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      Comprehensive genomic characterization defines human glioblastoma genes and core pathways

      The Cancer Genome Atlas (TCGA) Research Network

      Nature

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          Abstract

          Human cancer cells typically harbor 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 multidimensional 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 (GBM), the most common type of adult brain cancer, and nucleotide sequence aberrations in 91 of the 206 GBMs. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the PI3 kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of GBM. 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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          Most cited references 56

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          MGMT gene silencing and benefit from temozolomide in glioblastoma.

          Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit. Copyright 2005 Massachusetts Medical Society.
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            Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.

            Previously undescribed 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 markers either of proliferation or of angiogenesis and mesenchyme. Upon recurrence, tumors frequently shift toward the mesenchymal subclass. Chromosomal locations of genes distinguishing tumor subclass parallel DNA copy number differences between subclasses. Functional relevance of tumor subtype molecular signatures is suggested by the ability of cell line signatures to predict neurosphere growth. A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.
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              • Record: found
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              • Article: found

              High frequency of mutations of the PIK3CA gene in human cancers.

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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                30 September 2008
                4 September 2008
                23 October 2008
                23 April 2009
                : 455
                : 7216
                : 1061-1068
                nihpa68048
                10.1038/nature07385
                2671642
                18772890
                Funding
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U54 HG003273-01 ||HG
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U54 HG003079-05 ||HG
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U54 HG003067-01 ||HG
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA126563-01 ||CA
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA126561-01 ||CA
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA126554-01 ||CA
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA126551-01 ||CA
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA126546-01 ||CA
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA126544-01 ||CA
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: U24 CA126543-01 ||CA
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA099041-05 ||CA
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