Generation of a Comprehensive Epigenomic Atlas in Clear Cell Renal Cell Carcinoma Informs Kidney Cancer Progression and Heritability

By generating 194 epigenomic and transcriptomic datasets from 57 human tissue samples using H3K27ac and HIF2α chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and RNA sequencing, we provide a comprehensive, integrated characterization of clear cell renal cell carcinoma (ccRCC) across normal, tumor, and metastatic states. Our analyses provide several insights into ccRCC biology. First, we demonstrate significant reprogramming of enhancer and HIF2α cistromes as well as chromatin accessibility during the normal-to-tumor transition, whereas localized and metastatic tumors show minimal epigenomic differences. Second, we show reactivation of kidney-specific developmental pathways driving malignancy. Third, we perform a cistrome-wide association study in ccRCC, validating five established RCC risk loci and identifying six novel loci, including a locus at 12q24 linked to SCARB1 that was functionally validated. These datasets provide new perspectives on the role of developmental pathways in ccRCC tumorigenesis, insights into epigenetic mechanisms of ccRCC heritability, and a comprehensive epigenomic atlas for the research community.