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SWI/SNF complex heterogeneity is related to polyphenotypic differentiation, prognosis, and immune response in rhabdoid tumors.
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.
Afiliación
  • Panwalkar P; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Pratt D; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Chung C; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Dang D; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Le P; Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Martinez D; Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Bayliss JM; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Smith KS; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • Adam M; Division of Pediatric Urology and Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Potter S; Division of Pediatric Urology and Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Northcott PA; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • Mascarenhas L; Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California, USA.
  • Shows J; Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
  • Pawel B; Department of Pathology, Long Beach Memorial Medical Center/Miller Children's Hospital, Long Beach, California, USA.
  • Margol A; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine University of Southern California, Los Angeles, California, USA.
  • Huang A; Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California, USA.
  • Judkins AR; Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
  • Venneti S; Division of Hematology/Oncology, Department of Pediatrics, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Neuro Oncol ; 22(6): 785-796, 2020 06 09.
Article en En | MEDLINE | ID: mdl-31912158
ABSTRACT

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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tumor Rabdoide Tipo de estudio: Prognostic_studies Límite: Child / Humans Idioma: En Revista: Neuro Oncol Asunto de la revista: NEOPLASIAS / NEUROLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tumor Rabdoide Tipo de estudio: Prognostic_studies Límite: Child / Humans Idioma: En Revista: Neuro Oncol Asunto de la revista: NEOPLASIAS / NEUROLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos