Cancers are extremely complex and variable, however a common feature appears to be the presence of critical driver events (e.g. genetic mutations in tumor suppressors) that drive tumor formation and progression. Key driver events, such as mutations in TP53, have been identified in many well-studied tumors. However, many human solid tumors do not have clearly identified driver events, even after common oncogenes and tumor suppressors have been systematically examined. We have termed this the ?missing driver? problem. Our bioinformatics based approach to identify cancer driver events is to use innovative analyses of forward genetic screens for tumor formation in mice to identify genomic locations to systematically and exhaustively investigate within the increasing amounts of human cancer tumor genome-wide data in both publicly available as well as data generated within our lab. We expect to identify novel driver events and that the elucidation of the complete spectrum of tumor driver events will be extremely important to personalized approaches to cancer.
Forward genetic screens for tumor formation in mice have identified many previously unknown oncogenes and tumor suppressor genes. Many of the targets that have been identified using the forward genetic screens would not have been identified by mutation or other traditional analyses of human tumors although their importance is now clear. The tumor biology learned from these types of studies have already had direct relevance to clinical disease management. The proposed research will identify additional molecular events responsible for tumor formation, which will fill key knowledge gaps. This will allow more effective treatment strategies and result in improved cancer patient outcomes.
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