Somatic alterations and dysregulation of epigenetic modifiers in cancers

• Genomic analysis in cancer has identified recurrent mutations in epigenetic modifiers.
• Recurrent mutations affecting DNA cytosine modifications have been identified.
• Recurrent mutations affecting H3K4, H3K79, and H3K27 methylation have also been identified.
• Identification of cancer dependency on these mutations has provided new therapeutic avenues.

Genomic discovery efforts in patients with cancer have been critical in identifying a recurrent theme of mutations in epigenetic modifiers. A number of novel and exciting basic biological findings have come from this work including the discovery of an enzymatic pathway for DNA cytosine demethylation, a link between cancer metabolism and epigenetics, and the critical importance of post-translational modifications at specific histone residues in malignant transformation. Identification of cancer cell dependency on a number of these mutations has quickly resulted in the development of therapies targeting several of these genetic alterations. This includes, the development of mutant-selective IDH1 and IDH2 inhibitors, DOT1L inhibitors for MLL rearranged leukemias, EZH2 inhibitors for several cancer types, and the development of bromodomain inhibitors for many cancer types—all of which are in early phase clinical trials. In many cases, however, specific genetic targets linked to malignant transformation following mutations in individual epigenetic modifiers are not yet known. In this review we present functional evidence of how alterations in frequently mutated epigenetic modifiers promote malignant transformation and how these alterations are being targeted for cancer therapeutics.