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<p>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.</p>

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Integrative multiomic analysis identifies transcription factors and target proteins in renal cell carcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月5日

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  • Surya B. Chhetri,
  • Timothy D. Winter,
  • Mitchell J. Machiela,
  • Kevin M. Brown,
  • Alexis Battle,
  • Mark P. Purdue,
  • Stephen J. Chanock,
  • Diptavo Dutta

摘要

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.