Inactivation of tumor suppressor genes constitutes a driving mechanism in oncogenesis. In normal cells, tumor suppressors act as central hubs coordinating cell cycle, cell death, and cell fate via regulation of gene expression. The loss of tumor suppressor activities disrupts these processes, permitting aberrant cell growth. Recent work has shown that ~20% of human cancers carry mutations in at least one subunit of the SWI/SNF chromatin-remodeling complex. While genetic, animal and cell culture studies have established that several SWI/SNF subunits function as tumor suppressors, few studies have comprehensively established the mechanisms by which they act. We recently identified inactivating mutations in the SWI/SNF ATPase subunit, SMARCA4, in the majority of small cell carcinoma of the ovary of hypercalcemic type (SCCOHT), a poorly- differentiated and aggressive tumor, with concomitant protein loss in nearly 90% of primary tumors. We also found loss of expression of the alternative SWI/SNF ATPase subunit, SMARCA2, in all tumors lacking SMARCA4. In contrast to most adult cancers, SCCOHT genomes remain predominantly diploid with rare secondary mutations in other cancer genes. Therefore, we hypothesize that 1) SMARCA4 mutations drive tumor development through disruption of normal differentiation; and 2) that these mutations will define a global therapeutic vulnerability in cancer. To test this hypothesis, we propose to 1) Investigate the epigenetic consequences of SMARCA4/A2 re-expression; 2) Model the histogenesis of SCCOHT; and 3) Identify and validate targets for tumor treatment. To carry out the proposed studies, we take advantage of the cutting-edge technologies available at the University of British Columbia (UBC), the Translational Genomics Research Institute (TGen) and the University of North Carolina (UNC) and the complementary expertise of the 3 multiple principal investigators including ovarian cancer pathology and biology (UBC), systems biology and translational applications (TGen) and chromatin biology and cancer epigenetics (UNC). We will also generate novel cell culture and animal models to parse the mechanisms by which inactivation of SMARCA4 and/or SMARCA2 drive SCCOHT development and to identify and validate new reagents for treatment of this deadly disease. In addition, the predominance of SMARCA4 mutations along with the scarcity of secondary mutations in other cancer genes yields a unique model for understanding the specific contributions of SWI/SNF complex mutations to human cancer development. Thus, the results of these studies will significantly impact the diagnosis and treatment of SCCOHT by providing seminal insights into the mechanisms that drive its development, including the disruption of SWI/SNF complex function. Furthermore, the ubiquitous nature of SWI/SNF complex mutations in human malignancies broadens the scope of our findings to other deadly human cancers including lung cancer, renal cell carcinoma and brain tumors.
This project examines how mutations in genes that regulate the structure of DNA and proteins in the nuclei of cells lead to the development of a rare but deadly cancer of the ovaries. The findings from these studies will identify novel targets for treatment of this disease as well as assess the potency of existing drugs. Furthermore, our results will prove applicable to other deadly human cancers, such as lung and brain tumors, that also contain the same mutations.
