Functional role and clinical relevance of mutated SMARCB1/INI1 protein in atypical teratoid/rhabdoid tumors (AT/RT)

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The SWI/SNF chromatin remodeling complex modulates chromatin structure and regulates gene transcription. Genetic alterations affecting members of the SWI/SNF complex play a critical role in developmental disorders and cancer. The SMARCB1/INI1 protein represents a core member of the SWI/SNF complex. Atypical teratoid/rhabdoid tumor (AT/RT) is a pediatric brain tumor characterized by mutations of the SMARCB1 gene. AT/RT is a highly aggressive tumor with dismal prognosis, but some patients also respond well to therapy and even experience long-term survival. Molecular factors that might explain differences in biological tumor behavior remain to be identified. Preliminary findings from our group suggest that lower proliferative activity and longer overall survival in a subgroup of AT/RT could be explained by the presence of a truncated SMARCB1/INI1 protein, which might have some residual function. Within the proposed DFG project, we will systematically explore the functional role and clinical relevance of mutated SMARCB1/INI1 protein in AT/RT. In particular, (1) we aim at a better understanding how various SMARCB1 mutations encountered in AT/RT affect SMARCB1/INI1 protein expression, (2) explore how the presence of mutated SMARCB1/INI1 proteins affects tumor biology and (3) investigate if the presence of mutated SMARCB1/INI1 proteins might explain the epigenetic and clinical heterogeneity of AT/RT. To this end, expression of mutated SMARCB1/INI1 protein will be examined in a large series of AT/RT tissue samples using a panel of antibodies directed against various epitopes of the SMARCB1/INI1 protein. Next, the functional role of mutated SMARCB1/INI1 protein will be studied in rhabdoid tumor cells using site-directed mutagenesis and transient transfection. The functional consequences of re-expression of mutant SMARCB1/INI1 proteins as compared to wildtype SMARCB1/INI1 protein (control) on proliferation and apoptosis will be examined. Finally, the clinical relevance of SMARCB1 mutations causing less aggressive tumor behavior in vitro will be examined in patients with AT/RT from the European Rhabdoid Tumor Registry EU RHAB. The effect on progression-free survival and overall survival will be examined also taking into account other important clinical and molecular factors such as age, tumor location and germ line mutation status. The results from this project will contribute to a better understanding of SMARCB1/INI1 protein function in AT/RT, but will also have implications for other tumors with SWI/SNF complex dysfunction. In the long term, they are expected to aid the development of prognostic markers and better treatment stratification for children with AT/RT.