This study provides a comprehensive molecular characterization of clear cell renal cell carcinoma (ccRCC), identifying 19 significantly mutated genes, including those involved in oxygen sensing (VHL), chromatin maintenance (PBRM1), and metabolic pathways. The PI(3)K/AKT pathway was recurrently mutated, suggesting it as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutations in the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations in the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers showed evidence of a metabolic shift, involving downregulation of TCA cycle genes, decreased AMPK and PTEN 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. These metabolic changes are recurrent in ccRCC and correlate with tumour stage and severity, offering new insights into treatment opportunities. ccRCC is a common chemotherapy-resistant disease associated with VHL gene mutations, leading to stabilization of hypoxia inducible factors (HIF-1α and HIF-2α). PBRM1, BAP1, and SETD2 were found to be altered in ccRCC, implicating major roles for epigenetic regulation in disease development and progression. Oncogenic metabolism and epigenetic reprogramming are central features of ccRCC. The study evaluated clinical and pathological features, genomic alterations, DNA methylation profiles, and RNA and proteomic signatures in ccRCC. Over 500 primary nephrectomy specimens were analyzed, with data from at least one analytical platform ('Extended' data set) and data from all platforms available for 372 samples ('Core' data set). No substantial batch effects were detected. Somatic alterations in 417 samples showed recurrent arm-level and focal copy number alterations (SCNAs), with SCNAs involving entire chromosomes or chromosome arms being more common. Mutations in key genes (VHL, PBRM1, SETD2, etc.) were validated, with VHL, PBRM1, SETD2, KDM5C, PTEN, BAP1, MTOR, and TP53 being the most significantly mutated. BAP1 mutations correlated with poor survival. RNA fusion events were identified in 416 samples, with 11 of 13 predicted events validated. A recurrent SFPQ-TFE3 fusion was found in five samples, all of which were VHL wild type, indicating either a clear cell variant or histologically indistinguishable tumours. DNA methylation profiles showed epigenetic silencing of VHL in aboutThis study provides a comprehensive molecular characterization of clear cell renal cell carcinoma (ccRCC), identifying 19 significantly mutated genes, including those involved in oxygen sensing (VHL), chromatin maintenance (PBRM1), and metabolic pathways. The PI(3)K/AKT pathway was recurrently mutated, suggesting it as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutations in the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations in the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers showed evidence of a metabolic shift, involving downregulation of TCA cycle genes, decreased AMPK and PTEN 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. These metabolic changes are recurrent in ccRCC and correlate with tumour stage and severity, offering new insights into treatment opportunities. ccRCC is a common chemotherapy-resistant disease associated with VHL gene mutations, leading to stabilization of hypoxia inducible factors (HIF-1α and HIF-2α). PBRM1, BAP1, and SETD2 were found to be altered in ccRCC, implicating major roles for epigenetic regulation in disease development and progression. Oncogenic metabolism and epigenetic reprogramming are central features of ccRCC. The study evaluated clinical and pathological features, genomic alterations, DNA methylation profiles, and RNA and proteomic signatures in ccRCC. Over 500 primary nephrectomy specimens were analyzed, with data from at least one analytical platform ('Extended' data set) and data from all platforms available for 372 samples ('Core' data set). No substantial batch effects were detected. Somatic alterations in 417 samples showed recurrent arm-level and focal copy number alterations (SCNAs), with SCNAs involving entire chromosomes or chromosome arms being more common. Mutations in key genes (VHL, PBRM1, SETD2, etc.) were validated, with VHL, PBRM1, SETD2, KDM5C, PTEN, BAP1, MTOR, and TP53 being the most significantly mutated. BAP1 mutations correlated with poor survival. RNA fusion events were identified in 416 samples, with 11 of 13 predicted events validated. A recurrent SFPQ-TFE3 fusion was found in five samples, all of which were VHL wild type, indicating either a clear cell variant or histologically indistinguishable tumours. DNA methylation profiles showed epigenetic silencing of VHL in about