It was not until the advent of next-generation sequencing technologies that we learned about the somatic cytogenetic alterations in renal cell carcinoma. A linkage analysis of hereditary renal cell carcinoma identified mutations in the VHL gene, which has been the focus of genetic studies in this type of tumor for many years.The VHL gene, located on chromosome 3p, is an oncogene that is widely mutated in hereditary clear cell renal cell carcinoma, usually in a sporadic form. Previous studies have evaluated the possible association between VHL mutational status and patient clinical prognosis, but unfortunately have not found a clear and stable link between the two. Recent studies on tumor sequencing have shown that in addition to VHL mutations, there are several recurrent mutations in patients with clear cell renal cell carcinoma, including mutations at the 3p locus, one of which is PBRM1, a truncatingmutation that occurs in 40% of patients with clear cell renal cell carcinoma. PBRM1 encodes the Baf180 protein, which is associated with a subunit of the SWI/WNF chromatin remodeling complex in the transcriptional apparatus. BAP1, also located at 3p, is mutated in 15% of patients with clear cell renal cell carcinoma, and it encodes a protein associated with deubiquitin, which is part of the ubiquitin-mediated protein hydrolysis bypass (UMPP), which has 135 genes including VHL. Genes encoding UMPP are associated with hypoxia-inducible factor overexpression, even in the absence of VHL gene mutations. Interestingly, PBRM1 mutations and BAP1 mutations are often mutually exclusive, suggesting the need for further investigation of the clinical implications of the gene split. This led Payal Kapur and his colleagues to build on their initial study on the association of BAP1 deletion to go deeper – to determine the clinical characteristics of patients with clear cell renal cell carcinoma with either PBRM1 mutations or BAP1 mutations or both. This work is representative of the coming era of next-generation sequencing technologies that can explore the correlation between genetic changes and patient clinical outcomes in patients with renal cell carcinoma. In the study, the researchers used patient data from the University of Texas Southwestern Medical Center (UTSW) to create a local database and then applied patient data from public databases published by the Cancer Genome Atlas Project (TCGA) to form a validation cohort to verify their findings. The results of the study showed that patients with BAP1 mutated tumors were more likely to have aggressive lesions and poorly expressed pathological features compared to patients with PBRM1 mutated tumors, resulting in significantly different overall patient survival. Comparing the risk ratio (HR) for survival between patients with BAP1-mutated tumors and patients with PBRM1-mutated tumors revealed that the HR was identical in both cohorts, with an HR of 2.7 (95% confidence interval 0.99 to 7.6) in the UTSW cohort and 2.8 (95% confidence interval 1.4 to 5.9) in the TCGA cohort. In addition, BAP1-mutated tumors and PBRM1-mutated tumors exhibited distinct gene expression profiles with non-overlapping biology. Although PBRM1 and BAP1 mutation status are not immediately available as biomarkers for renal cell carcinoma in routine clinical practice, these findings are still of great clinical value. Second, it is important to determine the predictive value of these mutations in patients receiving systemic therapies, such as targeted therapies like VEGF and mTOR inhibitors. The unique genetic profile of renal cell carcinoma may suggest how well the disease will respond to targeted therapies. The US FDA approved seven treatments in 2012. But the selection of these treatments is not limited to the genetic characteristics of the patient alone, but is based on whether the patient meets the enrollment criteria for the pivotal phase 3 clinical study, patient choice, possible toxic effects of the treatment, and cost issues. Furthermore, if it is confirmed that BAP1 and PBRM1 mutations are early events in the development of carcinogenesis in clear cell renal cell carcinoma and are prevalent in patients’ tumors, a recently proposed mutation status regarding tumor heterogeneity makes the use of mutation status as a biomarker less focused. From the available data we were able to select other useful classifications to pick out new candidate genes suitable for clear cell renal cell carcinoma. Mutations are less common in genes encoding the two methyltransferases SETD2 and MLL2 and the two demethylases UTX (KDM6A) and JARID1C (KDM5C), which may be able to define other molecular subtypes with different biological features and outcomes. A potential classification scheme could include the presence or absence of mutations in a particular bypass. As previously mentioned, several in the UMPP group encode or degrade proteins in the proteasome system. A recent study tested the UMPP gene and found that 48 of 98 patients with clear cell renal cell carcinoma had non-silent somatic mutations in the UMPP bypass, suggesting that patients with clear cell renal cell carcinoma can be classified as UMPP mutated or non-UMPP mutated. In conclusion, this study is well designed to help better understand the data obtained by exome sequencing in patients with renal cell carcinoma and the application of this information in the clinical setting. With the knowledge and understanding of the above data, in the future, we hope to further improve the effectiveness of targeted therapies and the role of biomarkers in clinical decision making.