Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Nature, Volume 455 Number 7209, September 4, 2008 [doi:10.1038/nature07385]

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.

Principal Findings

Associated Data Files

• GBM Publication Data Freeze - a list of archives that contain the data used for analysis in the publication
• GBM Publication sample list - a cumulative list of samples that were used for the GBM publication
• Somatic Mutations - Open-access validated somatic mutation data used for analysis in the GBM publication. The latest somatic mutations are also summarized.
• Median expression data used in the publication that is based on Level 3 data from three expression centers: [Broad] [LBL] [UNC]
• GISTIC results from 12 GISTIC runs (3 variants of GISTIC x 4 centers) as described in the Supplemental Text of the paper

Data Viewers

• Data Access Matrix: a tool for creating customized archives of TCGA data
• Cancer Molecular Analysis Portal: an analysis tool for genomic characterization, sequencing, and clinical data
• NCICB Cancer Genome Workbench: a browser-based viewer for integrated cancer genomic data
• Broad Institute Integrative Genomics Viewer: a desktop application for viewing genomic data
• MSKCC CancerGenomics Analysis: presents the results of detailed analysis and access to analysis tools in the areas of signaling pathways, mutations, and copy number alterations

Additional Information

• Descriptions of TCGA data levels are provided in the TCGA Data Primer