Genetic analysis of glioblastoma multiforme provides evidence for subgroups within the grade

Mohapatra, Gayatry; Bollen, Andrew W.; Lamborn, Kathleen R.; Moore, Dan H.; Prados, Michael D.; Feuerstein, Burt G.

doi:10.1002/(sici)1098-2264(199803)21:3<195::aid-gcc3>3.0.co;2-v

Cited by 76 publications

(38 citation statements)

References 47 publications

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“…Table 3 combines the results of Table 2 and Figure 6 and summarizes the molecular aberrations in the four GBM transcriptional subtypes and G-CIMP positive tumors. GBM is typically characterized by chromosome 7 amplification, chromosome 10 deletion and NF1 loss-of-function mutations (9), (8,10,11). All these molecular aberrations become effectors of association modules.…”

Section: Discussionmentioning

confidence: 99%

An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

Sintupisut

Yeang

2013

Nucleic Acids Research

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Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between ‘effector’ molecular aberrations and ‘target’ gene expressions in GBMs. A rich collection of prior studies attempted to combine copy number variation (CNV) and mRNA expression data. However, systematic methods to integrate multiple types of cancer genomic data—gene mutations, single nucleotide polymorphisms, CNVs, DNA methylations, mRNA and microRNA expressions and clinical information—are relatively scarce. We proposed an algorithm to build ‘association modules’ linking effector molecular aberrations and target gene expressions and applied the module-finding algorithm to the integrated TCGA GBM data sets. The inferred association modules were validated by six tests using external information and datasets of central nervous system tumors: (i) indication of prognostic effects among patients; (ii) coherence of target gene expressions; (iii) retention of effector–target associations in external data sets; (iv) recurrence of effector molecular aberrations in GBM; (v) functional enrichment of target genes; and (vi) co-citations between effectors and targets. Modules associated with well-known molecular aberrations of GBM—such as chromosome 7 amplifications, chromosome 10 deletions, EGFR and NF1 mutations—passed the majority of the validation tests. Furthermore, several modules associated with less well-reported molecular aberrations—such as chromosome 11 CNVs, CD40, PLXNB1 and GSTM1 methylations, and mir-21 expressions—were also validated by external information. In particular, modules constituting trans-acting effects with chromosome 11 CNVs and cis-acting effects with chromosome 10 CNVs manifested strong negative and positive associations with survival times in brain tumors. By aligning the information of association modules with the established GBM subclasses based on transcription or methylation levels, we found each subclass possessed multiple concurrent molecular aberrations. Furthermore, the joint molecular characteristics derived from 16 association modules had prognostic power not explained away by the strong biomarker of CpG island methylator phenotypes. Functional and survival analyses indicated that immune/inflammatory responses and epithelial-mesenchymal transitions were among the most important determining processes of prognosis. Finally, we demonstrated that certain molecular aberrations uniquely recurred in GBM but were relatively rare in non-GBM glioma cells. These results justify the utility of an integrative analysis on cancer genomes and provide testable characterizations of driver aberration events in GBM.

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Section: Discussionmentioning

confidence: 99%

An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

Sintupisut

Yeang

2013

Nucleic Acids Research

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“…Loss of chromosome 10 is highly frequent in GBM [27,123], and emerged as an important influence on global changes in the tumor gene expression, being reported as the most important copy number alteration for GBM classification and associated with a negative prognosis in GBM [27]. In addition, although codeletions of 1p/19q in oligodendrogliomas have been established as clinically relevant prognostic markers associated with increased patient survival time [140], these codeletions are uncommon in GBM, and the studies concerning their prognostic value in GBM have currently reported controversial findings [124,125].…”

Section: Other Putative Prognostic Factorsmentioning

confidence: 99%

Molecular prognostic factors in glioblastoma: state of the art and future challenges

Nandhabalan¹,

Jones²,

Costa³

2013

CNS Oncol.

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Gliomas account for the majority of primary tumors of the CNS, of which glioblastoma (GBM) is the most common and malignant, and for which survival is very poor. Despite significant inter- and intra-tumor heterogeneity, all patients are treated with a standardized therapeutic approach. While some clinical features of GBM patients have already been established as classic prognostic factors (e.g., patient age at diagnosis and Karnofsky performance status), one of the most important research fields in neuro-oncology today is the identification of novel molecular determinants of patient survival and tumor response to therapy. Here, we aim to review and discuss some of the most relevant and novel prognostic biomarkers in adult and pediatric GBM patients that may aid in stratifying subgroups of GBMs and rationalizing treatment decisions.

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“…The drug resistance gene, MDR1/Pglycoprotein, is located at 7q21.1 (Callen et al, 1987) and is overexpressed in drug-selected cell lines and patients with drug-refractory leukemia (Knutsen et al, 1998). 7q is known to be frequently deleted or amplified in multiple forms of cancer: hepatocellular carcinoma, myeloid malignancies, esophageal carcinoma, gastric carcinoma, glioblastoma multiforme, prostate cancer, and renal cell carcinoma (Jenkins et al, 1998;Mohapatra et al, 1998;Du Plessis et al, 1999;Tosi et al, 1999;Zimonjic et al, 1999;Chun et al, 2000;Yang et al, 2000). Gains of 8q and 8q22-qter were found in SCK, JCK, and Cho-CK.…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of chromosomal aberrations in human cholangiocarcinoma cell lines by cross-species color banding

Kim

Park

You

et al. 2000

Genes Chromosom. Cancer

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Genetic analysis of glioblastoma multiforme provides evidence for subgroups within the grade

Cited by 76 publications

References 47 publications

An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

Molecular prognostic factors in glioblastoma: state of the art and future challenges

Establishment and characterization of chromosomal aberrations in human cholangiocarcinoma cell lines by cross-species color banding

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