LAUSR

Simple Summary Loss of SMARCB1 has been identified as the sole mutation in a number of rare pediatric and adult cancers, most of which have a poor prognosis despite intensive therapies including surgery, radiation, and chemotherapy. Thus, a more robust understanding of the mechanisms driving this set of cancers is vital to improving patient treatment and outcomes. This review outlines recent advances made in our understanding of the function of SMARCB1 and how these advances have been used to discover putative therapeutic vulnerabilities. Abstract SMARCB1 is a critical component of the BAF complex that is responsible for global chromatin remodeling. Loss of SMARCB1 has been implicated in the initiation of cancers such as malignant rhabdoid tumor (MRT), atypical teratoid rhabdoid tumor (ATRT), and, more recently, renal medullary carcinoma (RMC). These SMARCB1-deficient tumors have remarkably stable genomes, offering unique insights into the epigenetic mechanisms in cancer biology. Given the lack of druggable targets and the high mortality associated with SMARCB1-deficient tumors, a significant research effort has been directed toward understanding the mechanisms of tumor transformation and proliferation. Accumulating evidence suggests that tumorigenicity arises from aberrant enhancer and promoter regulation followed by dysfunctional transcriptional control. In this review, we outline key mechanisms by which loss of SMARCB1 may lead to tumor formation and cover how these mechanisms have been used for the design of targeted therapy.