Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer

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.

PMID: 32461072
PMCID: PMC8954568
DOI: 10.1016/j.eururo.2020.05.009

Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer

Amar U Kishan et al. Eur Urol. 2020 Sep.

. 2020 Sep;78(3):327-332.

doi: 10.1016/j.eururo.2020.05.009. Epub 2020 May 24.

Authors

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.

PMID: 32461072
PMCID: PMC8954568
DOI: 10.1016/j.eururo.2020.05.009

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.

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Conflict of interest statement

Financial disclosures: Amar U. Kishan certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Amar Kishan reports honoraria and consulting fees from Varian Medical Systems, Inc., and honoraria from ViewRay, Inc., outside the scope of the submitted work. Mohammed Alshalalfa reports personal fees from GenomeDx outside the submitted work. Brandon Mahal reports grants from the Department of Defense, Prostate Cancer Foundation, and American Society for Radiation Oncology; and travel honoraria from Genzyme, the Exeter Group, and the Prostate Health Education Network, outside the submitted work. Elai Davicioni reports personal fees from GenomeDx (Decipher) outside the submitted work. R. Jeffrey Karnes reports royalties from GenomeDx outside the submitted work. Tamara L. Lotan reports grants from the Prostate Cancer Foundation outside the submitted work. Daniel E. Spratt reports grants from the Prostate Cancer Foundation and personal fees from Janssen, Blue Earth, and AstraZeneca, outside the submitted work. Felix Y. Feng reports personal fees from Dendreon, EMD Serono, Janssen Oncology, Ferring, Sanofi, Bayer, Blue Earth Diagnostics, Celgene, Medivation/Astellas, and Clovis Oncology, and ownership interests in PFS Genomics outside the submitted work; in addition, Feng has a patent issued (EP3047037 A4). Paul L. Nguyen reports the receipt of consulting fees from Ferring, Bayer, Janssen, Astellas, Dendreon, GenomeDx, Blue Earth Diagnostics, Cota, Boston Scientific, and Nanobiotix; grant funding from Janssen, Bayer, and Astellas; and equity in Augmenix. Ashley Ross reports stock in GenomeDx, honoraria from Healthtronics, and research funding from Metamark Genetics, outside the scope of the current work. Edward Schaeffer reports consulting or advisory roles at Genome Dx, OPKO Health, and Abbvie, outside the scope of the submitted work. Eric A. Klein reports consulting roles for GenomeDx, outside the scope of the submitted work.

Figures

**Fig. 1 –**
Heatmap of 2138 patients with Gleason grade group 5 disease after consensus clustering based on transcriptomic activation of 56 hallmark gene sets. Four clusters were identified: brown, low genomic risk cluster; gray, high genomic risk cluster; blue, blue cluster; and purple, purple cluster.

**Fig. 2 –**
Box plots showing (A) transcriptional activation of hallmark pathways related to DNA repair, immune response, and androgen response, segregated by cluster; and(B) average genomic risk scores and Decipher scores.

See this image and copyright information in PMC

Comment in

High-risk Prostate Cancer Patients Are Not All Alike.
Troyer D. Troyer D. Eur Urol. 2020 Sep;78(3):333-334. doi: 10.1016/j.eururo.2020.06.024. Epub 2020 Jun 27. Eur Urol. 2020. PMID: 32605857 No abstract available.

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Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer

Affiliations

Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer

Authors

Affiliations

Abstract

Conflict of interest statement

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MeSH terms

Grants and funding

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Full Text Sources

Medical