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

By generating 194 epigenomic and transcriptomic profiles datasets from 57 human tissue samples, using H3K27ac and HIF2a chromatin immunoprecipitation sequencing (ChIP-seq), ATAC-seq, and RNA-seq, we provide a comprehensive integrated characterization of clear cell renal cell carcinoma (ccRCC) across normal, tumor, and metastatic states. Our epigenomic analyses reveal insights into various aspects of ccRCC biology. First, we show that significant enhancer reprogramming (H3K27ac) and shifts in the transcription factor HIF2a cistrome and chromatin accessibility landscape occur during the transition from normal to tumor; by contrast, there areis no significant differences between localized tumors and metastatic samples. Second, we show that fetal kidney-specific developmental pathways are reactivated to drive malignancy. Third, we performed the first cistrome cistrome-wide association study (CWAS) in ccRCC, validating five established RCC risk loci and identifying six novel regions associated with RCC risk, including a significant association on 12q24 linked to the SCARB1 gene that was functionally validated. These datasets provide new perspectives on the role of developmental pathways in ccRCC tumorigenesis and metastasis, insights into epigenetic mechanisms of ccRCC heritability, and a comprehensive epigenomic atlas for the research community. Overall design: We performed H3K27ac ChIP-seq, HIF2a ChIP-seq, ATAC-seq, and RNA-seq on 57 independent tissue samples (194 total datasets), spanning 32 individuals diagnosed with clear-cell renal cell carcinoma. We also generated H3K27ac ChIP-seq, HIF2a ChIP-seq, ATAC-seq, and RNA-seq on 5 human clear-cell renal cell carcinoma cell lines.