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 Feng; Robert 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

doi:10.1016/j.eururo.2020.05.009

Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer

Eur Urol. 2020 Sep;78(3):327-332. doi: 10.1016/j.eururo.2020.05.009. Epub 2020 May 24.

Authors

Amar U Kishan¹, Tahmineh Romero², Mohammed Alshalalfa³, Yang Liu⁴, Phuoc T Tran⁵, Nicholas G Nickols⁶, Huihui Ye⁷, Dipti Sajed⁷, Matthew B Rettig⁸, Robert E Reiter⁹, Isla P Garraway¹⁰, Daniel E Spratt¹¹, Steven J Freedland¹², Xin Zhao⁴, Ziwen Li⁴, Matthew Deek⁵, Julie Livingstone¹³, Brandon A Mahal¹⁴, Paul L Nguyen¹⁴, Felix Y Feng³, Robert B Den¹⁵, Edward M Schaeffer¹⁶, Tamara L Lotan⁵, R Jeffrey Karnes¹⁷, Eric A Klein¹⁸, Ashley E Ross¹⁹, Tristan Grogan², Elai Davicioni⁴, David Elashoff², Paul C Boutros²⁰, Joanne B Weidhaas¹³

Affiliations

¹ Department of Radiation Oncology, University of California, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, CA, USA. Electronic address: aukishan@mednet.ucla.edu.
² Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³ Department of Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
⁴ Decipher Biosciences, San Diego, CA, USA.
⁵ Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Radiation Oncology, University of California, Los Angeles, CA, USA; Department of Radiation Oncology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁷ Department of Pathology, University of California, Los Angeles, CA, USA.
⁸ Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Division of Hematology and Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁹ Department of Urology, University of California, Los Angeles, CA, USA.
¹⁰ Department of Urology, University of California, Los Angeles, CA, USA; Division of Urology, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.
¹¹ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Surgery, Division of Urology, Veteran Affairs Healthcare System, Durham, NC, USA.
¹³ Department of Radiation Oncology, University of California, Los Angeles, CA, USA.
¹⁴ Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
¹⁶ Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁷ Department of Urology, Mayo Clinic, Rochester, MN, USA.
¹⁸ Glickman Urological Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁹ Texas Urology Specialists, Dallas, TX, USA.
²⁰ Department of Urology, University of California, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, CA, USA.

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.

Keywords: Biomarkers; Gleason grade group 5; Gleason score 10; Gleason score 9; Transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Cohort Studies
Genetic Variation
Humans
Male
Middle Aged
Neoplasm Grading
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / pathology*
Transcriptome*

Abstract

Publication types

MeSH terms

Grants and funding