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Driver mutations of cancer epigenomes

Protein & Cell 2014年第4期5卷 265-296页

作者： David M. Roy Logan A. Walsh Timothy A. Chan Human Oncology and Pathogenesis Program Memorial Sloan-Kettering Cancer Center New York NY 10065 USA Weill Cornell/Rockefeller/Sloan-Kettering Tri-lnstitutional MD-PhD Program New York NY 10065 USA Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center New York NY 10065 USA

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 chro- matin organization contribute significantly to cancer- associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mecha- nistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers （i.e. IDHll2, EZH2, DNMT3A）, pinpointing epigenetic path- ways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers （i.e. KDM6A, CREBBPIEP300, SMARCB1） implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regu- lators, including renal, bladder, and adenoid cystic car- cinomas. 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.

关键词： chromatin cancer epigenetics mutations,methylation

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