DNA methylation in brain development and gliomagenesis.
The underlying basis of human tumors involves genomic alterations that activate oncogenes and inactivate tumor suppressor genes, culminating in unregulated cell growth. The existing models of tumorigenesis, the selection of subsets of genes contributing to this process and many cancer therapies are based on this genomic approach. However, epigenomic alterations such as gene silencing by aberrant methylation of promoters are also involved in tumorigenesis, but because methylation is not detected by standard genome screening many of these genes have remained undiscovered. Advances in our ability to observe the methylation status of the entire cancer cell genome have led to the unmistakable conclusion that methylation abnormalities are far more prevalent than expected, particularly in low-grade gliomas where genomic changes are less common. In addition, the aberrant methylation of particular genes can influence tumor response to therapy and is strongly associated with patient survival. Thus it is likely that our understanding of tumor genomes is far from complete, and that a significant number of prognostic indicators and therapeutic targets remain to be explored. These studies raise important questions regarding the relative contribution of genomic and epigenomic mechanisms in the genesis and malignant progression of gliomas. Here I begin with the evidence supporting a role for methylation in normal brain cell function and the consequence of its dysfunction, and conclude with an effort to integrate epigenomic views of the genesis of sporadic brain tumors with the traditional genomic model.
Costello
Joseph F
JF
The Brain Tumor Research Center, Department of Neurological Surgery, University of California, San Francisco, 2340 Sutter, San Francisco, CA 94115, USA. jcostello@cc.ucsf.edu
D000818:Animals; D001921:Brain / Q000254:growth & development*; D001923:Brain Chemistry / Q000235:genetics; D001932:Brain Neoplasms / Q000209:etiology / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019175:DNA Methylation; D005910:Glioma / Q000209:etiology / Q000235:genetics*; D006801:Humans