The Cancer Genome Atlas (TCGA) Research Network conducted a comprehensive genomic analysis of 206 glioblastomas (GBMs), the most common type of adult brain cancer, to understand the molecular basis of the disease. The study integrated DNA copy number, gene expression, and DNA methylation data, as well as nucleotide sequence aberrations in 91 GBMs. Key findings include: 1. **ERBB2, NF1, and TP53**: These genes were identified as important in GBM development, with frequent mutations in *ERBB2* and *NF1* and recurrent mutations in *TP53*. 2. **PIK3R1 Mutations**: A significant mutation in the PI3 kinase regulatory subunit gene *PIK3R1* was uncovered, suggesting its role in GBM pathogenesis. 3. **MGMT Methylation and Hypermutator Phenotype**: MGMT promoter methylation was linked to a hypermutator phenotype in treated GBMs, likely due to mismatch repair deficiency, which has potential clinical implications. 4. **Core Pathways**: Integrative analyses revealed that deregulation of receptor tyrosine kinases (RTKs), the p53/RB tumor suppressor pathways, and the RB pathway are core requirements for GBM development. 5. **Clinical Implications**: The findings suggest that targeting specific pathways and biomarkers, such as MGMT methylation, could be crucial for developing effective treatments. The study highlights the power of TCGA in advancing our understanding of cancer genetics and the potential for personalized medicine.The Cancer Genome Atlas (TCGA) Research Network conducted a comprehensive genomic analysis of 206 glioblastomas (GBMs), the most common type of adult brain cancer, to understand the molecular basis of the disease. The study integrated DNA copy number, gene expression, and DNA methylation data, as well as nucleotide sequence aberrations in 91 GBMs. Key findings include: 1. **ERBB2, NF1, and TP53**: These genes were identified as important in GBM development, with frequent mutations in *ERBB2* and *NF1* and recurrent mutations in *TP53*. 2. **PIK3R1 Mutations**: A significant mutation in the PI3 kinase regulatory subunit gene *PIK3R1* was uncovered, suggesting its role in GBM pathogenesis. 3. **MGMT Methylation and Hypermutator Phenotype**: MGMT promoter methylation was linked to a hypermutator phenotype in treated GBMs, likely due to mismatch repair deficiency, which has potential clinical implications. 4. **Core Pathways**: Integrative analyses revealed that deregulation of receptor tyrosine kinases (RTKs), the p53/RB tumor suppressor pathways, and the RB pathway are core requirements for GBM development. 5. **Clinical Implications**: The findings suggest that targeting specific pathways and biomarkers, such as MGMT methylation, could be crucial for developing effective treatments. The study highlights the power of TCGA in advancing our understanding of cancer genetics and the potential for personalized medicine.