. 2024 Jun 25;43(6):114350.

doi: 10.1016/j.celrep.2024.114350. Epub 2024 Jun 12.

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

Talal El Zarif¹, Karl Semaan², Marc Eid³, Ji-Heui Seo³, Simon Garinet⁴, Matthew P Davidsohn⁴, Pranshu Sahgal⁴, Brad Fortunato⁴, John Canniff⁴, Amin H Nassar⁵, Sarah Abou Alaiwi⁶, Ziad Bakouny⁷, Gitanjali Lakshminarayanan⁴, Hunter Savignano⁴, Kevin Lyons⁴, Sayed Matar⁸, Atef Ali⁹, Eddy Saad⁴, Renee Maria Saliby⁴, Paulo Cordeiro², Ziwei Zhang⁴, Nourhan El Ahmar⁸, Yasmin Nabil Laimon⁸, Chris Labaki¹⁰, Valisha Shah⁴, Dory Freeman⁴, Jillian O'Toole⁴, Gwo-Shu Mary Lee⁴, Justin Hwang⁹, Mark Pomerantz⁴, Sabina Signoretti⁸, Eliezer M Van Allen¹¹, Wanling Xie¹², Jacob E Berchuck⁴, Srinivas R Viswanathan¹³, David A Braun¹⁴, Toni K Choueiri¹⁵, Matthew L Freedman¹⁶, Sylvan C Baca¹⁷

Affiliations

¹ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁶ Section of Cardiology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁷ Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Department of Medicine, University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
¹² Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁴ Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: toni_choueiri@dfci.harvard.edu.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: matthew_freedman@dfci.harvard.edu.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA. Electronic address: sylvan_baca@dfci.harvard.edu.

PMID: 38870013
DOI: 10.1016/j.celrep.2024.114350

Free article

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

Talal El Zarif et al. Cell Rep. 2024.

Free article

. 2024 Jun 25;43(6):114350.

doi: 10.1016/j.celrep.2024.114350. Epub 2024 Jun 12.

Authors

Affiliations

¹ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁶ Section of Cardiology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁷ Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Department of Medicine, University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
¹² Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁴ Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: toni_choueiri@dfci.harvard.edu.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: matthew_freedman@dfci.harvard.edu.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA. Electronic address: sylvan_baca@dfci.harvard.edu.

PMID: 38870013
DOI: 10.1016/j.celrep.2024.114350

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.

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

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Conflict of interest statement

Declaration of interests S.R.V. reports consulting (current or past 3 years) for Jnana Therapeutics, research support from Bayer, and that their spouse is an employee of and holds equity in Kojin Therapeutics. D.A.B. reports honoraria from LM Education/Exchange Services; advisory board fees from Exelixis and AVEO; consulting fees from Merck, Pfizer, and Elephas; equity in Elephas, Fortress Biotech (subsidiary), and CurIOS Therapeutics; personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Accolade 2nd.MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, and Scholar Rock; and research support from Exelixis and AstraZeneca, outside of the submitted work. S.C.B., T.K.C., and M.L.F. are co-founders and shareholders of Precede Biosciences.

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

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

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