The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer

Arian Lundberg; Meng Zhang; Rahul Aggarwal; Haolong Li; Li Zhang; Adam Foye; Martin Sjöström; Jonathan Chou; Kevin Chang; Thaidy Moreno-Rodriguez; Raunak Shrestha; Avi Baskin; Xiaolin Zhu; Alana S Weinstein; Noah Younger; Joshi J Alumkal; Tomasz M Beer; Kim N Chi; Christopher P Evans; Martin Gleave; Primo N Lara; Rob E Reiter; Matthew B Rettig; Owen N Witte; Alexander W Wyatt; Felix Y Feng; Eric J Small; David A Quigley

doi:10.1158/0008-5472.CAN-23-0593

The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer

Cancer Res. 2023 Aug 15;83(16):2763-2774. doi: 10.1158/0008-5472.CAN-23-0593.

Authors

Arian Lundberg^{1

2}, Meng Zhang^{1

2}, Rahul Aggarwal^{1

3}, Haolong Li^{1

2}, Li Zhang^{1

4}, Adam Foye^{1

2}, Martin Sjöström^{1

2}, Jonathan Chou^{1

3}, Kevin Chang^{1

3}, Thaidy Moreno-Rodriguez^{1

5}, Raunak Shrestha^{1

2}, Avi Baskin^{1

2}, Xiaolin Zhu^{1

3}, Alana S Weinstein^{1

2}, Noah Younger^{1

3}, Joshi J Alumkal⁶, Tomasz M Beer⁷, Kim N Chi⁸, Christopher P Evans^{9

10}, Martin Gleave⁸, Primo N Lara^{9

11}, Rob E Reiter^{12

13}, Matthew B Rettig^{12

13

14}, Owen N Witte¹⁵, Alexander W Wyatt^{8

16}, Felix Y Feng^#^{1

2

3

5}, Eric J Small^#^{1

3}, David A Quigley^#^{1

5

4}

Affiliations

¹ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
² Department of Radiation Oncology, University of California San Francisco, San Francisco, California.
³ Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, California.
⁴ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California.
⁵ Department of Urology, University of California San Francisco, San Francisco, California.
⁶ Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, Michigan.
⁷ Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
⁸ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
⁹ Comprehensive Cancer Center, University of California Davis, Sacramento, California.
¹⁰ Department of Urologic Surgery, University of California Davis, Sacramento, California.
¹¹ Division of Hematology Oncology, Department of Internal Medicine, University of California Davis, Sacramento, California.
¹² Departments of Medicine, Hematology/Oncology and Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
¹³ Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.
¹⁴ VA Greater Los Angeles Healthcare System, Los Angeles, California.
¹⁵ Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
¹⁶ Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada.

^# Contributed equally.

Abstract

Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor (AR)-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by AR and neuroendocrine (NE) markers. Molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent mCRPC by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing from 210 tumors. AR-/NE- tumors were clinically and molecularly distinct from other mCRPC subtypes, with the shortest survival, amplification of the chromatin remodeler CHD7, and PTEN loss. Methylation changes in CHD7 candidate enhancers were linked to elevated CHD7 expression in AR-/NE+ tumors. Genome-wide methylation analysis nominated Krüppel-like factor 5 (KLF5) as a driver of the AR-/NE- phenotype, and KLF5 activity was linked to RB1 loss. These observations reveal the aggressiveness of AR-/NE- mCRPC and could facilitate the identification of therapeutic targets in this highly aggressive disease.

Significance: Comprehensive characterization of the five subtypes of metastatic castration-resistant prostate cancer identified transcription factors that drive each subtype and showed that the double-negative subtype has the worst prognosis.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Androgen Antagonists / therapeutic use
Androgens
Epigenomics
Genomics
Humans
Male
Neuroendocrine Tumors* / genetics
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Receptors, Androgen / genetics
Receptors, Androgen / metabolism

Substances

Receptors, Androgen
Androgen Antagonists
Androgens

Abstract

Publication types

MeSH terms

Substances

Grants and funding