Comprehensive genomic characterization defines human glioblastoma genes and core pathways

The Cancer Genome Atlas Research Network

doi:10.1038/nature07385

Cited by 7,735Glioma Diagnosis and TreatmentCancer Genomics and DiagnosticsChromatin Remodeling and Cancer

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Open access

The Cancer Genome Atlas Research Network·2008·Nature

DOI 10.1038/nature07385PMC PMC2671642

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Abstract

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

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In the TCGA database, patients enriched in sensitive-related genes had significantly better overall survival than patients enriched with resistant-related genes (p = 0.0016), with median overall survival of 16.2 and 7.5 months, respectively.
“patients in the TCGA database enriched in sensitive-related genes had significantly better OS than patients enriched with resistant-related genes (p = 0.0016), with median OS of 16.2 and 7.5 months, respectively (Figure 6E).”
From Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy (2025) · cites this paper as [36]
The Results (Biospecimen collection; page not available) describe the TCGA glioblastoma cohort and discuss its overall survival, supporting the identification of TCGA as the data source. Our copy does not report a survival comparison between sensitive- and resistant-related gene groups, the p = 0.0016 result, or the 16.2- and 7.5-month medians. (LLM, conf=0.85)
Experimental — accuracy not yet measured
PI3K signaling is hyperactivated in nearly 90% of GBMs, commonly as a consequence of EGFR amplification and activating mutation (EGFRvIII), and loss of the PTEN tumor suppressor protein.
“PI3K signaling is hyperactivated in nearly 90% of GBMs, commonly as a consequence of EGFR amplification and activating mutation (EGFRvIII), and loss of the PTEN tumor suppressor protein, a negative regulator of PI3K signaling (6–8).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [6]
The Results section reports that 86% of GBM samples had a genetic event in the RTK/PI3K pathway, and documents EGFR amplification, EGFRvIII, and PTEN deletions or mutations (page not provided). That supports the approximate prevalence and the named genetic alterations, but the paper does not establish that PI3K signaling was measured as hyperactivated in nearly 90% of tumors or that PTEN protein was lost in those cases. (LLM, conf=0.88)
Experimental — accuracy not yet measured
PI3K signaling is hyperactivated as a consequence of RTK amplifications and activating mutations, PTEN loss, PI3K point mutations and other genetic lesions, providing a core oncogenic pathway in many cancers, including up to 90% of GBMs.
“PI3K signaling is hyperactivated as a consequence of RTK amplifications and activating mutations, PTEN loss, PI3K point mutations and other genetic lesions, providing a core oncogenic pathway in many cancers, including up to 90% of GBMs (6, 8, 55).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [6]
The Results (Integrative analyses define core pathways required for GBM pathogenesis; page unavailable) report that 86% of sampled GBMs had a genetic event in the combined RTK/PI3K pathway, including RTK aberrations and PTEN lesions. The Discussion also describes RTK/RAS/PI3K deregulation as common in GBM. Those passages support a core pathway and an approximate ‘up to 90%’ figure for pathway alterations, but they do not establish that PI3K signaling itself was hyperactivated in that proportion of GBMs or establish the broader prevalence claim across many cancers. (LLM, conf=0.86)
Experimental — accuracy not yet measured
EGFR amplification and EGFRvIII activating mutation are the most common oncogenes promoting PI3K signaling in GBM.
“EGFR amplification, and EGFRvIII activating mutation are the most common oncogenes promoting PI3K signaling in GBM (1, 6).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [6]
The Results section on EGFR family activation (page unavailable) reports frequent EGFR activation in primary GBM, focal EGFR amplification, and EGFR alterations in 41 of 91 sequenced cases; it calls vIII the most commonly described EGFR event. The core-pathways Results section places EGFR in the RTK/PI3K pathway, but the paper does not establish that EGFR amplification and EGFRvIII are together the most common oncogenic drivers of PI3K signaling, or give a separate frequency for vIII. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Other PI3K pathway activating lesions commonly found in GBM, such as activation of other RTKs, could also promote increased LDLR expression.
“Therefore, other PI3K pathway activating lesions commonly found in GBM, such as the activation of other RTKs (6, 12, 39), could also promote increased LDLR expression.”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [6]

Patients who did not exhibit enrichment of either the sensitive or resistant signature had an intermediate overall survival, with a median overall survival of 13.5 months.
“Patients who did not exhibit enrichment of either the sensitive or resistant signature had an intermediate OS, with a median OS of 13.5 months.”
From Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy (2025) · cites this paper as [36]
The Results section on biospecimen collection says only that overall survival in the TCGA cohort was similar to published cohorts; it does not report survival by sensitive or resistant signature. Searches for signature enrichment and a median of 13.5 months found no passage supporting the claimed intermediate-survival group. (LLM, conf=0.76)
Experimental — accuracy not yet measured
During DNA damage, MDM2 moves to the nucleus and regulates DNA repair independently of p53 by binding and inactivating Nbs1 within the MRE11/Rad50/NBS1 complex.
“Moreover, in the context of DNA damage, MDM2 localizes to the nucleus and modulates DNA repair in a p53-independent manner by binding to and inactivating Nbs1 in the MRE11/Rad50/NBS1 complex.1,8,27”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [8]
MDM2 and MDMX are deregulated in many human cancers and act oncogenically mainly by inhibiting p53.
“The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [5]
Amplification of MDM genes or altered expression of MDM proteins is a feature of many tumours.
“Amplification of MDM genes or altered expression of MDM proteins is a feature of many tumours3–10 (Table 1).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [5]
A number of recent papers have used pathway analysis workflow to highlight genes and pathways active in specific model organisms or diseased tissues.
“A number of recent papers have used this pathway analysis workflow to highlight genes and pathways that are active in specific model organisms or diseased tissues, such as breast cancer, using gene and protein expression, copy number variants (CNVs) and SNPs19,44-49.”
From The BioPAX community standard for pathway data sharing (2010) · cites this paper as [47]
Multiple groups found tumor associated mutations are significantly related by pathway information.
“Multiple groups have found that tumor associated mutations are significantly related by pathway information47,48.”
From The BioPAX community standard for pathway data sharing (2010) · cites this paper as [47]

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Authors: The Cancer Genome Atlas Research Network
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2008-09-04
Volume: 455
Issue: 7216
Pages: 1061-1068
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature07385
PMC: PMC2671642
OpenAlex: W2025183726
Cited by: 7,735
References: 50
Citations by year: 2026: 225 · 2025: 261 · 2024: 320 · 2023: 392 · 2022: 411 · 2021: 494 · 2020: 436 · 2019: 413 · 2018: 450 · 2017: 484 · 2016: 469 · 2015: 512 · 2014: 592 · 2013: 566 · 2012: 564
FWCI: 174.57
Type: journal article
Language: en
Update notices: erratum (2013-02-06)
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Ghent University Academic Bibliography (Ghent University) (submittedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders: National Institutes of Health (7k08ns045077-06)
National Human Genome Research Institute (U54HG003067, U54HG003079, U54HG003273)
National Cancer Institute (U24CA126554, U24CA126546, U24CA126543, U24CA126563, R01CA099041, U24CA126544, U24CA143848, U24CA126551, U24CA126561)
National Institute of General Medical Sciences (T32GM007753)
National Institute of Neurological Disorders and Stroke (K08-NS045077)
Topics: Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords: glioblastoma, TCGA, DNA copy number alterations, DNA methylation, gene expression profiling, somatic mutations, PIK3R1, ERBB2, neurofibromatosis type 1, TP53, MGMT promoter methylation, mismatch repair deficiency, hypermutator phenotype, tumor suppressor, c-Myc, brain cancer, integrative genomics
MeSH terms: Adolescent, Adult, Aged, Aged, 80 and over, Brain Neoplasms, DNA Repair, Female, Glioblastoma, Humans, Male, Middle Aged, Models, Molecular, Mutation, Retrospective Studies, DNA Modification Methylases, Signal Transduction, Genome, Human, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Protein Structure, Tertiary, Gene Dosage, Genes, erbB-1, DNA Methylation, Phosphatidylinositol 3-Kinases, Genomics, Tumor Suppressor Proteins, Neurofibromin 1, DNA Repair Enzymes

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Comprehensive genomic characterization defines human glioblastoma genes and core pathways

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