Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma Journal Article
| Authors: | El Zarif, T.; Semaan, K.; Eid, M.; Seo, J. H.; Garinet, S.; Davidsohn, M. P.; Sahgal, P.; Fortunato, B.; Canniff, J.; Nassar, A. H.; Abou Alaiwi, S.; Bakouny, Z.; Lakshminarayanan, G.; Savignano, H.; Lyons, K.; Matar, S.; Ali, A.; Saad, E.; Saliby, R. M.; Cordeiro, P.; Zhang, Z.; El Ahmar, N.; Laimon, Y. N.; Labaki, C.; Shah, V.; Freeman, D.; O'Toole, J.; Lee, G. S. M.; Hwang, J.; Pomerantz, M.; Signoretti, S.; Van Allen, E. M.; Xie, W.; Berchuck, J. E.; Viswanathan, S. R.; Braun, D. A.; Choueiri, T. K.; Freedman, M. L.; Baca, S. C. |
| Article Title: | Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma |
| Abstract: | 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. © 2024 The Author(s) |
| Keywords: | clinical article; controlled study; human tissue; survival analysis; unclassified drug; human cell; sunitinib; quality control; transcription factor; tumor biopsy; cell differentiation; dna methylation; renal cell carcinoma; transcription factors; immunotherapy; epigenetics; chromatin immunoprecipitation; western blotting; immunoblotting; clear cell carcinoma; kidney cancer; axitinib; sarcomatoid; histone modification; principal component analysis; epigenomics; false discovery rate; histone modifications; sarcomatoid differentiation; human; article; whole genome sequencing; hierarchical clustering; differential gene expression; clustered regularly interspaced short palindromic repeat; lentivirus infection; gene set enrichment analysis; immune checkpoint inhibitors; sarcomatoid renal cell carcinoma; liquid biopsy; avelumab; hek293t cell line; cp: cancer; cp: genomics; fosl1; transcription factor fosl1 |
| Journal Title: | Cell Reports |
| Volume: | 43 |
| Issue: | 6 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2024-06-25 |
| Start Page: | 114350 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2024.114350 |
| PROVIDER: | scopus |
| PUBMED: | 38870013 |
| PMCID: | PMC11929466 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
