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The malignant transformation of normal cells is driven by both genetic and epigenetic changes. With the advent of next-generation sequencing and large-scale international consortia, it is now possible to profile the genomes and epigenomes of thousands of primary tumors from nearly every cancer type. These studies clearly demonstrate that the dynamic regulation of DNA methylation is a critical epigenetic mechanism of cancer initiation, maintenance, and progression. Proper control of DNA methylation is not only crucial for regulating gene transcription and tissue-specific cellular functions, but its broader consequences include maintaining the integrity of the genome and modulating the immune response. Here, we describe the aberrant DNA methylation changes in human cancers and how they contribute to the disease phenotypes. Aside from CpG island promoter DNA hypermethylation-based gene silencing, human cancers also display gene body DNA hypomethylation that is also associated with downregulated gene expression. In addition, the implementation of whole genome bisulfite sequencing (WGBS) has unveiled DNA hypomethylation of large blocks of the genome, known as partially methylated domains (PMDs), as well as cancer-specific DNA methylation aberrancies at enhancers and super-enhancers. Integrating WGBS and DNA methylation array data with mutation, copy number, and gene expression data has allowed for the identification of novel tumor suppressor genes and candidate driver genes of the disease state. Finally, we highlight potential clinical implications of these changes in the context of prognostic and diagnostic biomarkers, as well as therapeutic targets. Mounting evidence shows that DNA methylation data are effective and highly-sensitive disease classifiers, not only from analyses of the primary tumor but also from tumor-derived, cell free DNA (cfDNA) in blood of cancer patients. These findings highlight the power of DNA methylation aberrancies in providing efficacious biomarkers for clinical utility in improving patient diagnostics and their reversal using DNA methylation inhibitors in cancer treatment may be key in surveillance, treatment, and quality of life for cancer patients.

The malignant transformation of normal cells is driven by both genetic and epigenetic changes. With the advent of next-generation sequencing and large-scale multinational consortium studies, it has become possible to profile the genomes and epigenomes of thousands of primary tumors from nearly every cancer type. From these genome-wide studies, it became clear that the dynamic regulation of DNA methylation is a critical epigenetic mechanism of cancer initiation, maintenance, and progression. Proper control of DNA methylation is not only crucial for regulating gene transcription, but its broader consequences include maintaining the integrity of the genome and modulating immune response. Here, we describe the aberrant DNA methylation changes that take place in cancer and how they contribute to the disease phenotype. Further, we highlight potential clinical implications of these changes in the context of prognostic and diagnostic biomarkers, as well as therapeutic targets.