Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 23, Pages 11428-11436Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1902651116
Keywords
castration-resistant prostate cancer; integrative genomics; clinical outcomes; biomarkers
Categories
Funding
- Prostate Cancer Foundation
- Stand Up to Cancer Prostate Cancer Dream Team research grant
- American Association for Cancer Research Award [SU2C-AACR-DT0712]
- Prostate Cancer Foundation Young Investigator Awards
- Department of Defense Prostate Cancer Research Program [W81XWH-17-1-0124, W81XWH-09-1-0147, PC170510, PC170503P2, W81XWH-17-1-0380]
- NCI Prostate Cancer SPORE Awards [P50CA186786, P50CA092629, P50CA090381, P50CA211024, P50CA097186]
- NCI Cancer Center Award [P30 CA008748]
- NIH Award [R01CA125612]
- European Research Council Consolidator Grant [648670]
- Nuovo-Soldati Foundation
- Movember Foundation
- Prostate Cancer UK
- ECMC network from Cancer Research UK
- Department of Health in the UK
- BRC
- PCF
- European Research Council (ERC) [648670] Funding Source: European Research Council (ERC)
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Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA-and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
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