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

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 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).

ORGANISM(S): Homo sapiens

SUBMITTER: Victoria Clark

PROVIDER: E-GEOD-84263 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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 [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

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

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

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

2014-05-29 | GSE58037 | GEO

High-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling.

Project description:Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas.

2024-08-26 | GSE263122 | GEO

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

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 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.

| EGAS00001001916 | EGA

GSTM1 null genotype underpins recurrence of NF2 meningiomas

Project description:Introduction: Meningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited. Objective: To identify gene expression signatures of 1p-22q-NF2- meningioma recurrence, with concurrent biallelic inactivation of NF2 and loss of chr1p that are heterogenous but enriched for recurrent meningiomas. Methods: Transcriptomic alterations present in recurrent versus primary 1p-22q-NF2- meningiomas were identified using RNA sequencing (RNA-seq) data in a clinically annotated cohort. Results: Recurrent 1p-22q-NF2- meningiomas were enriched for a newly identified GSTM1 null genotype compared to primary meningiomas that showed variable GSTM1 expression and independent external validation was performed. Conclusions: The GSTM1 null genotype is a novel biomarker of 1p-22q-NF2- meningioma recurrence that resolves heterogeneity in existing meningioma subtypes and may be used to guide future clinical management decisions on extent of treatment to improve patient outcomes.

2024-12-09 | GSE283616 | GEO

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