Array comparative genomic hybridization identifies genetic subgroups in grade 4 human astrocytoma

Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, United States
Clinical Cancer Research (Impact Factor: 8.72). 05/2005; 11(8):2907-18. DOI: 10.1158/1078-0432.CCR-04-0708
Source: PubMed


Alterations of DNA copy number are believed to be important indicators of tumor progression in human astrocytoma. We used an array of bacterial artificial chromosomes to map relative DNA copy number in 50 primary glioblastoma multiforme tumors at approximately 1.4-Mb resolution. We identified 33 candidate sites for amplification and homozygous deletion in these tumors. We identified three major genetic subgroups within these glioblastoma multiforme tumors: tumors with chromosome 7 gain and chromosome 10 loss, tumors with only chromosome 10 loss in the absence of chromosome 7 gain, and tumors without copy number change in chromosomes 7 or 10. The significance of these genetic groups to therapeutics needs further study.

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    • "The GISTIC algorithm [27] was applied to the 456 TCGA samples with copy number information and results visualized using the Integrated Genomic Viewer (IGV) [28] to find copy number alterations (CNA) in the validation set. Broad copy number alterations in the discovery dataset were found as described previously [29] using a customized version of the Sanger CNV database []. For experiments that compare broad CNA in the discovery and validation dataset we identified broad copy number alterations in the validation dataset as follows. "
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    ABSTRACT: Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU (median survival 5.8 vs. 1.5 years; BCNU/CCNU vs other treatments; respectively). AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets.
    PLoS ONE 07/2014; 9(7):e100827. DOI:10.1371/journal.pone.0100827 · 3.23 Impact Factor
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    • "Large-scale genomic aberration and gene expression studies on gliomas have lead to identifications of genes, which are involved in numerous cellular functions and metabolic pathways (PCDH9, CXCL12, MYC, PDGFRA, PARK2, DMBT1, TOP2A, PTEN, ARF, TP53, P16, CDKN2B, RB1, EGFR, and NF1 [9], [10], [11], [12], [13], [14], [15], [16], [17]), as well as those related to neural development, cell signaling (RAS/RAF, RTK, MAPK, PI3K, and ROCK), and tumor suppression (p53 and RB) [1], [6], [11], [16], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. These genes serve as biomarkers useful for tumor classification, prognosis, and targeted therapies [17], [23], [29], [30], [31], [32], [33], [34]. "
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    ABSTRACT: Glioma is a type of tumor that develops in the central nerve system, mainly the brain. Alterations of genomic sequence and sequence segments (such as copy number variations or CNV and copy neutral loss of heterozygosities or cnLOH) are thought to be a major determinant of the tumor grade. We mapped genomic variations between low-grade and high-grade gliomas (LGG and HGG) in Chinese population based on Illumina's Beadchip and validated the results using real-time qPCR. AT THE CYTOBAND LEVEL, WE DISCOVERED: (1) unique losses in LGG on 5q, 8p and 11q, and in HGG on 6q, 11p, 13q and 19q; (2) unique gains in the LGG on 1p and in HGG at 5p, 7p, 7q and 20q; and (3) cnLOH in HGG only on 3q, 8q, 10p, 14q, 15q, 17p, 17q, 18q and 21q. Subsequently, we confirmed well-characterized oncogenes among tumor-related loci (such as and ) and detected novel genes that gained chromosome sequences (such as , , and ) in both LGG and HGG. In addition, we found gains, losses, and cnLOH in several genes, including , , and , in multiple samples. Mapping grade-associated pathways and their related gene ontology (GO) terms, we classified LGG-associated functions as ", " and " and the HGG-associated as ", " and ". LGG and HGG appear to have different molecular signatures in genomic variations and our results provide invaluable information for the diagnosis and treatment of gliomas in patients with variable duration or diverse tumor differentiation.
    PLoS ONE 02/2013; 8(2):e57168. DOI:10.1371/journal.pone.0057168 · 3.23 Impact Factor
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    • "Some alterations in astrocytomas can indicate an increased risk of dying, independently of its histological grade, such as the presence of +7q and -10q chromosomal alterations detected by the CGH analysis of astrocytomas [46]. Misra and coworkers [47] identified three groups in GBM patients: those with both 7 gain and 10 loss, some with 10 loss without gain of 7 and the group without these two alterations. In clinical evaluation, the patients with 7 gain and 10 loss showed typical characteristic of GBM short-term survivors. "
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    ABSTRACT: Cytogenetics is the branch of genetics that studies the cell activity focusing mainly on the chromosome structure, organization and function, isolated or as the whole karyotype, in order to understand aspects of cell biology, evolution or implicated diseases. The behavior of DNA and genes is greatly constrained by the fact that they are incorporated into chromosomes. The DNA is associated with proteins that control and catalyze the processes of transcription and replication. Gene expression is controlled by modifications in histones and by chromatin remodeling complexes. It can also be influenced by the position of the gene in the chromosome. Hence, errors in chromosome behavior are an important cause of ill-health. The presence of chromosomal abnormalities is usual in cancer, and specific chromosome abnormality may often be one of the first events in the development of cancer. The importance of cytogenetic analysis in oncology is demonstrated by the number of researches made on this area since the discovery of the Philadelphia chromosome, a 9/22 translocation, which is seen in chronic myelogenous leukemia (CML) patients. The focus of these studies is the relation between specific chromosome alterations to prognosis, drug resistance and diagnosis for some tumors entities. Moreover, DNA repair problems and others genomic stability pathways defects may lead to genome-wide genetic instability, which can drive further cancer progression. Although chromosome rearrangements are mainly used as markers in hematologic cancers, these alterations have been increasingly studied in solid tumors (90% of all human malignancies), showing that chromosomal numerical/structural aberrations are common in this kind of neoplasia.
    Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors, 1 edited by Terry Lichtor, 01/2013: chapter 17: pages 357-388; InTech., ISBN: 978-953-51-1058-3
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