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Clinical Trial
. 2020 Apr 1;130(4):1743-1751.
doi: 10.1172/JCI132031.

Genomics of lethal prostate cancer at diagnosis and castration resistance

Affiliations
Clinical Trial

Genomics of lethal prostate cancer at diagnosis and castration resistance

Joaquin Mateo et al. J Clin Invest. .

Abstract

The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.

Keywords: Cancer; Cell Biology; Molecular biology; Oncology; Prostate cancer.

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Conflict of interest statement

Conflict of interest: JM has served as a consultant for AstraZeneca, Roche, Janssen, Clovis, and Amgen. TE has received educational grants from Janssen. RJ has received fees from or acted in an advisory role for Astellas, AstraZeneca, Bristol-Myers Squibb, Bayer, Exelixis, Janssen, Ipsen, Merck Serono, Novartis, Pfizer, Roche, Sanofi, and EUSA Pharma. CR has received research grants from Oncolytics and Tusk Therapeutics, honoraria from Bristol-Myers Squibb, and support for travel from Roche, GlaxoSmithKline, Viralytics, Janssen, Novartis, Pfizer, and Ipsen. SJ has received fees from or acted in an advisory role for Astellas, Janssen, Bayer, Boston Scientific, and Almac Diagnostics. JSDB has served as a consultant for Astellas, AstraZeneca, Bayer, Daiichi, Genentech, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dome, Orion, Pfizer Oncology, Sanofi-Aventis, Silicon Biosystems, and Taiho.

Figures

Figure 1
Figure 1. Oncoprint of genomic aberrations.
The oncoprint includes nonsense, indels, splice site mutations, relevant missense mutations, and copy number changes for 470 untreated primary prostate cancer biopsies from patients who later developed metastatic castration-resistant disease.
Figure 2
Figure 2. Differences in genomic profiles among same-patient, matched, primary-untreated, and mCRPC biopsies.
(A) Mutation calls in genes of interest for the mCRPC biopsies which were not present in the treatment-naive primary tumor for the same patient (61 pairs, full gene set in Supplemental Figure 6). (B) Overall copy number profiles based on low-pass WGS (52 pairs). (C) Amplifications (Amp) and deep deletions (HomDel) detected in the mCRPC biopsies and not present in the treatment-naive primary tumors for the same patient (based on low-pass WGS, after adjusting for tumor purity and ploidy, and validated by SNP data from targeted panel sequencing).

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