Abstract IA13: SWI/SNF complexes are frequently mutated in cancer: Epigenetic mechanisms and therapeutic targeting

My laboratory began studying the SWI/SNF complex when the SNF5 subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in the highly aggressive pediatric cancers AT/RT and rhabdoid tumors. Data emerging over the last two 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 broad variety of cancers and overall in 20% of all human cancers. These include inactivating mutations of SWI/SNF subunits in some cases of pediatric neuroblastoma, medulloblastoma and Burkitt9s lymphoma as well as in adult ovarian, endometrioid, bladder, breast, stomach, colorectal, pancreatic, renal, hepatocellular, and lung cancers, and melanomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. We 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. Using mouse models, we have shown that biallelic inactivation of murine Snf5 leads to the rapid onset of cancer formation in 100% of mice with a median latency of only 11 weeks. Heterozygous mice develop rhabdoid tumors that are histologically indistinguishable from their human counterpart and Mx-Cre-mediated conditional inactivation results in 85% of mice developing aggressive mature T cell lymphomas and 15% developing rhabdoid tumors. Intriguingly, the rapid cancer onset arises neither due to defective DNA repair nor due to genome instability, as we have found that the genomes of both the murine and human SNF5-deficient cancers are diploid and indistinguishable from normal cells via high-density SNP arrays. Most recently, by sequencing the exomes of 35 human pediatric rhabdoid tumors we have shown that these cancer genomes contain an extremely low rate of mutations, with loss of SNF5 being essentially the sole recurrent event. Indeed, in two of the cancers there were no other identified mutations. Our results suggest that high mutation rates are dispensable for the genesis of cancers driven by mutation of this chromatin remodeling complex and further that epigenetic dysfunction caused by mutation of the SWI/SNF complex may underlie the broad spectrum of cancers caused by mutation of this complex. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and opportunities for therapeutic intervention will be presented. Citation Format: Charles W. M. Roberts. SWI/SNF complexes are frequently mutated in cancer: Epigenetic mechanisms and therapeutic targeting. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA13.