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<p>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 &gt;6 years, we established the clonal relationship of all samples, defined shared complex structural variants, and demonstrated both divergent and convergent evolution at <i>AR</i>. 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.</p>

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A complex phylogeny of lineage plasticity in metastatic castration resistant prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月28日

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  • 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

摘要

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.