. Promoter hypermethylation events can lead to silencing of genes functioning in pathways reflecting hallmarks of cancer, including DNA repair, cell cycle regulation, promotion of apoptosis or control of key tumor-relevant signaling networks. A convincing argument for a tumor-driving role of DNA methylation can be made when the same genes are also frequently mutated in cancer. Many of the most commonly hypermethylated genes encode developmental transcription factors, the methylation of which may lead to permanent gene silencing. Inactivation of such genes will deprive the cells in which the tumor may initiate from the option of undergoing or maintaining lineage differentiation and will lock them into a perpetuated stem cell-like state thus providing an additional window for cell transformation.

Keywords: 5-methylcytosine; DNA methylation; cell differentiation; genomic instability; hallmarks of cancer.

Figure 1

Schematic outline of the most relevant DNA methylation changes observed in human cancers. These events include CpG-island-specific DNA hypermethylation often occurring at gene promoters, which locks the affected gene into an inactive state. Loss of DNA methylation (hypomethylation) occurs genome-wide and is often observed at repetitive regions of the genome. White circles indicate unmethylated CpG sites and red circles show methylated CpG sites. The crossed-out arrow indicates the transcription start site and the permanent lack of transcription after DNA methylation. Green boxes show exons and the blue rectangle marks the position of a repetitive element.

Figure 2

Genome-scale consequences of DNA hypomethylation and DNA hypermethylation in cancer. DNA hypomethylation can lead to perturbations in gene expression or genomic instability. Likewise, DNA hypermethylation may promote widespread changes in gene expression patterns through different mechanisms. White circles indicate unmethylated CpG sites and red circles show methylated CpG sites.

Figure 3

Potential tumor-driving consequences of CpG island hypermethylation. When DNA hypermethylation occurs at gene regulatory elements, the resulting gene silencing may have a tumor-promoting effect if the targeted genes function within the framework of the ‘hallmarks’ of cancer. These genes include, for example, DNA repair genes, genes encoding factors involved in cell growth control, or genes involved in promoting apoptosis or cell differentiation. Some examples are shown. White circles indicate unmethylated CpG sites and red circles show methylated CpG sites.