Integrative multi-omic analysis identifies key transcription factors and target proteins in renal cell carcinoma and its subtypes

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To characterize key transcription factors (TFs) whose differential DNA binding can be altered by genetic variants associated with risk for renal cell carcinoma (RCC), we conducted a series of mixed model-based analyses integrating 449 TF ChIP-seq profiles across 9 kidney-related cell lines and summary statistics from a multi-ancestry genome-wide association study of RCC. We identified 96 unique TFs for which presence of SNPs in a neighborhood of TF ChIP-seq peaks are significantly associated (p-value <1×10-4) with their effect on RCC, including EPAS1, ARNT, PAX8 and PBRM1, previously implicated in RCC pathogenesis. Most TFs overlapped active promoters/enhancers in RCC tumors but remained significant after adjusting for tumor chromatin accessibility. Further, we found the co-occupancy of 220 pairs of RCC-related TFs to be associated with RCC risk (FDR<5%) beyond effects of individual TFs, highlighting synergistic regulation between pairs of TFs. To further investigate distal (trans) regulation of TF-binding disruption at RCC associated loci on the proteome, we used a set-based regression to aggregate the trans-effects of multiple loci overlapping with TF binding sites. Across 2,732 proteins profiled in UKB-PPP, identified 169 trans-associated (p-value<1.6×10-7) proteins, nominating specific targets for each TF. For example, we identified TLR3 and ZP3 to be associated with EPAS1, ARNT, and PBRM1, indicating these proteins are likely affected by RCC-related variants disrupting binding sites of the corresponding TFs. These results characterize the landscape of RCC-related TFs and implicate TF-mediated proteomic mechanisms in RCC pathogenesis, nominating testable targets for laboratory studies.

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