PQB - 5 How does the order in which mutations or epigenetic changes occur alter cancer phenotypes or affect the efficacy of targeted therapies? Background: It is well understood that some mutations or epigenetic changes are characteristically found at different stages of tumor development. However, we still understand very little of the relationships between the appearance of specific changes and what mutations or epigenetic changes must or frequently follow. These temporal relationships could be due to new physiological states that are induced by the appearance of the earlier changes. Some of these relationships are likely to be between classes of changes in which multiple mutations in a pathway establish the same end results, but other temporal orders may be dictated by individual gene mutations or epigenetic changes. A consequence of the development of a temporal pattern of mutations or epigenetic changes is that early mutations may dictate some aspects of tumor fate and thus may influence what subtypes of tumors may develop or what types of therapeutic approaches may eventually be most effective. Feasibility: One useful system to look for temporal orders of mutational and epigenetic changes will be provided by mouse tumor models. A large number of different oncogene or tumor suppressor mutations can be activated in well-defined settings and then tumor development followed. Mutations or other changes that occur following the induction of a tumorigenic event could be studied easily here, and the functional relationships then tested in subsequent studies. Similar studies in humans will be more difficult because sequential sampling of the same tumors is difficult or impossible. Some clues might be found by examining the rapidly growing collection of mutations found from genome sequencing projects such as TCGA, in which pairwise associations or lack of association of specific changes could be sought and then tested for any functional relationship. In addition there may be specific human tumor systems that have sufficient similarity in their development that studies of populations of tumors could provide clues for obligatory or preferred orders of changes. One potential type of human system for these studies may be found in virally induced human tumors. Here, it may be possible that some viral tumor systems may provide identical initiating steps that could generate a useful model to identify patterns of subsequent changes. Similar settings may be possible when tumors arise from other common initiating events. Implications of success: Obligatory or preferred orders of mutational or epigenetic changes suggest specific responses to either earlier changes or other environmental selective pressures. Deciphering these patterns will increase our understanding of how to predict the developmental patterns of these tumors and types of therapies that will be most effective. |
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