The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer-Reference-Cited by-同舟云学术

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

Published:2023-06-08 Issue:16 Volume:83 Page:2763-2774
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Lundberg Arian¹²^ORCID,Zhang Meng¹²^ORCID,Aggarwal Rahul¹³^ORCID,Li Haolong¹²^ORCID,Zhang Li¹⁴^ORCID,Foye Adam¹²^ORCID,Sjöström Martin¹²^ORCID,Chou Jonathan¹³^ORCID,Chang Kevin¹³^ORCID,Moreno-Rodriguez Thaidy¹⁵^ORCID,Shrestha Raunak¹²^ORCID,Baskin Avi¹²^ORCID,Zhu Xiaolin¹³^ORCID,Weinstein Alana S.¹²^ORCID,Younger Noah¹³^ORCID,Alumkal Joshi J.⁶^ORCID,Beer Tomasz M.⁷^ORCID,Chi Kim N.⁸^ORCID,Evans Christopher P.⁹¹⁰^ORCID,Gleave Martin⁸^ORCID,Lara Primo N.⁹¹¹^ORCID,Reiter Rob E.¹²¹³^ORCID,Rettig Matthew B.¹²¹³¹⁴^ORCID,Witte Owen N.¹⁵^ORCID,Wyatt Alexander W.⁸¹⁶^ORCID,Feng Felix Y.¹²³⁵^ORCID,Small Eric J.¹³^ORCID,Quigley David A.¹⁵¹⁷^ORCID

Affiliation:

1. 1Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.

2. 2Department of Radiation Oncology, University of California San Francisco, San Francisco, California.

3. 3Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, California.

4. 4Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California.

5. 5Department of Urology, University of California San Francisco, San Francisco, California.

6. 6Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, Michigan.

7. 7Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.

8. 8Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

9. 9Comprehensive Cancer Center, University of California Davis, Sacramento, California.

10. 10Department of Urologic Surgery, University of California Davis, Sacramento, California.

11. 11Division of Hematology Oncology, Department of Internal Medicine, University of California Davis, Sacramento, California.

12. 12Departments of Medicine, Hematology/Oncology and Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

13. 13Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.

14. 14VA Greater Los Angeles Healthcare System, Los Angeles, California.

15. 15Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

16. 16Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada.

17. 17Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California.

Abstract

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.

Funder

Stand Up To Cancer

Movember Foundation

Prostate Cancer Foundation

Pilot grant, Department of Urology, UCSF

UCSF Benioff Initiative for Prostate Cancer Research

National Institutes of Health (NIH)/National Cancer Institute

NIH/NCI

NIH

Publisher

American Association for Cancer Research (AACR)

Subject