Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer

Amar U. Kishan, Tahmineh Romero, Mohammed Alshalalfa, Yang Liu, Phuoc T. Tran, Nicholas G. Nickols, Huihui Ye, Dipti Sajed, Matthew B. Rettig, Robert E. Reiter, Isla P. Garraway, Daniel E. Spratt, Steven J. Freedland, Xin Zhao, Ziwen Li, Matthew Deek, Julie Livingstone, Brandon A. Mahal, Paul L. Nguyen, Felix Y. FengRobert B. Den, Edward M. Schaeffer, Tamara L. Lotan, R. Jeffrey Karnes, Eric A. Klein, Ashley E. Ross, Tristan Grogan, Elai Davicioni, David Elashoff, Paul C. Boutros, Joanne B. Weidhaas

Research output: Contribution to journalArticle

Abstract

Gleason grade group (GG) 5 prostate cancer has been associated with an aggressive natural history, and retrospective data support a role for treatment intensification. However, clinical outcomes remain heterogeneous in this cohort, and intensified treatments carry an increased risk of adverse events. We sought to explore the transcriptomic heterogeneity of GG 5 tumors by querying transcriptomic data from the tumors of 2138 patients with GG 5 disease who underwent prostatectomy. Four distinct consensus clusters were identified with respect to differential transcriptional activation of hallmark pathways, with distinct molecular subtyping profiles and different average genomic risks (AGRs). One cluster, accounting for 325 tumors (15.2% of the population), was enriched for genes related to the cell cycle/proliferation, metabolic pathways, androgen response pathways, and DNA repair, and had a higher AGR than the other clusters (p < 0.001). This clustering, with an identification of a high genomic risk cluster, was subsequently validated in a separate cohort of 1921 patients as well as a third cohort of 201 patients. The latter cohort had outcomes available, and it was found that patients in the high genomic risk cluster had significantly worse distant metastasis-free survival than the other clusters. Tumors in this high genomic risk cluster of GG 5 disease may be particularly likely to benefit from treatment intensification. Patient summary: In this report, we examined differences in gene expression in tumors from men with Gleason grade group 5 prostate cancer. We identified significant diversity, with one specific subgroup of tumors associated with expression profiles that suggest a worse prognosis. Using transcriptomic data from a large cohort of men treated with radical prostatectomy for Gleason grade group 5 prostate cancer, we identified four distinct clusters of patients based on transcriptional activation of different hallmark pathways. This clustering was replicated in two additional datasets, including one with long-term clinical outcomes. In the latter, patients in one cluster were found to be at a particularly high risk of distant metastases.

Original languageEnglish (US)
JournalEuropean urology
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • Biomarkers
  • Gleason grade group 5
  • Gleason score 10
  • Gleason score 9
  • Transcriptomics

ASJC Scopus subject areas

  • Urology

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  • Cite this

    Kishan, A. U., Romero, T., Alshalalfa, M., Liu, Y., Tran, P. T., Nickols, N. G., Ye, H., Sajed, D., Rettig, M. B., Reiter, R. E., Garraway, I. P., Spratt, D. E., Freedland, S. J., Zhao, X., Li, Z., Deek, M., Livingstone, J., Mahal, B. A., Nguyen, P. L., ... Weidhaas, J. B. (Accepted/In press). Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer. European urology. https://doi.org/10.1016/j.eururo.2020.05.009