Plasma epigenomic profiling reveals treatment-emergent squamous transformation in prostate cancer

Karl Semaan; Rashad Nawfal; John Canniff; Hunter Savignano; Ji-Heui Seo; Stephanie E Siegmund; Sarah J Wu; Julia K Rotow; Gwo-Shu Mary Lee; Razane El Hajj Chehade; Ze Zhang; Gunsagar S Gulati; Noa Phillips; Garyoung Gary Lee; Christopher A French; Michelle S Hirsch; Heather A Jacene; Atish D Choudhury; Toni K Choueiri; Matthew L Freedman; Sylvan C Baca; Jacob E Berchuck

doi:10.1038/s41698-025-01031-3

Plasma epigenomic profiling reveals treatment-emergent squamous transformation in prostate cancer

NPJ Precis Oncol. 2025 Jul 9;9(1):233. doi: 10.1038/s41698-025-01031-3.

Authors

Karl Semaan^#^{1

2

3

4}, Rashad Nawfal^#^{1

2}, John Canniff^{1

2}, Hunter Savignano^{1

2}, Ji-Heui Seo^{1

2}, Stephanie E Siegmund⁵, Sarah J Wu⁵, Julia K Rotow⁶, Gwo-Shu Mary Lee¹, Razane El Hajj Chehade^{1

2

3}, Ze Zhang^{1

2

3}, Gunsagar S Gulati^{1

2}, Noa Phillips^{1

2}, Garyoung Gary Lee^{1

2

3}, Christopher A French⁵, Michelle S Hirsch⁵, Heather A Jacene⁷, Atish D Choudhury¹, Toni K Choueiri¹, Matthew L Freedman^{1

2

3}, Sylvan C Baca^{8

9

10}, Jacob E Berchuck^{11

12

13}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
³ The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
⁴ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Department of Imaging, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. sylvan_baca@dfci.harvard.edu.
⁹ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. sylvan_baca@dfci.harvard.edu.
¹⁰ The Eli and Edythe L. Broad Institute, Cambridge, MA, USA. sylvan_baca@dfci.harvard.edu.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. jberchuck@emory.edu.
¹² Winship Cancer Institute of Emory University, Atlanta, GA, USA. jberchuck@emory.edu.
¹³ Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. jberchuck@emory.edu.

^# Contributed equally.

Abstract

Squamous transformation of prostate adenocarcinoma is a rare resistance mechanism in patients with advanced prostate cancer that impacts both prognosis and treatment. Herein, we profile circulating chromatin in serial plasma samples collected from a patient with metastatic prostate cancer that experienced squamous transformation. We detect dynamic changes in gene regulation from circulating chromatin reflecting the emergence of squamous differentiation, enabling non-invasive diagnosis and monitoring of this resistance phenotype, with potential therapeutic implications.

Grants and funding

U01 CA296432/CA/NCI NIH HHS/United States