Clinical and Genomic Features of Androgen Indifferent Prostate Cancer

Masur, Jack; Ratan, Aakrosh; Wierbilowicz, Krzysztof; Ayanambakkam, Adanma; Churchman, Michelle L.; Graham, Laura S.; Grass, George Daniel; Gupta, Sumati; Kern, Sean Q.; King, Jennifer; Myint, Zin; Rounbehler, Robert J.; Salhia, Bodour; Singer, Eric A.; Zakharia, Yousef; Paschal, Bryce M.; Viscuse, Paul V.

doi:10.3390/ijms26020679

Open AccessArticle

Clinical and Genomic Features of Androgen Indifferent Prostate Cancer

by

Jack Masur

^1,*

,

Aakrosh Ratan

²,

Krzysztof Wierbilowicz

³

,

Adanma Ayanambakkam

⁴

,

Michelle L. Churchman

⁵,

Laura S. Graham

⁶

,

George Daniel Grass

⁷,

Sumati Gupta

⁸

,

Sean Q. Kern

⁹

,

Jennifer King

¹⁰,

Zin Myint

¹¹

,

Robert J. Rounbehler

⁵,

Bodour Salhia

¹²,

Eric A. Singer

¹³,

Yousef Zakharia

¹⁴

,

Bryce M. Paschal

³ and

Paul V. Viscuse

¹

Division of Hematology/Oncology, University of Virginia, Charlottesville, VA 22903, USA

²

Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA

³

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA

⁴

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

⁵

Aster Insights, Hudson, FL 34667, USA

⁶

Department of Medicine, Division of Medical Oncology, University of Colorado Cancer Center Anschutz Medical Campus, Aurora, CO 80045, USA

⁷

H. Lee Moffitt Cancer Center, Department of Radiation Oncology, Tampa, FL 33612, USA

⁸

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84103, USA

⁹

Murtha Cancer Center, Uniformed Services University, Bethesda, MD 20814, USA

¹⁰

Department of Medicine, Division of Hematology and Medical Oncology, Indiana University Health Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA

¹¹

Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40546, USA

¹²

Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA

¹³

Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA

¹⁴

Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA

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^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(2), 679; https://doi.org/10.3390/ijms26020679

Submission received: 12 December 2024 / Revised: 7 January 2025 / Accepted: 12 January 2025 / Published: 15 January 2025

(This article belongs to the Special Issue Prostate Cancer: Novel Research and Innovative Therapeutic Strategies)

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Abstract

Androgen-indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse, and AIPC remains a poorly understood malignancy. Utilizing the Oncology Research Information Exchange Network (ORIEN) database, we enriched for tumors with features of AIPC using previously described characteristics. Our AIPC cohort included three subgroups: aggressive variant prostate cancer (AVPC), neuroendocrine PC (NEPC), and double-negative PC (DNPC). Of 1496 total PC patients available for analysis, we identified 323 (22%) as MCRPC. Of those, 39 (12%) met AIPC criteria (17 AVPC, 13 NEPC, 9 DNPC) and 284 (88%) were non-AIPC. Forty-three percent of AIPC patients had de novo metastatic disease vs. 15% for non-AIPC (p = 0.003). Homologous recombination deficiency (HRD) and tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) were significantly higher in AIPC (p = 0.019). Using Gene Set Enrichment Analysis (GSEA), we found that genes defining response to androgens and genes involved in oxidative phosphorylation were the most downregulated, whereas genes involved in epithelial–mesenchymal transition (EMT) and immune signaling were significantly upregulated in AIPC vs. non-AIPC. Our study demonstrates the potential for predefined criteria that aim to enrich for AIPC and suggests opportunities for therapeutic investigation.

Keywords: prostate cancer; androgen-indifferent prostate cancer; molecular biology; genomics; biomarkers; therapeutic targets

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MDPI and ACS Style

Masur, J.; Ratan, A.; Wierbilowicz, K.; Ayanambakkam, A.; Churchman, M.L.; Graham, L.S.; Grass, G.D.; Gupta, S.; Kern, S.Q.; King, J.; et al. Clinical and Genomic Features of Androgen Indifferent Prostate Cancer. Int. J. Mol. Sci. 2025, 26, 679. https://doi.org/10.3390/ijms26020679

AMA Style

Masur J, Ratan A, Wierbilowicz K, Ayanambakkam A, Churchman ML, Graham LS, Grass GD, Gupta S, Kern SQ, King J, et al. Clinical and Genomic Features of Androgen Indifferent Prostate Cancer. International Journal of Molecular Sciences. 2025; 26(2):679. https://doi.org/10.3390/ijms26020679

Chicago/Turabian Style

Masur, Jack, Aakrosh Ratan, Krzysztof Wierbilowicz, Adanma Ayanambakkam, Michelle L. Churchman, Laura S. Graham, George Daniel Grass, Sumati Gupta, Sean Q. Kern, Jennifer King, and et al. 2025. "Clinical and Genomic Features of Androgen Indifferent Prostate Cancer" International Journal of Molecular Sciences 26, no. 2: 679. https://doi.org/10.3390/ijms26020679

APA Style

Masur, J., Ratan, A., Wierbilowicz, K., Ayanambakkam, A., Churchman, M. L., Graham, L. S., Grass, G. D., Gupta, S., Kern, S. Q., King, J., Myint, Z., Rounbehler, R. J., Salhia, B., Singer, E. A., Zakharia, Y., Paschal, B. M., & Viscuse, P. V. (2025). Clinical and Genomic Features of Androgen Indifferent Prostate Cancer. International Journal of Molecular Sciences, 26(2), 679. https://doi.org/10.3390/ijms26020679

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Clinical and Genomic Features of Androgen Indifferent Prostate Cancer

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