Whole‐genome paired‐end analysis confirms remarkable genomic stability of atypical teratoid/rhabdoid tumors

Hoell, Jessica I.; Gombert, Michael; Bartenhagen, Christoph; Ginzel, Sebastian; Husemann, Peter; Felsberg, Jörg; Reifenberger, Guido; Eggert, Angelika; Dugas, Martin; Schönberger, Stefan; Fischer, Ute

doi:10.1002/gcc.22092

Cited by 4 publications

(3 citation statements)

References 5 publications

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“…Across 35 of these SMARCB1-deficient cancers, there were essentially no other recurrent mutations and in two of the cancers there were no other identified mutations at all. The same conclusion was reached in other studies as well(53, 54). Given the paucity of other mutations and the extremely rapid onset of cancer in mouse models, these findings seem to suggest that SMARCB1-deficiency may not cause cancer via defects in DNA repair but rather due to epigenetic alterations such as disruption of chromatin-based contributions to control of cell fate.…”

Section: Introductionsupporting

confidence: 90%

Molecular Pathways: SWI/SNF (BAF) Complexes Are Frequently Mutated in Cancer—Mechanisms and Potential Therapeutic Insights

Haswell

Roberts

2014

Clinical Cancer Research

175

136

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SWI/SNF chromatin remodeling complexes are pleomorphic multi-subunit cellular machines that utilize the energy of ATP hydrolysis to modulate chromatin structure. The complexes interact with transcription factors at promoters and enhancers to modulate gene expression and contribute to lineage specification, differentiation and development. Initial clues to a role in tumor suppression for SWI/SNF complexes came over a decade ago when the gene encoding the SMARCB1/SNF5 core subunit was found specifically inactivated in nearly all pediatric rhabdoid tumors. In the last 3 years, cancer genome sequencing efforts have revealed an unexpectedly high mutation rate of SWI/SNF subunit genes, which are collectively mutated in 20% of all human cancers and approach the frequency of p53 mutations. Here we provide a background on these newly recognized tumor suppressor complexes, discuss mechanisms implicated in the tumor suppressor activity, and highlight findings that may lead to potential therapeutic targets for SWI/SNF mutant cancers.

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Section: Introductionsupporting

confidence: 90%

Molecular Pathways: SWI/SNF (BAF) Complexes Are Frequently Mutated in Cancer—Mechanisms and Potential Therapeutic Insights

Haswell

Roberts

2014

Clinical Cancer Research

175

136

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“…Genetic alterations in subunits of the SWI/SNF complex are quite common and occur in up to 20% of all human cancers [34, 35]. According to accumulating evidence, biallelic inactivation of the SMARCB1 gene has repeatedly been found to be the almost sole driving genetic alteration in AT/RTs [5, 7, 8, 36]. A variety of mechanisms, such as deletions, mutations, and loss of heterozygosity, are responsible for SMARCB1 inactivation in AT/RTs [37].…”

Section: Discussionmentioning

confidence: 99%

“…The SMARCB1 protein is a core subunit of the switch/sucrose non-fermentable chromatin remodeling (SWI/SNF) complex that regulates the expression of thousands of genes [6]. High-resolution genomic analysis and whole exome sequencing studies identified extremely low mutation rates for genes other than the biallelic inactivation of SMARCB1 in rhabdoid tumors [5, 7]. A recent study in which whole genome sequencing was undertaken for many AT/RT samples also reported rare recurrent mutations aside from the mutations in SMARCB1 [8].…”

Section: Introductionmentioning

confidence: 99%

NPM1 as a potential therapeutic target for atypical teratoid/rhabdoid tumors

Sun¹,

Lee

et al. 2019

BMC Cancer

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Background Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets. Methods Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines. Results WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1 . However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNA-Seq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells. Conclusions We propose that NPM1 is a novel therapeutic target for AT/RTs. Electronic supplementary material The online version of this article (10.1186/s12885-019-6044-z) contains supplementary material, which is available to authorized users.

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Synergistic action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells

et al. 2022

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Rhabdoid tumors (RT) are rare and deadly pediatric cancers driven by loss of SMARCB1, which encodes the SNF5 component of the SWI/SNF chromatin remodeler. Loss of SMARCB1 is associated with a complex set of phenotypic changes including vulnerability to inhibitors of protein synthesis and of the p53 ubiquitin-ligase HDM2. Recently, we discovered small molecule inhibitors of the ‘WIN’ site of WDR5, which in MLL-rearranged leukemia cells decrease the expression of a set of genes linked to protein synthesis, inducing a translational choke and causing p53-dependent inhibition of proliferation. Here, we characterize how WIN site inhibitors act in RT cells. As in leukemia cells, WIN site inhibition in RT cells causes the comprehensive displacement of WDR5 from chromatin, resulting in a decrease in protein synthesis gene expression. Unlike leukemia cells, however, the growth response of RT cells to WIN site blockade is independent of p53. Exploiting this observation, we demonstrate that WIN site inhibitor synergizes with an HDM2 antagonist to induce p53 and block RT cell proliferation in vitro. These data reveal a p53-independent action of WIN site inhibitors and forecast that future strategies to treat RT could be based on dual WDR5/HDM2 inhibition.

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Whole‐genome paired‐end analysis confirms remarkable genomic stability of atypical teratoid/rhabdoid tumors

Abstract: in Wiley Online Library (wileyonlinelibrary.com).

Cited by 4 publications

References 5 publications

Molecular Pathways: SWI/SNF (BAF) Complexes Are Frequently Mutated in Cancer—Mechanisms and Potential Therapeutic Insights

Molecular Pathways: SWI/SNF (BAF) Complexes Are Frequently Mutated in Cancer—Mechanisms and Potential Therapeutic Insights

NPM1 as a potential therapeutic target for atypical teratoid/rhabdoid tumors

Synergistic action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells

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