Renal cell carcinoma (RCC) is a complex disease with remarkable immune and metabolic heterogeneity. In this thesis, proteomic, epigenomic and transcriptomic analyses on a cohort of patients spanning three main RCC subtypes were utilized to better characterize the altered proteomic and epigenomic landscape of RCC. The analysis revealed significant disruptions in the proteomic and epigenomic landscapes in tumor tissue compared to normal adjacent tissue (NAT) in clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC) subtypes. Stark and global loss of 5-hydroxymethylcytosine (5hmC) in tumor tissue compared to NAT in all three subtypes was observed. Furthermore, it was demonstrated that in the gene body and enhancer regions, loss of 5hmC is correlated with gain of 5- methylcytosine (5mC). Through integration of transcriptome and proteome data, it was demonstrated that loss of 5hmC in gene body and enhancer regions is an epigenetic hallmark for all three of main RCC subtypes and may be associated with cancer progression. Proteomic analysis revealed significant dysregulation of many protein regulons in all three subtypes, with several epigenetic regulators particularly affected and differentially expressed in tumor compared to matched normal tissue. Integration of proteomic and epigenomic approaches highlights the myriad of regulators and networks that are dysregulated in ccRCC, pRCC and chRCC, which can assist in refining the molecular characterization of these subtypes and facilitate the improvement of therapeutic responses.
