A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer
Aggressive variant and androgen receptor (AR)-independent castration resistant prostate cancers (CRPC) represent the most significant diagnostic and therapeutic challenges in prostate cancer. This study examined a case of simultaneous progression of both adenocarcinoma and squamous tumors from the same common origin. Using whole-genome and transcriptome sequencing from 17 samples collected over >6 years, we established the clonal relationship of all samples, defined shared complex structural variants, and demonstrated both divergent and convergent evolution at AR. Squamous CRPC-associated circulating tumor DNA was identified at clinical progression prior to biopsy detection of any squamous differentiation. Dynamic changes in the detection rate of histology-specific clones in circulation reflected histology-specific sensitivity to treatment. This dataset serves as an illustration of non-neuroendocrine transdifferentiation and highlights the importance of serial sampling at progression in CRPC for the detection of emergent non-adenocarcinoma histologies with implications for the treatment of lineage plasticity and transdifferentiation in metastatic CRPC.
Authors
- Lara Winterkorn
- Zoe Steinsnyder (ORCID: https://orcid.org/0000-0001-6156-1694)
- Scott T. Tagawa (ORCID: https://orcid.org/0000-0003-2777-8587)
- Jyothi Manohar (ORCID: https://orcid.org/0000-0001-6357-910X)
- William F. Hooper (ORCID: https://orcid.org/0000-0002-0078-8921)
- Marcin Imieliński (ORCID: https://orcid.org/0000-0002-2211-4741)
- Heather Geiger
- Jones T. Nauseef (ORCID: https://orcid.org/0000-0003-2302-4171)
- Nicolas Robine (ORCID: https://orcid.org/0000-0001-5698-8183)
- Michael Sigouros (ORCID: https://orcid.org/0000-0002-0328-8359)
- David M. Nanus (ORCID: https://orcid.org/0000-0003-3514-2976)
- Timothy R. Chu (ORCID: https://orcid.org/0000-0002-9724-9739)
- Juan Miguel Mosquera (ORCID: https://orcid.org/0000-0003-4666-6476)
- Andrea Sboner (ORCID: https://orcid.org/0000-0001-6915-3070)
- Himisha Beltran (ORCID: https://orcid.org/0000-0003-3259-2226)
- Brian D. Robinson (ORCID: https://orcid.org/0000-0001-5374-890X)
- Olivier Elemento (ORCID: https://orcid.org/0000-0002-8061-9617)
- Zoe R. Goldstein
- Iman Hajirasouliha (ORCID: https://orcid.org/0000-0002-0600-3371)
- Alicia Alonso (ORCID: https://orcid.org/0000-0002-2730-7470)
- Ali Oku
- Minita Shah
Institutions
- Cornell University (US)
- Lander Institute (IL)
- Dana-Farber Cancer Institute (US)
- New York Genome Center (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-03-28
- DOI
- https://doi.org/10.1038/s41698-025-00854-4
- Citations
- 1
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 1.52