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Molecular subclasses of high-grade glioma: prognosis, disease progression, and neurogenesis

ABSTRACT: Novel 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. Keywords: Disease state comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE4271 | GEO | 2006/03/15

SECONDARY ACCESSION(S): PRJNA94953

REPOSITORIES: GEO

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Project description:BACKGROUND: Despite the moderate incidence of papillary renal cell carcinoma; (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphological classification of PRCC into Type 1 and Type 2 tumors has been recently proposed, but its biological relevance remains uncertain. PATIENTS AND METHODS. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analysis. Comparative genomic microarray analysis (CGMA) was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples, with 15 independent tumors. RESULTS. We identified 2 highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to 3 histological subtypes: Type 1, low-grade Type 2 and mixed Type 1/low-grade Type 2 tumors. The second class, with poor survival, corresponded to high-grade Type 2 tumors (n=11). Dysregulation of G1/S and G2/M checkpoint genes were found in Class 1 and Class 2 tumors respectively, alongside characteristic chromosomal aberrations. We identified a 7-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in Class 1 tumors, and of topoisomerase IIa in Class 2 tumors. CONCLUSIONS. We report 2 molecular subclasses of PRCC, which are biologically and clinically distinct, which may be readily distinguished in a clinical setting. Experiment Overall Design: 34 individual samples analyzed, no technical replicates. Based on histologic features and Fuhrman grading system, we designated four categories of tumors: type 1 (n = 14) characterized by small tumor cells of low Fuhrman grade (2); type 2A (n = 4) characterized by large eosinophilic tumor cells of low Fuhrman grade (2); combined type 1 and 2A (n = 5); and type 2B (n = 11) characterized by large eosinophilic tumor cells with Fuhrman grade.

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Molecular subclasses of high-grade glioma: prognosis, disease progression, and neurogenesis

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