Pilocytic astrocytomas (PAs) are the most common glioma in children. While many PAs are slow growing or clinically indolent, others exhibit more aggressive features with tumor recurrence and death. In order to identify genetic signatures that might predict PA clinical behavior, we performed gene expression profiling on 41 primary PAs arising sporadically and in patients with neurofibromatosis type 1 (NF1). While no expression signature was found that could discriminate clinically-aggressive or recurrent tumors from more indolent cases, PAs arising in patients with NF1 did exhibit a unique gene expression pattern. In addition, we identified a gene expression signature that stratified PAs by location (supratentorial versus infratentorial).
Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin.
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View SamplesAffymetrix Mouse Genome 430 2.0 GeneChip microarrays were used to analyze murine neocortical and cerbellar astrocytes generated from postnatal (PN) day 1 wild-type (ICR) pups.
Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin.
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View SamplesNovel prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit either markers of proliferation or of angiogenesis and mesenchyme. Analysis of gene expression data is described in Phillips et al., Cancer Cell, 2006.
Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.
Sex, Age, Disease stage
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The transcriptional network for mesenchymal transformation of brain tumours.
Time
View SamplesUsing a novel combination of cellular-network reverse-engineering algorithms and experimental validation assays, we identified a transcriptional module, including six transcription factors that synergistically regulates the mesenchymal signature of malignant glioma. This is a poorly understood molecular phenotype, never observed in normal neural tissue. It represents the hallmark of tumor aggressiveness in high-grade glioma, and its upstream regulation is so far unknown. Overall, the newly discovered transcriptional module regulates >74% of the signature genes, while two of its transcription factors (C/EBP and Stat3) display features of initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBP and Stat3 is sufficient to reprogram neural stem cells along the aberrant mesenchymal lineage, while simultaneously suppressing differentiation along the default neural lineages (neuronal and glial). Conversely, silencing the two transcription factors in human glioma cell lines and glioblastoma-derived tumor initiating cells leads to collapse of the mesenchymal signature with corresponding loss of tumor aggressiveness in vitro and in immunodeficient mice after intracranial injection. In human tumor samples, combined expression of C/EBP and Stat3 correlates with mesenchymal differentiation of primary glioma and is a predictor of poor clinical outcome. Taken together, these results reveal that activation of a small regulatory module inferred from the accurate reconstruction of transcriptional networks is necessary and sufficient to initiate and maintain an aberrant phenotypic state in eukaryotic cells.
The transcriptional network for mesenchymal transformation of brain tumours.
Time
View SamplesUsing a novel combination of cellular-network reverse-engineering algorithms and experimental validation assays, we identified a transcriptional module, including six transcription factors that synergistically regulates the mesenchymal signature of malignant glioma. This is a poorly understood molecular phenotype, never observed in normal neural tissue. It represents the hallmark of tumor aggressiveness in high-grade glioma, and its upstream regulation is so far unknown. Overall, the newly discovered transcriptional module regulates >74% of the signature genes, while two of its transcription factors (C/EBP and Stat3) display features of initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBP and Stat3 is sufficient to reprogram neural stem cells along the aberrant mesenchymal lineage, while simultaneously suppressing differentiation along the default neural lineages (neuronal and glial). Conversely, silencing the two transcription factors in human glioma cell lines and glioblastoma-derived tumor initiating cells leads to collapse of the mesenchymal signature with corresponding loss of tumor aggressiveness in vitro and in immunodeficient mice after intracranial injection. In human tumor samples, combined expression of C/EBP and Stat3 correlates with mesenchymal differentiation of primary glioma and is a predictor of poor clinical outcome. Taken together, these results reveal that activation of a small regulatory module, inferred from the accurate reconstruction of transcriptional networks, is necessary and sufficient to initiate and maintain an aberrant phenotypic state in eukaryotic cells.
The transcriptional network for mesenchymal transformation of brain tumours.
No sample metadata fields
View SamplesThe biphasic epithelioid (E-) and sarcomatoid(S-) components of sarcomatoid RCC and epithelioid (E-) and rhabdoid (R-) components of rhabdoid RCC shared a similar transcriptomic signature, despite morphologic differences; by contrast, the transcriptome of sarcomatoid and rhabdoid RCC was sharply distinct from non-sarcomatoid RCC. Overall design: Total RNA was processed for RNA-seq from the following patient samples: 7 sarcomatoid RCC (E- and S- pairs), 4 rhabdoid RCC (E- and R- pairs) and 15 non-sarcomatoid RCC.
Biphasic components of sarcomatoid clear cell renal cell carcinomas are molecularly similar to each other, but distinct from, non-sarcomatoid renal carcinomas.
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Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target.
Sex, Specimen part, Subject
View SamplesAn improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and protein expression and activation, quantitatively analyzed by molecular inversion probe arrays, microarrays and reverse phase protein array (RPPA) were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors.
Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target.
Specimen part, Subject
View SamplesTo identify the role of the SH3PXD2A-HTRA1 fusion on gene expression in Schwann cells
The genomic landscape of schwannoma.
Specimen part
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