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

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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Publication Details

Journal
Molecular Oncology
Published
2025-02-22
DOI
https://doi.org/10.1002/1878-0261.70001
Citations
3
Primary Topic
Prostate Cancer Treatment and Research
Type
article
Field-Weighted Citation Impact
4.56

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article

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

Emily Feng, Eric Jay Small, Aishwarya Subramanian, Nicholas R. Rydzewski et al.
3 citations
Molecular Oncology
Prostate Cancer Treatment and Research
4.56
article

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

Emily Feng, Eric Jay Small, Aishwarya Subramanian, Nicholas R. Rydzewski, Joshua M. Lang, Anders Bjartell, Manish Kohli, Kyle T. Helzer, Alex H. Chang, Pernilla Wikström, Martin Sjöström, Yue Shi, Eric Feng, David A. Quigley, Marina N. Sharifi, Jamie M. Sperger, Grace C. Blitzer, Scott M. Dehm, Amy K. Taylor, Rendong Yang, Andreas Josefsson, Matthew L. Bootsma, Shuang George Zhao, Rahul Aggarwal, Luke A. Nunamaker, V. Carreño, Tianfu Andy Shang
article en
3 citations

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: (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.

Molecular OncologyVol. 19(8)
Northwestern University (US), University of Minnesota (US), University of Wisconsin–Madison (US), University of California, San Francisco (US), Lund University (SE), University of Utah (US), Huntsman Cancer Institute (US), University of Wisconsin Carbone Cancer Center (US), University of Minnesota Medical Center (US), Skåne University Hospital (SE), William S. Middleton Memorial Veterans Hospital (US), UCSF Helen Diller Family Comprehensive Cancer Center (US), Umeå University (SE)
U.S. Department of Defense, Doris Duke Charitable Foundation, Prostate Cancer Foundation, Movember Foundation, Cancerfonden, Knut och Alice Wallenbergs Stiftelse, National Institutes of Health, National Cancer Institute, Division of Graduate Education
Good health and well-being
Openalex Percentile: Top 7%
Prostate Cancer Treatment and Research
4.56
DOIOpen Access PDFOpenAlex
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