RNA polymerase II at histone genes predicts outcome in human cancer

Science, Journal Year: 2025, Volume and Issue: 387(6735), P. 737 - 743

Published: Jan. 2, 2025

Genome-wide hypertranscription is common in human cancer and predicts poor prognosis. To understand how might drive cancer, we applied our formalin-fixed paraffin-embedded (FFPE)–cleavage under targeted accessible chromatin method for mapping RNA polymerase II (RNAPII) genome-wide FFPE sections. We demonstrate global RNAPII elevations mouse gliomas assorted tumors small clinical samples discover regional corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. occupancy at S-phase-dependent histone genes correlated with WHO grade meningiomas, accurately predicted rapid recurrence, corresponded whole-arm chromosome losses. Elevated meningiomas diverse breast cancers consistent production being rate-limiting S-phase progression gene driving overproliferation aneuploidy general implications precision oncology.

Language: Английский

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Meningioma: current updates on genetics, classification, and mouse modeling

Upsala Journal of Medical Sciences, Journal Year: 2024, Volume and Issue: 129, P. e10579 - e10579

Published: March 18, 2024

Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive growth behavior as well invasion, recurs even after several rounds surgery. Increasing evidence suggests that tumor classification grading primarily based on histopathology do not always accurately predict aggressiveness recurrence behavior. The underlying biology treatment-resistant meningiomas impact specific genetic aberrations present these high-grade still only insufficiently understood. Therefore, an in-depth research into this type warranted. More recent studies large-scale molecular data such whole exome/genome sequencing, DNA methylation RNA sequencing have provided new insights revealed risk factors prognostic subtypes. aberration functional loss NF2 occurs both low- meningiomas, whereas NF2-wildtype enriched for recurrent mutations TRAF7, KLF4, AKT1, PI3KCA, SMO more frequently benign. Most meningioma mouse models patient-derived xenografts recently genetically engineered been developed will aid systematic evaluation found their In article, we review advances understanding highlight mutations, discuss meningioma.

Language: Английский

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Total whole-arm chromosome losses predict malignancy in human cancer

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Aneuploidy is observed as gains or losses of whole chromosomes chromosome arms and a common hallmark cancer. Whereas models for the generation aneuploidy in cancer invoke mitotic segregation errors, whole-arm might occur simply result centromere breakage. We recently showed that elevated RNA Polymerase II (RNAPII) level over S-phase-dependent histone genes predicts rapid recurrence human meningioma correlated with total relative to gains. To explain this imbalance arm gains, we have proposed overexpression at S-phase competes H3 variant CENP-A, resulting breaks losses. test whether alone can drive aneuploidy, ask aneuploids predict outcome across different types large whole-genome sequencing databanks. find generally outcome, suggesting breakage major initiating factor leading changes selective landscape most cancers. also present evidence sufficient account contrary spindle error aneuploidy. Our results suggest therapeutic intervention targeting has potential reducing slowing progression. Gain loss following frequent cancer, but not there event unknown. Here show number patient outcomes types, causal relationship. This general excess predicted by rather suggests themselves initiate aneuploidies. Insofar reshapes landscapes cancers, our clinical implications.

Language: Английский

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Total whole-arm chromosome losses predict malignancy in human cancer

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(18)

Published: May 2, 2025

Aneuploidy is observed as gains or losses of whole chromosomes chromosome arms and a common hallmark cancer. Whereas models for the generation aneuploidy in cancer invoke mitotic segregation errors, whole-arm might occur simply result centromere breakage. We recently showed that elevated RNA Polymerase II level over S-phase-dependent histone genes predicts rapid recurrence human meningioma correlated with total relative to gains. To explain this imbalance arm gains, we have proposed overexpression at S-phase competes H3 variant CENP-A, resulting breaks losses. test whether alone can drive aneuploidy, ask aneuploids predict outcomes across different types large whole-genome sequencing databanks. find generally outcome, suggesting breakage major initiating factor leading changes selective landscape most cancers. also present evidence sufficient account contrary spindle error aneuploidy. Our results suggest therapeutic intervention targeting has potential reduce slow progression.

Language: Английский

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GSTM1 null genotype underpins recurrence of NF2 meningiomas

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Dec. 12, 2024

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

Language: Английский

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Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 31, 2024

Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset of meningiomas is higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half all harbor inactivating mutations NF2. While benign low-grade NF2 mutant exhibit few genetic events addition to inactivation, high-grade frequently highly aberrant genome. We others have previously shown that inactivation leads YAP1 activation acts as pivotal oncogenic driver meningiomas. Using bulk single-cell RNA-Seq data from large cohort human meningiomas, we show decreased levels activity compared their counterparts. Decreased expression YAP target genes significantly associated with an increased risk recurrence. then identify competitor VGLL4 well upstream regulators FAT3/4 potential mechanism for downregulation High these In vitro, overexpression resulted meningioma cells, confirming direct link between observed Our results shed new insight on biology may important implications efficacy therapies targeting

Language: Английский

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How to visualize high‐dimensional data

Acta Physiologica, Journal Year: 2024, Volume and Issue: 240(10)

Published: Aug. 19, 2024

Recently, a colleague asked after lecture about fancy diagram where the axis designation was not clear to him and discussion that raised few interesting thoughts specific matter. Physiological knowledge is often taught at university seminars in textbooks with help of diagrams. A very important first step when discussing diagrams clarify which physical, physiological variable what scale unit represented on axis. Examples typical classical low dimensional physiology publications Acta Physiologica might be blood pressure over time,1 infarct size as percentage Left ventricular mass depending genotype2 or urine excretion volume per time diet.3 Not knowing axes diagrams, they well "just" pieces modern art. We strongly believe graphical representation complex data—for example, diagrams—is essential communicating them. However, for types understanding interpretation their content more complex, requires explanation than Specifically, we refer high-dimensional data, have, recent years, played an increasing role new understandings processes. To visualize data reduction dimensionality applied. simple example black/white photograph colorful moving three object. The snapshot "eliminated" dimension optical projection plane camera eliminated one space gray values just reduced spectral information intensity value photograph. Although does represent compete "dataset" it gives us most cases good impression situation captured by photographer. Times have changed. describe "amount" obtained study 1960s physiologist referred length paper plots curved measurements he analyzing particular study. Compared amount back then are nowadays faced completely situation. With development technology handle huge today. For studies single RNAseq scientists thousands expression genes each cells multiple experimental points possibly interventions. Obviously you cannot produce meaningful plot dimensions. In order make sense out hugely researches can employ methods dimensionality. One would so called principal component analysis (PCA). This linear method projects onto coordinate system (principal components) directions maximum variance. Without diving too deep into mathematics, this done calculating eigenvectors matrix. It turned PCA its transformation sufficient above described case. Here statistical approaches nonlinear been developed. t-Distributed Stochastic Neighbor Embedding (t-SNE) method4 later kind improved version Uniform Manifold Approximation Projection (UMAP).5 Both techniques used visualizing data. features regarding that, unlike well-defined physical quantities such voltage axes, t-SNE UMAP abstract interpretations. positions reflect (probability)-relationships between individual original space, whereby find clustered clouds. clouds close together considered similar closely related space. When comparing UMAP, differentiate local structure global diagram. preserves is, diagram, cluster point higher However accurately preserved method. main comes play. aims preserve both structures effectively Therefore, suitable feature topology relevant interpretation. case lineage stem cell maturation. illustrate performance generated datasets them all tree (Figure 2). also possible perform analysis.6 widely field neurophysiology,7 immunology,8 cancer9, 10 infectious diseases like COVID-19.11 Taken together, applied far. Clusters revealed usage literature has growing steadily scientific since publication 1). meaning straightforward compared traditional physiology, spread showing variance what? mapping while scales neighboring relationships aimed preserve. better preserving scales; however, cautious distances clusters due transformations. There efforts further improve those methods.12 will see whether resonance application community. come beginning: please remember take second explain your show presentation. As rather interdisciplinary develop rapidly, likely part audience otherwise admiring beautiful graphic Generation displayed Figure 2: set (upper row) array 200 5 mean 1, 2, 3, 4, 0.8 standard deviation. (middle accordingly means 8, 16 deviation 0.5 mean. third (lower 10, 100, 1000, 000 deviations equal Data graphs were using R software 4.4.0 (2024-04-24) library RtSNE,13 ggplot2, umap14 default parameters. RM did statistics pubmed occurences. RS anaysis figure 2. wrote initial text. authors edited final manuscript. project these results based funded FreeState Thuringia under number 2018 IZN0002 (Thimedop) co-financed funds from European Union within framework Regional Development Fund (EFRE). Another Carl Zeiss Foundation. None.

Language: Английский

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Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4

Neuro-Oncology Advances, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 23, 2024

Meningiomas are the most common primary central nervous system tumors in adults. Although generally benign, a subset is of higher grade and ultimately fatal. Around half all meningiomas harbor inactivating mutations NF2, leading to deregulation oncogenic YAP1 activity. While benign NF2 mutant exhibit few genetic events addition inactivation, aggressive high-grade frequently highly aberrant genome. It unclear if different grades equally reliant on YAP

Language: Английский

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Transcriptomic landscape identifies two unrecognized ependymoma subtypes and novel pathways in medulloblastoma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 22, 2024

Abstract Medulloblastoma and ependymoma are prevalent pediatric central nervous system tumors with significant molecular clinical heterogeneity. We collected bulk RNA sequencing data from 888 medulloblastoma 370 to establish a comprehensive reference landscape. Following rigorous batch effect correction, normalization, dimensionality reduction, we constructed unified landscape explore gene expression, signaling pathways, fusions, copy number variations. Our analysis revealed distinct clustering patterns, including two primary compartments, EPN-E1 EPN-E2, each specific fusions signatures. In medulloblastoma, achieved precise stratification of Group 3/4 by subtype in SHH patient age. serves as vital resource for identifying biomarkers, refining diagnoses, enables the mapping new patients’ RNA-seq onto framework facilitate accurate disease identification. The is accessible via Oncoscape, an interactive platform, empowering global exploration application. One Sentence Summary A built using only Transcriptomic reveals novel insights about biology.

Language: Английский

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