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Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

ABSTRACT: RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II1, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC42,3. In addition to POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA and SMO4-8, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

PROVIDER: EGAS00001001916 | EGA |

REPOSITORIES: EGA

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Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas [RNA-seq]

Project description:RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features. RNAseq data from 19 meningioma tumors representing major mutation groups (NF2/chr22 loss, POLR2A, KLF4/TRAF7, PI3K mutant)

2016-08-21 | E-GEOD-85133 | biostudies-arrayexpress

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas [array]

Project description:RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features. Expression microarray data from 121 total samples, including 96 tumors representing the major meningioma mutation groups (NF2/chr22 loss, POLR2A, KLF4/TRAF7, PI3K mutant, Sonic Hedgehog mutant) and 25 control samples (3 dura, 13 adult meninges, and 9 embryonic meninges).

2016-08-21 | E-GEOD-84263 | biostudies-arrayexpress

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas [RNA-seq]

2016-08-21 | GSE85133 | GEO

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas [ChIP-seq]

2016-08-21 | GSE85132 | GEO

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas [array]

2016-08-21 | GSE84263 | GEO

Mutations in TRAF7 drive meningioma development by dysregulating proteostasis of the RAS-like GTPases

Project description:Meningiomas are the most common primary brain tumors, where complete surgical resection is often challenging giving rise to recurrence. Mutations of the E3 ubiquitin ligase TRAF7 are found in one-fourth of meningioma patients and typically co-occur with mutations in either KLF4, AKT1, or PI3KCA. By creating an in vitro meningioma model derived from primary meningeal cells, we elucidated the cooperative interactions that conspire meningioma development. A multi-omics framework on meningeal cells revealed TRAF7-mediated rewiring of the proteome with the majority of protein expression being post‐transcriptionally‐regulated. Integrating TRAF7-driven ubiquitinome and proteome alterations and TRAF7 interactome highlight the role of TRAF7 in posttranslational regulation of the cytoskeleton organization. TRAF7 controls actin dynamics by acting as a proteostatic regulator of the RAS-related small GTPases. TRAF7 loss-of-function diminishes ubiquitination of RAS and CDC42, leading to the activation of the PAK and MAPK signaling pathways. Up-regulation of CDC42 signaling promotes anchorage-independent growth of meningeal cells. On the other hand, the RAS/MAPK pathway triggers the tumor suppressive activity of KLF4 that inhibits meningeal cell growth due to the activation of the Semaphorin pathway. Simultaneous loss of KLF4 and TRAF7 function enhances tumorigenic transformation of meningeal cells, functionally confirming their roles in meningioma development.

2024-06-19 | PXD021188 | Pride

Functional genomics of Non-NF2 meningioma development and progression [RNA-seq]

2020-08-14 | GSE156211 | GEO

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

Project description:We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics. Analysis of meningioma gene expression data for each mutation subtype. Includes gene expression data from 75 unique meningiomas and 39 replicates.

2014-05-29 | E-GEOD-58037 | biostudies-arrayexpress

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

2014-05-29 | GSE58037 | GEO

Mutated KLF4(K409Q) in meningioma binds STRs and activates FGF3 gene expression

Project description:Meningiomas are the most common primary tumors of the central nervous system. The genetic landscape of the most common subtype of meningioma involves mutation or copy loss of the NF2 gene in approximately 50% of cases. Other recurrent canonical somatic mutations are present in ~40% of sporadic meningiomas and are not defined by NF2 inactivation. These genes include TRAF7, AKT1, SMO, and KLF4, among others. Tumors with KLF4 and TRAF7 mutations share a unique secretory phenotype, which is characterized by glandular lumina with secretory globules, and tend to cause disproportional peritumoral edema, which can cause severe medical and neurological complications in pre- and post-operative management. The K409Q mutation in KLF4 is found in ~15% of meningiomas. The mutated allele KLF4K409Q is the same in all affected patients and occurs together with TRAF7 missense mutations. The contribution of the meningioma-specific KLF4 mutation to tumorigenesis and mechanism of action is unknown. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis was performed to investigate different DNA recognition sequences by ectopically expressed KLF4 and KLF4(K409Q) proteins in transiently transfected HEK293 cells.

2022-08-18 | GSE205920 | GEO

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