SWI/SNF complex heterogeneity is related to polyphenotypic differentiation, prognosis, and immune response in rhabdoid tumors

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Bibliographische Detailangaben
Zeitschriftentitel:	Neuro-Oncology
Personen und Körperschaften:	Panwalkar, Pooja, Pratt, Drew, Chung, Chan, Dang, Derek, Le, Paul, Martinez, Daniel, Bayliss, Jill M, Smith, Kyle S, Adam, Mike, Potter, Steven, Northcott, Paul A, Mascarenhas, Leo, Shows, Jared, Pawel, Bruce, Margol, Ashley, Huang, Annie, Judkins, Alexander R, Venneti, Sriram
In:	Neuro-Oncology, 22, 2020, 6, S. 785-796
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	Oxford University Press (OUP)
Schlagwörter:	Cancer Research Neurology (clinical) Oncology

Details
Zusammenfassung:	<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>
Umfang:	785-796
ISSN:	1522-8517 1523-5866
DOI:	10.1093/neuonc/noaa004