Abstract IA15: SWI/SNF (BAF) chromatin remodeling complexes are frequently mutated in cancer: Mechanisms and vulnerabilities

Abstract Data emerging over the last several years implicate SWI/SNF (BAF) chromatin remodeling complexes as a major tumor suppressor as frequent inactivating mutations in at least nine different SWI/SNF subunits, collectively identified in 20% of all cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal, and pancreatic cancers and neuroblastoma; of the BRG1 (SMARCA4) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; and of the BRD7 subunit in breast cancers. 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 SNF5 (SMARCB1/INI1/BAF47) became the first SWI/SNF subunit linked to tumor suppression over fifteen years ago when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT, we have shown that these cancers are diploid and have remarkably simple genomes. We now study the complex using mouse models, cell lines, and primary human tumor samples. 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, including our recent efforts that identify a central role for SWI/SNF complexes in enhancer regulation. Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) chromatin remodeling complexes are frequently mutated in cancer: Mechanisms and vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA15.