The study provides a comprehensive molecular characterization of clear cell renal cell carcinoma (ccRCC) using genomic platforms and integrates clinical, pathological, genomic, DNA methylation, RNA, and proteomic data from over 500 primary nephrectomy specimens. Key findings include: 1. **Genetic Alterations**: Recurrent mutations in genes controlling cellular oxygen sensing (VHL) and chromatin maintenance (PBRII) were identified. The PI(3)K/AKT pathway was frequently mutated, suggesting it as a therapeutic target. Widespread DNA hypomethylation was associated with SETD2 mutation, and mutations in the SWI/SNF chromatin remodeling complex (PBRII, ARID1A, SMARCA4) had far-reaching effects on other pathways. 2. **Metabolic Shift**: Aggressive ccRCCs showed a metabolic shift, involving downregulation of TCA cycle genes, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 and GRB10. 3. **Molecular Subtypes**: Unsupervised clustering identified four stable mRNA and miRNA expression subtypes, with survival differences correlating with mRNA and miRNA patterns. miR-21, associated with poor outcome, was strongly regulated by high glucose levels and negatively regulated PTEN. 4. **Integrative Pathway Analysis**: Pathway analyses using HotNet2 and PARADIGM algorithms revealed significant sub-networks involving VHL, PBRII, ARID1A, and SMARCA4. The PI(3)K/AKT pathway was altered in 28% of tumors, with mutually exclusive gene alterations targeting multiple components. 5. **Survival Correlates**: Poor prognosis was associated with downregulation of AMPK complex and Krebs cycle genes, increased fatty acid synthesis, and upregulation of genes involved in the pentose phosphate pathway. Better survival correlated with upregulation of AMPK complex genes, Krebs cycle genes, and PI(3)K pathway inhibitors. 6. **Epigenetic Regulation**: promoter methylation events involving *MIR21* and *GRB10* were correlated with survival outcomes, with decreased promoter methylation leading to worse or better outcomes, respectively. The study highlights the importance of chromatin remodeling, the PI(3)K/AKT pathway, and metabolic shifts in ccRCC, providing new insights into disease progression and potential therapeutic targets.The study provides a comprehensive molecular characterization of clear cell renal cell carcinoma (ccRCC) using genomic platforms and integrates clinical, pathological, genomic, DNA methylation, RNA, and proteomic data from over 500 primary nephrectomy specimens. Key findings include: 1. **Genetic Alterations**: Recurrent mutations in genes controlling cellular oxygen sensing (VHL) and chromatin maintenance (PBRII) were identified. The PI(3)K/AKT pathway was frequently mutated, suggesting it as a therapeutic target. Widespread DNA hypomethylation was associated with SETD2 mutation, and mutations in the SWI/SNF chromatin remodeling complex (PBRII, ARID1A, SMARCA4) had far-reaching effects on other pathways. 2. **Metabolic Shift**: Aggressive ccRCCs showed a metabolic shift, involving downregulation of TCA cycle genes, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 and GRB10. 3. **Molecular Subtypes**: Unsupervised clustering identified four stable mRNA and miRNA expression subtypes, with survival differences correlating with mRNA and miRNA patterns. miR-21, associated with poor outcome, was strongly regulated by high glucose levels and negatively regulated PTEN. 4. **Integrative Pathway Analysis**: Pathway analyses using HotNet2 and PARADIGM algorithms revealed significant sub-networks involving VHL, PBRII, ARID1A, and SMARCA4. The PI(3)K/AKT pathway was altered in 28% of tumors, with mutually exclusive gene alterations targeting multiple components. 5. **Survival Correlates**: Poor prognosis was associated with downregulation of AMPK complex and Krebs cycle genes, increased fatty acid synthesis, and upregulation of genes involved in the pentose phosphate pathway. Better survival correlated with upregulation of AMPK complex genes, Krebs cycle genes, and PI(3)K pathway inhibitors. 6. **Epigenetic Regulation**: promoter methylation events involving *MIR21* and *GRB10* were correlated with survival outcomes, with decreased promoter methylation leading to worse or better outcomes, respectively. The study highlights the importance of chromatin remodeling, the PI(3)K/AKT pathway, and metabolic shifts in ccRCC, providing new insights into disease progression and potential therapeutic targets.