PQB - 2 As we improve methods to identify epigenetic changes that occur during tumor development, can we develop approaches to discriminate between "driver" and "passenger" epigenetic events? Background: The continuing improvement in high-throughput analysis of epigenetic regulation is advancing our understanding of the complex nature of tumor development. Several observations argue that epigenetic regulation is key to many stages of tumor development. First, proteins that are important for epigenetic regulation are frequently mutated during tumor development, and these mutations are important for the cancer phenotype. These mutations include point mutations, translocations, amplifications, and loss of miRNA regulation. Second, some chemotherapeutic agents that target DNA methyltransferases or histone deacetylases have shown good efficacy in the clinic, suggesting the changes in these epigenetic regulatory events are key to maintaining the tumorigenic phenotype. Third, the plasticity of tumor cells altering phenotypic states ---for example during epithelial to mesenchymal transition (EMT) or following division of cancer stem or initiating cells---is under epigenetic regulation. Finally, there is growing evidence that at least some forms of drug resistance are due to changes regulated by the epigenetic state. As we are achieving higher resolution of epigenetic events, it will be increasingly important to learn which epigenetic changes are critical for tumor survival. This question sets the challenge to learn which epigenetic events are most important for tumor development and maintenance. Feasibility: Modern molecular biological methods, including molecular profiling, high throughput ChIP analysis, and functional tests, will be needed to identify and study various epigenetic states. Computational methods to characterize various epigenetic regulatory states could be used to help define potentially important changes. Functional tests, including RNAi knockdown or overexpression of key proteins, may be helpful in changing chromatin structure and linking these changes to cancer phenotypes. Implications of success: As a field, we anticipate that epigenetic regulation of chromatin states will play important roles in tumor development. These links seem most clear in cases in which mutations that directly alter the epigenetic state have been shown to be important for tumor development. However, many phenotypes of a cancer cell are certainly regulated by epigenetic changes not deregulated by mutation, and the demonstration of this link promises to open the way for the identification of new therapeutic or prevention targets. Similarly, advances in this area will likely provide important advances in the identification of new diagnostic markers. |
| Download Plugins: |  |
 |
 |
 |
 |
 |
 |
 |
 |
|
