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.
NPJ precision oncology. 2025 Mar 28*** epublish ***
Jones T Nauseef, Timothy R Chu, William F Hooper, Alicia Alonso, Ali Oku, Heather Geiger, Zoe R Goldstein, Minita Shah, Michael Sigouros, Jyothi Manohar, Zoe Steinsnyder, Lara Winterkorn, Brian D Robinson, Andrea Sboner, Himisha Beltran, Olivier Elemento, Iman Hajirasouliha, Marcin Imielinski, David M Nanus, Scott T Tagawa, Nicolas Robine, Juan Miguel Mosquera
Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY, USA. ., New York Genome Center, New York, NY, USA., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY, USA., New York Genome Center, New York, NY, USA. ., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. .