Surya B. Chhetri, Timothy Winter, Mitchell J. Machiela, Kevin M. Brown, Alexis Battle, Mark P. Purdue, Stephen J. Chanock, Diptavo Dutta
Integrated analysis of genetic association studies, genomic maps of transcription factor binding, and blood protein measurements identified RCC-associated transcription factors and target proteins. The study identified 96 RCC-associated transcription factors, including known regulators like EPAS1, ARNT, PBRM1, and PAX8, and 169 proteins affected by their binding sites. Majority of associations remained even after accounting for open chromatin regions. The work nominates TF-mediated regulatory and proteomic mechanisms for functional studies of RCC susceptibility, highlighting joint occupancy effects of transcription factors.
Abstract Renal cell carcinoma risk is partly shaped by germline genetic variants that often reside in regulatory regions. However, the transcription factors (TFs) and downstream proteins via which they shape RCC susceptibility remain incompletely characterized. Here we show that an integrated analysis of genetic association studies with genomic maps showing where TFs bind DNA in 449 experiments across kidney-related models and blood protein measurements can identify RCC risk-relayed TFs and the proteins associated with them. We identify 96 RCC-associated TFs including known kidney cancer regulators, like EPAS1, ARNT, PBRM1 and PAX8. Majority of associations remain even after accounting for open chromatin regions in tumors. We also find 220 pairs of transcription factors with joint occupancy effects beyond the effects of single TF. Further we identify 169 proteins that may be affected by RCC-associated TF binding sites. This work nominates TF-mediated regulatory and proteomic mechanisms for functional studies of RCC susceptibility.