Comprehensive genomic characterization defines human glioblastoma genes and core pathways.

TitleComprehensive genomic characterization defines human glioblastoma genes and core pathways.
Publication TypeJournal Article
Year of Publication2008
Corporate AuthorsCancer Genome Atlas Research Network
JournalNature
Volume455
Issue7216
Pagination1061-8
Date Published2008 Oct 23
ISSN1476-4687
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Brain Neoplasms, DNA Methylation, DNA Modification Methylases, DNA Repair, DNA Repair Enzymes, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, erbB-1, Genes, Tumor Suppressor, Genome, Human, Genomics, Glioblastoma, Humans, Male, Middle Aged, Models, Molecular, Mutation, Neurofibromin 1, Phosphatidylinositol 3-Kinases, Protein Structure, Tertiary, Retrospective Studies, Signal Transduction, Tumor Suppressor Proteins
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.

DOI10.1038/nature07385
Alternate JournalNature
PubMed ID18772890
PubMed Central IDPMC2671642
Grant ListU54 HG003067-01 / HG / NHGRI NIH HHS / United States
U24CA126561 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
R01 CA099041-05 / CA / NCI NIH HHS / United States
U24CA126551 / CA / NCI NIH HHS / United States
U24CA126543 / CA / NCI NIH HHS / United States
U24 CA126554-01 / CA / NCI NIH HHS / United States
U24CA126554 / CA / NCI NIH HHS / United States
R01 CA099041 / CA / NCI NIH HHS / United States
U24CA126544 / CA / NCI NIH HHS / United States
U24 CA126551 / CA / NCI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
U24 CA126544-01 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U24 CA126543-01 / CA / NCI NIH HHS / United States
U54HG003079 / HG / NHGRI NIH HHS / United States
U24 CA126554 / CA / NCI NIH HHS / United States
U24 CA126561 / CA / NCI NIH HHS / United States
U24 CA126546-01 / CA / NCI NIH HHS / United States
U24 CA143848 / CA / NCI NIH HHS / United States
U24 CA126543 / CA / NCI NIH HHS / United States
U24CA126563 / CA / NCI NIH HHS / United States
U54 HG003079-05 / HG / NHGRI NIH HHS / United States
U24CA126546 / CA / NCI NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
U54 HG003273-01 / HG / NHGRI NIH HHS / United States
U24 CA126551-01 / CA / NCI NIH HHS / United States
U24 CA126561-01 / CA / NCI NIH HHS / United States
U24 CA126563-01 / CA / NCI NIH HHS / United States
U24 CA126546 / CA / NCI NIH HHS / United States
U24 CA126563 / CA / NCI NIH HHS / United States
U24 CA126544 / CA / NCI NIH HHS / United States