A systematic sequencing study of renal cell carcinoma (RCC) identified inactivating mutations in genes involved in histone modification, revealing the role of chromatin modification in cancer. The study sequenced 101 RCC cases across 3544 protein-coding genes, identifying mutations in SETD2, JARID1C, and UTX, which are enzymes involved in histone modification. These findings highlight the importance of chromatin modification in cancer development. Additionally, mutations in NF2 were found in non-VHL mutated RCCs, indicating genetic heterogeneity in RCC. The study also identified other potential cancer genes, including PMS1 and WRN, which are involved in DNA repair and repair of DNA double strand breaks. The results suggest that systematic screening is essential for understanding the genetic architecture of cancer. The study also found that mutations in SETD2 and JARID1C are associated with a hypoxic gene expression pattern, and that these mutations may not be redundant in RCC development. The study also identified that mutations in HIF1A and HIF2A have overlapping but distinct targets and activities. The study further suggests that there are likely to be other mutated genes in RCC, and that large-scale studies are needed to fully understand the genetic heterogeneity of cancer. The study was conducted using genomic DNA samples from clinical tumour samples, and RNA was harvested from fresh frozen patient tissue for gene expression analysis. The study found that mutations in the VHL gene are common in RCC, but that other genes, such as SETD2 and JARID1C, are also involved in RCC development. The study also identified that mutations in the DNA mismatch repair gene PMS1 may contribute to RCC development. The study was supported by the Wellcome Trust and other foundations, and the results have implications for understanding the role of genetic subtypes in clinical behaviour and response to treatment.A systematic sequencing study of renal cell carcinoma (RCC) identified inactivating mutations in genes involved in histone modification, revealing the role of chromatin modification in cancer. The study sequenced 101 RCC cases across 3544 protein-coding genes, identifying mutations in SETD2, JARID1C, and UTX, which are enzymes involved in histone modification. These findings highlight the importance of chromatin modification in cancer development. Additionally, mutations in NF2 were found in non-VHL mutated RCCs, indicating genetic heterogeneity in RCC. The study also identified other potential cancer genes, including PMS1 and WRN, which are involved in DNA repair and repair of DNA double strand breaks. The results suggest that systematic screening is essential for understanding the genetic architecture of cancer. The study also found that mutations in SETD2 and JARID1C are associated with a hypoxic gene expression pattern, and that these mutations may not be redundant in RCC development. The study also identified that mutations in HIF1A and HIF2A have overlapping but distinct targets and activities. The study further suggests that there are likely to be other mutated genes in RCC, and that large-scale studies are needed to fully understand the genetic heterogeneity of cancer. The study was conducted using genomic DNA samples from clinical tumour samples, and RNA was harvested from fresh frozen patient tissue for gene expression analysis. The study found that mutations in the VHL gene are common in RCC, but that other genes, such as SETD2 and JARID1C, are also involved in RCC development. The study also identified that mutations in the DNA mismatch repair gene PMS1 may contribute to RCC development. The study was supported by the Wellcome Trust and other foundations, and the results have implications for understanding the role of genetic subtypes in clinical behaviour and response to treatment.