ATRT-10. HETEROGENEITY OF BAF AND PBAF SWI/SNF COMPLEX SUBUNITS IN MALIGNANT RHABDOID TUMORS RELATES WITH POLYPHENOTYPIC DIFFERENTIATION AND THE IMMUNE MICROENVIRONMENT Free

Malignant Rhabdoid Tumors (MRT’s) are aggressive tumors characterized by loss of the SWI/SNF complex protein SMARCB1. They occur in the CNS (atypical teratoid/rhabdoid tumors-AT/RT) or outside (extra-CNS, eCNS). MRTs are defined by tumor cells that exhibit varying cell lineage phenotypes including neuroglial, mesenchymal and epithelial differentiation. The mechanisms that regulate polyphenotypic differentiation are not known. Because the SWI/SNF complex regulates differentiation, we hypothesized that heterogeneity in expression of various SWI/SNF components regulate multiple lineage differentiation. We examined expression of various BAF and PBAF SWI/SNF complex proteins in MRTs (24 AT/RT and 19 eCNS MRT) in relation to neuroglial, mesenchymal and epithelial differentiation. Surprisingly, we found that a subset of tumors co-expressed the mutually exclusive BAF complex components: ACTL6A and ACTL6B in eCNS MRTs and ARID1A and ARID1B in AT/RTs. ACTL6A and ACTL6B are critical regulators of neuronal differentiation. Accordingly, MRTs that co-expressed ACTL6A/ACTL6B exhibited greater neuronal differentiation. In contrast, tumors that did not express both ACTL6A/ACTL6B showed more epithelial and mesenchymal differentiation. Conversely, ARID1A and ARID1B are known to regulate epithelial differentiation and AT/RTs that showed expression of both ARID1A and ARID1B demonstrated greater epithelial and mesenchymal differentiation in comparison to tumors that did not. These data suggest that aberrant co-expression of specific mutually exclusive subunits may govern lineage differentiation in MRT. Finally, the SWI/SNF-PBAF subunits - ARID2, PBRM1 and BRD7 also showed heterogeneity in MRTs. PBRM1 regulates the immune tumor microenvironment and accordingly PBRM1 expression related inversely with cytotoxic CD8+-T cell levels and overall prognosis. Finally, tumors with high PBAF expression exhibited cell-cycle deregulation and worse prognosis. Together, our data suggest in addition to SMARCB1 deletion, the composition of residual BAF and PBAF subunits govern the biology of MRTs in relation to polyphenotypic differentiation and the immune tumor microenvironment.