Driver mutations of cancer epigenomes

DM Roy, LA Walsh, TA Chan - Protein & cell, 2014 - academic.oup.com
Protein & cell, 2014academic.oup.com
Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to
cancer progression and metastasis. It is now well understood that both losses and gains of
DNA methylation as well as altered chromatin organization contribute significantly to cancer-
associated phenotypes. More recently, new sequencing technologies have allowed the
identification of driver mutations in epigenetic regulators, providing a mechanistic link
between the cancer epigenome and genetic alterations. Oncogenic activating mutations are …
Abstract
Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancer-associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies.
Oxford University Press