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Establishment and Molecular Characterization of Glioblastoma Primary Cultures

ABSTRACT: Glioblastoma, the most frequent and malignant adult brain tumor has been extensively studied; yet no effective treatment exists. To overcome this dismal scenario, it is essential to improve preclinical biological models. This study aimed to establish and molecularly characterize glioblastoma primary cultures. Additionally, it intended to assess the efficacy of molecular-targeted therapies, in the presence of putative targeting cell lines. Five glioblastoma primary cultures were established exhibiting a diversity of chromosomal alterations by aCGH, with gain of chromosome 7 and loss of chromosome 10, 13 and 17p, the most frequent alterations. Mutation profiling by Ion Torrent and Sanger sequencing showed the present of hotspot mutations in TERT (4/5), TP53 (2/5) and RB, BRAF, PTEN and EGFR (1/5). A similar chromosomal and mutation pattern was observed in the primary cultures and matched frozen tumors. The MTS cell viability assay of the p.Gly598Val EGFR mutated cell line, revealed AST1306 as the most potent EGFR inhibitor, when compared with afatinib, erlotinib, or lapatinib. Herein, glioblastoma primary cultures were successfully established and molecularly characterized. Importantly, we showed that AST1306 inhibits EGFR mutated cells, suggesting that primary cultures are suitable in vitro models for glioblastoma biology and preclinical drugs studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE59967 | GEO | 2016/07/01

SECONDARY ACCESSION(S): PRJNA257196

REPOSITORIES: GEO

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Establishment and Molecular Characterization of Glioblastoma Primary Cultures

Project description:Glioblastoma, the most frequent and malignant adult brain tumor has been extensively studied; yet no effective treatment exists. To overcome this dismal scenario, it is essential to improve preclinical biological models. This study aimed to establish and molecularly characterize glioblastoma primary cultures. Additionally, it intended to assess the efficacy of molecular-targeted therapies, in the presence of putative targeting cell lines. Five glioblastoma primary cultures were established exhibiting a diversity of chromosomal alterations by aCGH, with gain of chromosome 7 and loss of chromosome 10, 13 and 17p, the most frequent alterations. Mutation profiling by Ion Torrent and Sanger sequencing showed the present of hotspot mutations in TERT (4/5), TP53 (2/5) and RB, BRAF, PTEN and EGFR (1/5). A similar chromosomal and mutation pattern was observed in the primary cultures and matched frozen tumors. The MTS cell viability assay of the p.Gly598Val EGFR mutated cell line, revealed AST1306 as the most potent EGFR inhibitor, when compared with afatinib, erlotinib, or lapatinib. Herein, glioblastoma primary cultures were successfully established and molecularly characterized. Importantly, we showed that AST1306 inhibits EGFR mutated cells, suggesting that primary cultures are suitable in vitro models for glioblastoma biology and preclinical drugs studies. Two-color Agilent 8x60K array CGH (aCGH) was performed in 10 glioblastoma multiforme samples (CY3) and reference DNA (CY5). The 10 glioblastoma multiforme samples were: DNA extracted from 5 primary cultured cells; DNA of 5 primary tumors (matched with the 5 primary cell lines). Gender-matched commercial DNA of each case was used as control.

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Project description:The EGF-receptor (EGFR) is amplified and mutated in glioblastoma (GBM) where its common mutation, (∆EGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ∆EGFR might exert its influence through pleiotropic effectors and we hypothesized that microRNAs (miRs) might serve such a function. To test this, we determined the miR profiles of GBM cells with activated wild type EGFR (wtEGFR) and mutant EGFR (∆EGFR) to cells with non-activated EGFR or kinase dead ∆EGFR. To identify miRs regulated by EGFR, RNA from 2 different glioma cell lines (U87 and U373) were hybridized to miR expression arrays and analyzed. Each cell type was engineered to express wild type EGFR (wtEGFR), dead kinase ∆EGFR (DK) or ∆EGFR at elevated levels similar to those observed in primary glioblastomas displaying EGFR overexpression. Parental cells expressing endogenous EGFR and wtEGFR cells stimulated with EGF for 1hr were also included in the analyses.

2013-12-20 | E-GEOD-53504 | biostudies-arrayexpress

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Project description:Glioblastoma (GBM) is the most frequent and most aggressive form of diffuse glioma. The prognosis is very poor, with a median overall survival of 15 months after maximum safe resection and radiochemotherapy.GBM is one of the most genetically unstable cancers. It is characterized by numerous chromosome (chr) copy number alterations (CNA), such as chr 7 gain, chr 9p loss, and chr 10 loss, along with CDKN2A homozygous deletion (chr 9p21) and EGFR amplification (chr 7p11).Chromosome instability (CIN) may be the cause or the consequence of GBM development. In high-grade diffuse gliomas (HGG), CIN may initiate tumorigenesis. To identify recurrent genomic abnormalities in IDH WT glioblastomas, SNP arrays (Illumina 850K CytoSNP) were analyzed for 123 IDH WT GBM cases.

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Project description:AML with mutated NPM1 usually carries normal karyotype (NK) but it may harbor chromosomal aberrations whose significance remains unclear. We addressed this question in 631 AML patients with mutated/cytoplasmic NPM1. An abnormal karyotype (AK) was present in 93/631 cases (14.7%), the most frequent abnormalities being +8, +4, -Y, del(9q), +21. Chromosome aberrations in NPM1-mutated AML were similar to, but occurred less frequently than additional chromosome changes found in other AML with recurrent cytogenetic abnormalities according to WHO classification. Four of the 31 NPM1-mutated AML patients karyotyped at different time points had NK at diagnosis but AK at relapse: del(9q) (n=2), t(2;11) (n=1), inv(12) (n=1). NPM1-mutated AML with NK or AK showed overlapping morphological, immunophenotypic (CD34-negativity) and gene expression profile (downregulation of CD34 and upregulation of HOX genes). No difference in survival was observed among NPM1-mutated AML patients independently of whether they carried a normal or abnormal karyotype, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Findings in our patients point to chromosomal aberrations as secondary events, reinforce the concept that NPM1 mutation is a founder genetic lesion and indicate that NPM1-mutated AML should be clinically handled as one entity, irrespective of the karyotype. All bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.

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AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping features

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