Dataset Information

Proteogenomics reveals two distinct biological pilocytic astrocytoma subgroups

ABSTRACT: Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and driven by aberrant MAPK signaling, typically mediated by BRAF alterations. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapies. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing and LC/MS-based proteomic profiling data from a cohort of 58 confirmed, primary PA samples. An integrative genomics approach was conducted to discern the biological heterogeneity of PA and to identify aberrant pathway activation in these biological subgroups. In summary, Pilocytic astrocytomas segregate into two groups where younger patients are significantly associated with Group 1. Importantly, we validate the two distinct biological subgroups in two non-overlapping cohorts. The biological heterogeneity seen here may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of recurrent or progressive disease.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Cancer

SUBMITTER: Maike Langini

LAB HEAD: Marc Remke

PROVIDER: PXD035773 | Pride | 2023-10-24

REPOSITORIES: Pride

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Publications

Integrative multi-omics reveals two biologically distinct groups of pilocytic astrocytoma.

Picard Daniel D Felsberg Jörg J Langini Maike M Stachura Paweł P Qin Nan N Macas Jadranka J Reiss Yvonne Y Bartl Jasmin J Selt Florian F Sigaud Romain R Meyer Frauke-D FD Stefanski Anja A Stühler Kai K Roque Lucia L Roque Rafael R Pandyra Aleksandra A AA Brozou Triantafyllia T Knobbe-Thomsen Christiane C Plate Karl H KH Roesch Alexander A Milde Till T Reifenberger Guido G Leprivier Gabriel G Faria Claudia C CC Remke Marc M

Acta neuropathologica 20230901 4

Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene fusions or activating mutations. While 5-year overall survival rates exceed 95%, tumor recurrence or progression constitutes a major clinical challenge in incompletely resected tumors. Here, we used similarity network fusion (SNF) analysis in an integrative multi-omics approach employing RNA transcriptomic and mass spectrometry-base ...[more]

PMID: 37656187

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Project description:Propionate is a common three-carbon intermediate produced from the breakdown of propiogenic substrates, such as branched-chain amino acids and odd-numbered fatty acids, and by gut bacteria. Propionate can chemically modify proteins, and if this involves histones, it may underpin a disease-relevant link between short-chain acyls and gene expression in the heart. Here, we sought to characterize how propionate-dependent modifications to histones affect cardiac gene expression and contractile function in a mouse model producing elevated levels of propionate/propionyl-CoA. An adult mouse model of propionic acidaemia (PA) was used to investigate how propionate affects histones and gene expression in the heart, an organ strongly affected in PA patients. Mass spectrometry confirmed elevated plasma propionate in 8-week PA mice, reaching levels detected in PA patient serum. Metabolomic analyses confirmed a metabolic signature of PA, but male mice had enhanced propionate processing towards -alanine. Female PA hearts had expanded end-diastolic and end-systolic volumes, and weaker systolic contractions, without major electrocardiographic changes. Ca2+ signals were deranged in female PA mice (raised diastolic Ca2+), consistent with contractile dysfunction. Differentially-expressed genes (DEGs) included Pde9a and Mme, previously linked to cardiac dysfunction. These DEGs also responded to 48-h culture of wild-type myocytes with propionate as well as butyrate, an HDAC inhibitor, suggesting a role for increased histone acetylation alongside propionylation in inducing these genes. Indeed, histone acetylation (H3K27ac) and propionylation were elevated genome-wide in the PA heart and at the promoters of Pde9a and Mme. These propionate-associated epigenetic responses were more pronounced in female PA mice. The greater prominence of epigenetic, transcriptional, and functional responses in female PA mice, despite a mostly sex-indiscriminate overall metabolic milieu, argues that histone acylation plays a defining role in the cardiac phenotype. We conclude that perturbed propionate metabolism in vivo alters histone acylation and gene expression, which impacts cardiac contractile function.

Dataset Information

Proteogenomics reveals two distinct biological pilocytic astrocytoma subgroups

Publications

Integrative multi-omics reveals two biologically distinct groups of pilocytic astrocytoma.

Similar Datasets

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