Genome-Scale Profiling of DNA Methylation in Sporadic Pituitary Macroadenomas: Association with Tumor Invasion and Histopathological Subtype
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE54415 | GEO | 2014/01/28
SECONDARY ACCESSION(S): PRJNA236458
REPOSITORIES: GEO
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Project description:The pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic pituitary macroadenomas (PAs) remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation patterns and RNA sequencing.
2014-01-28 | E-GEOD-54415 | biostudies-arrayexpress
Project description:Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germline AIP mutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigate the role of miRNA dysregulation in AIPmut+ versus AIPmut- PA samples by array analysis. miR-34a and miR-145 were found highly expressed in AIPmut+ vs AIPmut-somatotropinomas. Ectopic expression of AIPmut (p.R271W) in Aip-/- mouse embryonic fibroblasts upregulated miR-34a and miR-145, establishing a causal link between AIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and anti-proliferative effects. miR-34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIPmut+ versus AIPmut- PA. Taken together, somatotropinomas with AIP mutations overexpress miR-34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut+ acromegaly.
2020-08-18 | GSE140604 | GEO
Project description:Pilocytic astrocytomas (PA) are the most common brain tumor in pediatric patients and can cause significant morbidity, including chronic neurological deficiencies. They are characterized by activating alterations in the mitogen-activated protein kinase (MAPK) pathway, but little else is known about their development. To further define their molecular development, we analysed the global DNA methylation profiles of 61 PAs and 6 normal cerebellum samples and integrated this data with transcriptome profiling. These data revealed two subgroups of PA that separate according to tumor location (infratentorial versus supratentorial), and identified key neural developmental genes that are differentially methylated between the two groups. Significant expression differences were identified for the majority of differentially methylated genes, and these were unexpectedly associated with a strong positive correlation between methylation and expression. We also identified a large number of differentially methylated/expressed genes between cerebellar PAs and normal cerebellum, which included additional developmental genes. Total RNA from 49 PA tumour samples and 9 normal cerebellum samples (from commercial sources) were hybridised to the Affymetrix HG U133 Plus 2.0 microarrays.
2013-06-12 | E-GEOD-44971 | biostudies-arrayexpress
Project description:Pilocytic astrocytoma (PA) is a low-grade neoplasm frequently found in childhood. PA is characterized by slow growth and a relatively good prognosis. Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development. Epigenetic signature and miRNA expression profile are providing new insights about different types of tumor, including PAs. In the present study we evaluated global miRNA expression in 16 microdissected pediatric PA specimens, three NF1-associated PAs and 11 cerebral white matter (WM) samples by the microarray method. An additional cohort of 20 PAs was used to validate by qRT-PCR the expression of six miRNAs differentially expressed in the microarray data. Unsupervised hierarchical clustering analysis distinguished one cluster with nine PAs, including all NF1 cases and a second group consisting of the WM samples and seven PAs. Among 88 differentially expressed miRNAs between PAs and WM samples, the most underexpressed ones regulate classical pathways of tumorigenesis, while the most overexpressed miRNAs are related to pathways such as focal adhesion, P53 signaling pathway and gliomagenesis. The PAs/NF1 presented a subset of underexpressed miRNAs, which was also associated with known deregulated pathways in cancer such as cell cycle and hippo pathway. In summary, our data demonstrate that PA harbors at least two distinct miRNA signatures, including a subgroup of patients with NF1/PA lesions.
2019-08-01 | GSE135189 | GEO
Project description:Phenolic acids (PAs) secreted by donor plants suppress the growth of their susceptible plant neighbours. However, how structurally diverse ensembles of PAs are perceived by plants to mediate interspecific competition remains a mystery. Here, we show that a plant stress granule (SG) marker, RNA-BINDING PROTEIN 47B (RBP47B), is a sensor of PAs in Arabidopsis. PAs including salicylic acid (SA), 4-hydroxybenzoic acid, protocatechuic acid, etc. directly bind RBP47B, promote its phase separation and trigger SG formation accompanied by global translation inhibition. SA-induced global translation inhibition depends on RBP47 family members. RBP47s regulate the proteome rather than the absolute quantity of SG. The rbp47 quadruple mutant shows a reduced sensitivity to the inhibitory effect of the PA mixture as well as to that of PA-rich rice when tested in a co-culturing ecosystem. Our study discovers RBP47B as the long sought-after PA sensor and unveils PA-induced SG formation and translation inhibition as one of the PA perception mechanisms.
2023-08-29 | PXD043123 | Pride
Project description:Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, but the mechanisms involved in its pathogenesis remain incompletely understood. Here we present a single-cell transcriptomic atlas detailing the cellular differences between human PA and normal parathyroid gland (PG) tissues and delineating the transcriptome of individual cell types. We show that there is a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells (PGCs), with transcriptional upregulation of cyclin D2 driven by the transcriptional coactivator, histone-lysine N-methyltransferase 2A (KMT2A) through the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3) potentially involved in promoting PAC proliferation. Moreover, we demonstrate that PA tissues are heavily infiltrated with myeloid cells, and that fibroblasts, endothelial cells (ECs), as well as macrophages in the PA microenvironment are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. Collectively, these results provide new insights into the etiology of PA, where the pathogenesis likely involves the net contribution of the dysregulated KMT2A-STAT3/GATA3-cyclin D2 axis in PACs and the chronic inflammation of the microenvironment. These findings provide practical implications for the treatment of PA through KMT2A targeting and anti-inflammation therapies.
2024-05-01 | GSE190773 | GEO
Project description:Pilocytic astrocytomas (PA) are the most common brain tumor in pediatric patients and can cause significant morbidity, including chronic neurological deficiencies. They are characterized by activating alterations in the mitogen-activated protein kinase (MAPK) pathway, but little else is known about their development. To map the global DNA methylation profiles of these tumors, we analysed 61 PAs and 6 normal cerebellum samples using Illumina's Infinium HumanMethylation450 BeadChips. These data revealed two subgroups of PA that separate according to tumor location (infratentorial versus supratentorial), and identified key neural developmental genes that are differentially methylated between the two groups. Integration with transcriptome microarray data highlighted significant expression differences, which were unexpectedly associated with a strong positive correlation between methylation and expression. Differentially methylated probes were often identified within the gene body and/or regions up- or downstream of the gene, rather than at the transcription start site. We also identified a large number of differentially methylated genes between cerebellar PAs and normal cerebellum, which included additional developmental genes. Bisulphite converted DNA from 61 PA tumours (fresh frozen) and 6 normal cerebellum (from commerical sources) were hybridised to the Illumina Infinium HumanMethylation450 BeadChips.
2013-06-12 | E-GEOD-44684 | biostudies-arrayexpress
Project description:Alternative cleavage and polyadenylation (APA) generates diverse mRNA isoforms. We developed 3' region extraction and deep sequencing (3'READS) to address mispriming issues that commonly plague poly(A) site (pA) identification, and we used the method to comprehensively map pAs in the mouse genome. Thorough annotation of gene 3' ends revealed over 5,000 previously overlooked pAs (~8% of total) flanked by A-rich sequences, underscoring the necessity of using an accurate tool for pA mapping. About 79% of mRNA genes and 66% of long noncoding RNA genes undergo APA, but these two gene types have distinct usage patterns for pAs in introns and upstream exons. Quantitative analysis of APA isoforms by 3'READS indicated that promoter-distal pAs, regardless of intron or exon locations, become more abundant during embryonic development and cell differentiation and that upregulated isoforms have stronger pAs, suggesting global modulation of the 3' endM-bM-^@M-^Sprocessing activity in development and differentiation. 3'READS to map pAs in mouse genome
2012-12-17 | E-GEOD-42398 | biostudies-arrayexpress
Project description:Pilocytic astrocytomas (PA) are the most common brain tumor in pediatric patients and can cause significant morbidity, including chronic neurological deficiencies. They are characterized by activating alterations in the mitogen-activated protein kinase (MAPK) pathway, but little else is known about their development. To further define their molecular development, we analysed the global DNA methylation profiles of 61 PAs and 6 normal cerebellum samples and integrated this data with transcriptome profiling. These data revealed two subgroups of PA that separate according to tumor location (infratentorial versus supratentorial), and identified key neural developmental genes that are differentially methylated between the two groups. Significant expression differences were identified for the majority of differentially methylated genes, and these were unexpectedly associated with a strong positive correlation between methylation and expression. We also identified a large number of differentially methylated/expressed genes between cerebellar PAs and normal cerebellum, which included additional developmental genes.
2013-06-12 | GSE44971 | GEO