Abstract

Exome- and genome-wide sequencing studies in human cancer have revealed a striking frequency of mutations in the genes encoding subunits of the mammalian SWI /SNF (BAF) family of ATP -dependent chromatin remodeling complexes. We recently determined these mutations to be broadly recurrent in over 20% of all cancers. Here, we present studies focused on BAF complex assembly and architecture, cancer-specific complex subunit and associated protein factor composition, and novel approaches toward the identification of small molecule therapeutics for this class of human tumors.

To investigate the underlying mechanism, our group has studied genomically well-defined cancer types driven by both gain- and loss-of-function mutations to genes encoding BAF complex subunit or associated factors. These include human synovial sarcoma (SS) in which 100% of tumors have a precise translocation involving the SS18 subunit, malignant rhabdoid tumors which are driven by deletion of the BAF47 (SMARCB1) subunit, and more recently cancers driven by aberrant activation of transcription factors which bind to and direct BAF complex targeting. Taken together, the study of BAF complex-mediated oncogenesis in these disease settings has provided us with a powerful foundation upon which to understand the precise oncogenic mechanisms directed by altered subunit composition, structure and function of chromatin remodeling complexes.