A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer
Abstract 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 f...
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Nature Portfolio
2025-03-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-00854-4 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jones T. Nauseef |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-e1aa9fb72e604d00ad028a1f9f99368e |
| institution | OA Journals |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-e1aa9fb72e604d00ad028a1f9f99368e2025-08-20T02:10:09ZengNature Portfolionpj Precision Oncology2397-768X2025-03-019111410.1038/s41698-025-00854-4A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancerJones T. Nauseef0Timothy R. Chu1William F. Hooper2Alicia Alonso3Ali Oku4Heather Geiger5Zoe R. Goldstein6Minita Shah7Michael Sigouros8Jyothi Manohar9Zoe Steinsnyder10Lara Winterkorn11Brian D. Robinson12Andrea Sboner13Himisha Beltran14Olivier Elemento15Iman Hajirasouliha16Marcin Imielinski17David M. Nanus18Scott T. Tagawa19Nicolas Robine20Juan Miguel Mosquera21Division of Hematology & Medical Oncology, Weill Cornell MedicineNew York Genome CenterNew York Genome CenterEnglander Institute for Precision Medicine, Weill Cornell MedicineNew York Genome CenterNew York Genome CenterNew York Genome CenterNew York Genome CenterEnglander Institute for Precision Medicine, Weill Cornell MedicineEnglander Institute for Precision Medicine, Weill Cornell MedicineNew York Genome CenterNew York Genome CenterEnglander Institute for Precision Medicine, Weill Cornell MedicineEnglander Institute for Precision Medicine, Weill Cornell MedicineEnglander Institute for Precision Medicine, Weill Cornell MedicineEnglander Institute for Precision Medicine, Weill Cornell MedicineEnglander Institute for Precision Medicine, Weill Cornell MedicineEnglander Institute for Precision Medicine, Weill Cornell MedicineDivision of Hematology & Medical Oncology, Weill Cornell MedicineDivision of Hematology & Medical Oncology, Weill Cornell MedicineNew York Genome CenterEnglander Institute for Precision Medicine, Weill Cornell MedicineAbstract 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.https://doi.org/10.1038/s41698-025-00854-4 |
| spellingShingle | 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 A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer npj Precision Oncology |
| title | A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer |
| title_full | A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer |
| title_fullStr | A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer |
| title_full_unstemmed | A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer |
| title_short | A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer |
| title_sort | complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer |
| url | https://doi.org/10.1038/s41698-025-00854-4 |
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