Abstract IA06: SWI/SNF chromatin remodeling complex mutations in cancer: Mechanisms and potential therapeutic insights

Abstract Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented. Citation Format: Charles W.M. Roberts. SWI/SNF chromatin remodeling complex mutations in cancer: Mechanisms and potential therapeutic insights. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA06.