Cell Reports (Jun 2024)
Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma
- Talal El Zarif,
- Karl Semaan,
- Marc Eid,
- Ji-Heui Seo,
- Simon Garinet,
- Matthew P. Davidsohn,
- Pranshu Sahgal,
- Brad Fortunato,
- John Canniff,
- Amin H. Nassar,
- Sarah Abou Alaiwi,
- Ziad Bakouny,
- Gitanjali Lakshminarayanan,
- Hunter Savignano,
- Kevin Lyons,
- Sayed Matar,
- Atef Ali,
- Eddy Saad,
- Renee Maria Saliby,
- Paulo Cordeiro,
- Ziwei Zhang,
- Nourhan El Ahmar,
- Yasmin Nabil Laimon,
- Chris Labaki,
- Valisha Shah,
- Dory Freeman,
- Jillian O’Toole,
- Gwo-Shu Mary Lee,
- Justin Hwang,
- Mark Pomerantz,
- Sabina Signoretti,
- Eliezer M. Van Allen,
- Wanling Xie,
- Jacob E. Berchuck,
- Srinivas R. Viswanathan,
- David A. Braun,
- Toni K. Choueiri,
- Matthew L. Freedman,
- Sylvan C. Baca
Affiliations
- Talal El Zarif
- 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
- Karl Semaan
- 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
- Marc Eid
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
- Ji-Heui Seo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
- Simon Garinet
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Matthew P. Davidsohn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Pranshu Sahgal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Brad Fortunato
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- John Canniff
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Amin H. Nassar
- Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Sarah Abou Alaiwi
- Section of Cardiology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Ziad Bakouny
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Gitanjali Lakshminarayanan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Hunter Savignano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Kevin Lyons
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Sayed Matar
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
- Atef Ali
- Department of Medicine, University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA
- Eddy Saad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Renee Maria Saliby
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Paulo Cordeiro
- 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
- Ziwei Zhang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Nourhan El Ahmar
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
- Yasmin Nabil Laimon
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
- Chris Labaki
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Valisha Shah
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Dory Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Jillian O’Toole
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Gwo-Shu Mary Lee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Justin Hwang
- Department of Medicine, University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA
- Mark Pomerantz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Sabina Signoretti
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
- Eliezer M. Van Allen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
- Wanling Xie
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
- Jacob E. Berchuck
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Srinivas R. Viswanathan
- 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
- David A. Braun
- 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
- Toni K. Choueiri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Corresponding author
- Matthew L. Freedman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA; Corresponding author
- Sylvan C. Baca
- 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; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 6
p. 114350
Abstract
Summary: 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.
