Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma

Cell Rep. 2024 Jun 25;43(6):114350. doi: 10.1016/j.celrep.2024.114350. Epub 2024 Jun 12.


Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

Keywords: CP: Cancer; CP: Genomics; FOSL1; epigenomics; histone modifications; immune checkpoint inhibitors; immunotherapy; kidney cancer; liquid biopsy; renal cell carcinoma; sarcomatoid; transcription factors.

MeSH terms

  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / metabolism
  • Carcinoma, Renal Cell* / pathology
  • Cell Differentiation
  • DNA Methylation / genetics
  • Epigenesis, Genetic
  • Epigenomics* / methods
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / metabolism
  • Kidney Neoplasms* / pathology
  • Male
  • Middle Aged
  • Proto-Oncogene Proteins c-fos


  • fos-related antigen 1
  • Proto-Oncogene Proteins c-fos