Contributions of DNA methylation aberrancies in shaping the cancer epigenome

Genetic alterations, including DNA sequence and copy number alterations, have been characterized in human cancers for over several decades. However, it is becoming increasingly evident that in addition to these events, epigenetic changes are widespread in virtually every cancer type. The scientific literature is rich with reports of changes in DNA methylation, chromatin modifications and nucleosome occupancy, all of which contribute to the aberrant gene expression profiles described in human cancers. Whilst genetic and epigenetic alterations have been historically characterized on a candidate gene and cancer-type basis, the unprecedented acceleration in microarray and next-generation sequencing technologies used to profile large collections of primary specimens has provided a panoramic, genome-wide view of cancer genomes and epigenomes. For the first time, the relationships between individual alterations can be understood, with the ultimate goal of improving cancer detection, monitoring, surveillance and most importantly, treatment. A central aspect of these involves characterizing DNA methylation alterations in human cancers. DNA methylation aberrancies are present in every tumor type, serve as stable biomarkers of disease, are associated with patient clinical features, and are reversible through the application of DNA methylation inhibitors. DNA methylation inhibitors are currently used in treating patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML), and new inhibitors are currently in clinical trials for potential cancer treatment. This review highlights DNA methylation changes and their significance in human cancers from mechanistic, biomarker and treatment perspectives.