A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response

Hakimi, A. Ari; Attalla, Kyrollis; DiNatale, Renzo G.; Ostrovnaya, Irina; Flynn, Jessica; Blum, Kyle A.; Ged, Yasser; Hoen, Douglas R.; Kendall, Sviatoslav M.; Reznik, Ed; Bowman, Anita S.; Hwee, Jason; Fong, Christopher J.; Kuo, Fengshen; Voss, Martin H.; Chan, Timothy A.; Motzer, Robert J.

doi:10.1038/s41467-020-17965-0

Cited by 48 publications

(39 citation statements)

References 38 publications

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“…Other tumor types with more than 5% mutation rate include uterine, stomach, melanoma, mesothelioma, and bladder cancer (43,44). The overall prevalence of PBRM1 is 4.9% (2% as loss of function) across the 11 most frequent tumor types in TCGA (45). These mutations are distributed across the gene, including mutations in the BAH domains (46).…”

Section: Discussionmentioning

confidence: 99%

A cytoskeletal function for PBRM1 reading methylated microtubules

et al. 2021

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Epigenetic effectors “read” marks “written” on chromatin to regulate function and fidelity of the genome. Here, we show that this coordinated read-write activity of the epigenetic machinery extends to the cytoskeleton, with PBRM1 in the PBAF chromatin remodeling complex reading microtubule methyl marks written by the SETD2 histone methyltransferase. PBRM1 binds SETD2 methyl marks via BAH domains, recruiting PBAF components to the mitotic spindle. This read-write activity was required for normal mitosis: Loss of SETD2 methylation or pathogenic BAH domain mutations disrupt PBRM1 microtubule binding and PBAF recruitment and cause genomic instability. These data reveal PBRM1 functions beyond chromatin remodeling with domains that allow it to integrate chromatin and cytoskeletal activity via its acetyl-binding BD and methyl-binding BAH domains, respectively. Conserved coordinated activity of the epigenetic machinery on the cytoskeleton opens a previously unknown window into how chromatin remodeler defects can drive disease via both epigenetic and cytoskeletal dysfunction.

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Section: Discussionmentioning

confidence: 99%

A cytoskeletal function for PBRM1 reading methylated microtubules

et al. 2021

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“…Together, these results suggest that the allele-specific effect of rs4903064 could be partially mediated through STAT3 activation, comparable to the effect of select PBRM1 somatic mutations. 15 DPF3 effect on T-cell-mediated cytotoxic and immunotherapy response Previous studies have suggested that mutations within the SWI/SNF complexes, particularly in PBRM1, could contribute to response to immune checkpoint inhibitor therapy in RCC affected individuals, 77,78 but other studies could not find this association; [79][80][81] confirmation studies are needed. 82 Ex vivo data suggest that PBRM1 mutations are associated with enhanced sensitization to killing by T cells, 83 an effect most likely mediated through mSWI/ SNF complex regulation of chromatin accessibility for INF-g target genes.…”

Section: Dpf3 Changes Chromatin Accessibility Leading To Altered Gene Expressionmentioning

confidence: 99%

Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus

Colli

Jessop

Myers

et al. 2021

The American Journal of Human Genetics

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Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.

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“…In total, five genes were identified with significant mutation frequency among subtypes (Fisher's exact test p < 0.01; Figure S10). These genes have been found to play critical roles in cancer, such as VHL 52 and PBRM1 53 . In addition, we investigated the extent to which we can subtype the same kidney cancer patients by AS.…”

Section: Distinct Cancer Pathways Of Kidney Cancer Subtypesmentioning

confidence: 99%

Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer

Li¹,

Pan²,

Chen³

et al. 2021

Molecular Therapy - Nucleic Acids

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Alternative splicing (AS) plays an important role in gene regulation, and AS perturbations are frequently observed in cancer. RNA binding protein (RBP) is one of the molecular determinants of AS, and perturbations in RBP-gene network activity are causally associated with cancer development. Here, we performed a systematic analysis to characterize the perturbations in AS events across 18 cancer types. We showed that AS alterations were prevalent in cancer and involved in cancer-related pathways. Given that the extent of AS perturbation was associated with disease severity, we proposed a computational pipeline to identify RBP regulators. Pan-cancer analysis identified a number of conserved RBP regulators, which play important roles in regulating AS of genes involved in cancer hallmark pathways. Our application analysis revealed that the expression of 68 RBP regulators helped in cancer subtyping. Specifically, we identified four subtypes of kidney cancer with differences in cancer hallmark pathway activities and prognosis. Finally, we identified the small molecules that can potentially target the RBP genes and suggested potential candidates for cancer therapy. In summary, our comprehensive AS perturbation landscape analysis identified RBPs as potential therapeutic targets in cancer and provided novel insights into the regulatory functions of RBPs in cancer.

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A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response

Cited by 48 publications

References 38 publications

A cytoskeletal function for PBRM1 reading methylated microtubules

A cytoskeletal function for PBRM1 reading methylated microtubules

Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus

Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer

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