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Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer

Sharifi, Marina N. ; Feng, Eric ; Rydzewski, Nicholas R. ; Taylor, Amy K. ; Sperger, Jamie M. ; Shi, Yue ; Helzer, Kyle T. ; Bootsma, Matthew L. ; Carreno, Viridiana and Chang, Alex H. , et al. (2025) In Molecular Oncology
Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters:... (More)

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
biomarker, gene expression, metastatic castration-resistant prostate cancer, precision medicine, prognosis
in
Molecular Oncology
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:39985777
  • scopus:85218705563
ISSN
1574-7891
DOI
10.1002/1878-0261.70001
language
English
LU publication?
yes
id
0a1cded8-0abe-4ae4-83da-75ef30678fce
date added to LUP
2025-06-30 09:59:30
date last changed
2025-07-01 03:00:03
@article{0a1cded8-0abe-4ae4-83da-75ef30678fce,
  abstract     = {{<p>Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions.</p>}},
  author       = {{Sharifi, Marina N. and Feng, Eric and Rydzewski, Nicholas R. and Taylor, Amy K. and Sperger, Jamie M. and Shi, Yue and Helzer, Kyle T. and Bootsma, Matthew L. and Carreno, Viridiana and Chang, Alex H. and Nunamaker, Luke A. and Blitzer, Grace C. and Shang, Tianfu Andy and Subramanian, Aishwarya and Bjartell, Anders and Josefsson, Andreas and Wikström, Pernilla and Feng, Emily and Kohli, Manish and Yang, Rendong and Dehm, Scott M. and Small, Eric J. and Aggarwal, Rahul and Quigley, David A. and Lang, Joshua M. and Zhao, Shuang G. and Sjöström, Martin}},
  issn         = {{1574-7891}},
  keywords     = {{biomarker; gene expression; metastatic castration-resistant prostate cancer; precision medicine; prognosis}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Molecular Oncology}},
  title        = {{Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer}},
  url          = {{http://dx.doi.org/10.1002/1878-0261.70001}},
  doi          = {{10.1002/1878-0261.70001}},
  year         = {{2025}},
}