BAFfling pathologies: Alterations of BAF complexes in cancer

Arnaud, Ophélie; Loarer, François Le; Tirode, Franck

doi:10.1016/j.canlet.2018.01.046

Cited by 40 publications

(31 citation statements)

References 175 publications

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“…Based on SAINTexpress guidelines, we used an interaction confidence threshold of a 2-fold enrichment over IgG and an average probability of interaction (AvgP) ≥ 0.7 with at least 1 antibody. We detected all previously identified mammalian SWI/SNF subunits [48][49][50] in the SWI/SNF wild-type cell line HAP1, 26 of which passed our interaction threshold (Figure 1). Core SWI/SNF subunit (SMARCC1, SMARCC2, SMARCD1/2, SMARCB1, and SMARCE1) 13 interactions were detected above the AvgP threshold in all 3 SCCOHT cell lines, albeit at a lower protein abundance than HAP1 ( Figure 1A, processed data in Supplemental Table 1, fold change in Supplemental Table 2).…”

Section: Results: the Swi/snf Complex In Sccoht Cell Lines Shows Redumentioning

confidence: 82%

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Raupach

Garcia-Mansfield

Sharma

et al. 2019

Preprint

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Chromatin remodeling plays a critical role in tumor suppression as demonstrated by 20% of human cancers bearing inactivating mutations in SWI/SNF chromatin remodeling complex members. Mutations in different SWI/SNF subunits drive a variety of adult and pediatric tumor types, including non-small cell lung cancers, rhabdoid tumors, medulloblastomas, and ovarian cancers. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is an aggressive subtype of ovarian cancer occurring in young women. Nearly all (>98%) SCCOHTs have inactivating mutations in SMARCA4, which encodes 1 of 2 mutually exclusive catalytic subunits of the SWI/SNF complex. Less than half of SCCOHT patients survive 5 years despite aggressive surgery and multimodal chemotherapy. Empirical support for effective SCCOHT treatments is scarce, in part because of the poor understanding of SCCOHT tumorigenesis. To gain insight into the functional consequences of SWI/SNF subunit loss, we defined SWI/SNF composition and its protein-protein interactions (PPIs) by immunoprecipitation and mass spectrometry (IP-MS) of SWI/SNF subunits in 3 SCCOHT cell lines. Comparing these results to a cell line containing a wild-type SWI/SNF complex, the interaction of most canonical core SWI/SNF subunits was observed in all SCCOHT cell lines at a lower abundance. The SCCOHT SWI/SNF also lacked ATPase module subunits and showed a drastic reduction in PBAF-specific subunit interactions. The wild-type and SCCOHT SWI/SNF subunits immunoprecipitated a shared set of 26 proteins, including core SWI/SNF subunits and RNA processing proteins. We observed 131 proteins exclusively interacting with the wild-type SWI/SNF complex including isoform-specific SWI/SNF subunits, members of the NuRD complex, and members of the MLL3/4 complex. We observed 60 PPIs exclusive to the SCCOHT residual SWI/SNF shared in at least 2 of the 3 SCCOHT cell lines, including many proteins involved in RNA processing. Differential interactions with the residual SWI/SNF complex in SCCOHT may further elucidate altered functional consequences of SMARCA4 mutations in these tumors as well as identify synthetic lethal targets that translate to other SWI/SNF-deficient tumors.Introduction:

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Section: Results: the Swi/snf Complex In Sccoht Cell Lines Shows Redumentioning

confidence: 82%

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Raupach

Garcia-Mansfield

Sharma

et al. 2019

Preprint

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“…The best known of these "BAF-altered family of tumors" 2 are malignant rhabdoid tumors 3,4 characterized by the loss of SMARCB1 (INI1) and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) characterized by SMARCA4 mutations resulting in the loss of BRG1 protein. 5 We herein report a case of high grade undifferentiated SMARCA4-deficient gastroesophageal junction carcinoma metastatic to the liver diagnosed by FNA, after being initially interpreted as a hematolymphoid neoplasm.…”

Section: Introductionmentioning

confidence: 93%

“…Some of these undifferentiated tumors belong to a recently delineated group of neoplasms related to abnormalities in genes of the Switch/Sucrose non‐fermenting ( SWI/SNF ) chromatin remodeling complex, the mammalian counterpart of which is referred to as BAF (BRG1/BRM associated factors). The best known of these “BAF‐altered family of tumors” are malignant rhabdoid tumors characterized by the loss of SMARCB1 (INI1) and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) characterized by SMARCA4 mutations resulting in the loss of BRG1 protein . We herein report a case of high grade undifferentiated SMARCA4 ‐deficient gastroesophageal junction carcinoma metastatic to the liver diagnosed by FNA, after being initially interpreted as a hematolymphoid neoplasm.…”

Section: Introductionmentioning

confidence: 96%

A BAFfling liver aspirate: Metastatic high grade SMARCA4 deficient undifferentiated gastroesophageal junction carcinoma masquerading as a hematolymphoid malignancy

Kılıç

Mirza

Mehrotra

et al. 2019

Diagnostic Cytopathology

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Undifferentiated malignant SMARCA4‐deficient neoplasms are rare, recently characterized, high grade, potentially lethal malignancies. Such tumors are characterized by the loss of BRG1 encoded by SMARCA4, a key component of the Switch/Sucrose Non‐Fermenting (SWI/SNF) chromatin remodeling complex. As this complex, also referred as BAF (BRG1/BRM associated factors) complex, is involved in the epigenetic control of hundreds of genes, including those involved in lineage‐specific differentiation, BAF‐deficient tumors, show minimal or no differentiation and are difficult to classify. Their fine needle aspiration (FNA) cytologic features are still poorly defined. Here, we describe a 70‐year‐old man who presented with thickening of the wall of the distal esophagus and stomach and multiple liver and lung lesions. Liver FNA showed relatively uniform dispersed malignant cells with high nucleus: cytoplasm ratio, scant microvacuolated cytoplasm, eccentric nuclei and prominent nucleoli. Mitoses, necrotic debris, nuclear streak artifact, “ghost cells” and focal rhabdoid cytoplasmic inclusions were also present. The liver core biopsy and GI biopsies demonstrated sinusoidal and respectively submucosal involvement by a high grade undifferentiated malignant neoplasm. The tumor cells were negative for all applied markers on immunohistochemistry and flow cytometry, and only showed CD138 and weak PAX5 staining. After an initial diagnosis of hematolymphoid neoplasm, additional stains showed intact INI1 protein and loss of BRG1 protein immunoexpression, establishing the accurate diagnosis. This case highlights the difficulties and potential pitfalls encountered in the FNA diagnosis of BAF‐deficient tumors, the accurate diagnosis of which is important due to their lack of response to conventional therapy and potential response to targeted therapy.

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“…1 They are involved in essential cellular processes, such as transcriptional regulation, DNA replication, repair, and recombination. These large complexes are highly dynamic and are assembled combinatorially from multiple subunits (2)(3)(4)(5) encoded by more than 29 genes.…”

Section: Introductionmentioning

confidence: 99%

Structure of the BRK domain of the SWI/SNF chromatin remodeling complex subunit BRG1 reveals a potential role in protein–protein interactions

2020

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BRG1/SMARCA4 and its paralog BRM/SMARCA2 are the ATPase subunits of human SWI/SNF chromatin remodeling complexes. These multisubunit assemblies can act as either tumor suppressors or drivers of cancer, and inhibiting both BRG1 and BRM, is emerging as an effective therapeutic strategy in diverse cancers. BRG1 and BRM contain a BRK domain. The function of this domain is unknown, but it is often found in proteins involved in transcription and developmental signaling in higher eukaryotes, in particular in proteins that remodel chromatin. We report the NMR structure of the BRG1 BRK domain. It shows similarity to the glycine‐tyrosine‐phenylalanine (GYF) domain, an established protein–protein interaction module. Computational peptide‐binding‐site analysis of the BRK domain identifies a binding site that coincides with a highly conserved groove on the surface of the protein. This sets the scene for experiments to elucidate the role of this domain, and evaluate the potential of targeting it for cancer therapy.

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BAFfling pathologies: Alterations of BAF complexes in cancer

Cited by 40 publications

References 175 publications

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

A BAFfling liver aspirate: Metastatic high grade SMARCA4 deficient undifferentiated gastroesophageal junction carcinoma masquerading as a hematolymphoid malignancy

Structure of the BRK domain of the SWI/SNF chromatin remodeling complex subunit BRG1 reveals a potential role in protein–protein interactions

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