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SWI/SNF complex heterogeneity is related to polyphenotypic differentiation, prognosis, and immune response in
Pooja Panwalkar1, Drew Pratt1, Chan Chung1
1Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Background:
Rhabdoid tumors (RTs) arise within (atypical teratoid/rhabdoid tumor [AT/RT]) or outside the brain (extra [e]CNS-RT) and are driven mainly by inactivation of the SWItch/sucrose nonfermentable (SWI/SNF) complex subunit SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1). A pathognomonic hallmark of RTs is heterogeneous multilineage differentiation, including anomalous neuronal differentiation in some eCNS-RTs. Because remodeling of the SWI/SNF complex regulates differentiation, we hypothesized that SWI/SNF Brahma-associated factors (BAF) and polybromo-associated BAF (PBAF) complex heterogeneity are related to both multilineage differentiation and clinical outcome.
Methods:
We performed an integrated analysis of SWI/SNF complex alterations in the developing kidney and cerebellum (most common regions of RT origin) in comparison to eCNS-RT (n = 14) and AT/RT (n = 25) tumors. RT samples were interrogated using immunohistochemistry, DNA methylation, and gene expression analyses.
Results:
The SWI/SNF BAF paralogs actin-like protein (ACTL)6A and ACTL6B were expressed in a mutually exclusive manner in the developing cerebellum and kidney. In contrast, a subset of eCNS-RTs lost mutual exclusivity and coexpressed both subunits. These tumors showed aberrant DNA methylation of genes that regulate neuronal and renal development and demonstrated immunohistochemical evidence of neuronal differentiation. In addition, low expression of the PBAF subunit polybromo-1 (PBRM1) identified a group of AT/RTs in younger children with better overall prognosis. PBRM1-low AT/RT and eCNS-RTs showed altered DNA methylation and gene expression in immune-related genes. PBRM1 knockdown resulted in lowering immunosuppressive cytokines, and PBRM1 levels in tumor samples showed an inverse relationship with cluster of differentiation (CD)8 cytotoxic T-cell infiltration.
Conclusions:
Heterogeneity in SWI/SNF BAF (ACTL6A/ACTL6B) and PBAF (PBRM1) subunits is related to histogenesis, contributes to the immune microenvironment and prognosis in RTs, and may inform opportunities to develop immunotherapies.
Insights
Alterations in SWI/SNF complex subunits (BAF and PBAF) impact rhabdoid tumor (RT) differentiation and prognosis. Understanding these SWI/SNF changes may guide new immunotherapies for RTs.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Rhabdoid tumors (RTs), including atypical teratoid/rhabdoid tumors (AT/RT) and extra-CNS RTs (eCNS-RTs), are primarily driven by SWI/SNF complex inactivation.
- RTs exhibit diverse differentiation, with some eCNS-RTs showing anomalous neuronal differentiation.
- SWI/SNF complex remodeling is implicated in cellular differentiation processes.
Purpose of the Study:
- To investigate the relationship between SWI/SNF complex subunit heterogeneity (BAF and PBAF) and multilineage differentiation in RTs.
- To explore the correlation between SWI/SNF alterations and clinical outcomes in RT patients.
- To analyze SWI/SNF complex alterations in the developing kidney and cerebellum compared to RTs.
Main Methods:
- Integrated analysis of SWI/SNF complex alterations using immunohistochemistry, DNA methylation, and gene expression profiling.
- Comparison of SWI/SNF subunit expression in developing kidney and cerebellum with eCNS-RT (n=14) and AT/RT (n=25) tumors.
- Assessment of SWI/SNF BAF paralogs (ACTL6A/ACTL6B) and PBAF subunit (PBRM1) expression and their functional impact.
Main Results:
- Mutually exclusive expression of ACTL6A and ACTL6B in normal tissues was lost in a subset of eCNS-RTs, correlating with aberrant DNA methylation and neuronal differentiation.
- Low PBRM1 expression identified a subgroup of AT/RTs in younger children with a better prognosis.
- PBRM1-low tumors exhibited altered immune-related gene expression, with PBRM1 levels inversely correlating with CD8+ T-cell infiltration.
Conclusions:
- SWI/SNF BAF (ACTL6A/ACTL6B) and PBAF (PBRM1) subunit heterogeneity is linked to RT histogenesis and differentiation.
- These SWI/SNF alterations significantly influence the tumor immune microenvironment and patient prognosis.
- Understanding SWI/SNF heterogeneity offers potential targets for developing novel immunotherapies for RTs.
