Functional consequences of SMARCB1 variants

Emory University, Atlanta GA

Investigators

Abstract

ABSTRACT SMARCB1 deficient cancers constitute a growing number of rare and difficult to treat cancers affecting children, adolescents and young adults. Our clinical assessments of SMARCB1 function rely upon immunohistochemistry and thus our ability to determine nuances of SMARCB1 function remain limited. Unlike other better characterized tumor suppressors such as PTEN or TP53, SMARCB1 has been in the cancer biology literature since the 1990s. More recently, genetic variants of unknown significance in SMARCB1 have been identified across 1% of all cancers. Despite computational efforts to assign function, we know that members of the SWI/SNF chromatin remodeling complex such as SMARCB1 have been difficult to assess given the limited structural data available. To address this gap, we have performed deep mutagenesis scanning of SMARCB1 which enables the assessment of >99% of genetic mutations across SMARCB1. This proposal now focuses on understanding the mechanisms behind these genetic changes. Specifically, we will enhance our understanding of key mutations and residues that are important in SMARCB1’s ability to bind to other SWI/SNF complex members. We will understand how missense mutations in these key regions lead to oncogenic phenotypes. We will then study the effects of hyper-functional SMARCB1 missense mutants to further enhance our understanding of the biology of SMARCB1. Taken together, success of these aims will improve our understanding of these genetic variants of unknown significance as well as the biology of SMARCB1.