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- Title
Genomics of lethal prostate cancer at diagnosis and castration resistance.
- Authors
Mateo, Joaquin; Seed, George; Bertan, Claudia; Rescigno, Pasquale; Dolling, David; Figueiredo, Ines; Miranda, Susana; Nava Rodrigues, Daniel; Gurel, Bora; Clarke, Matthew; Atkin, Mark; Chandler, Rob; Messina, Carlo; Sumanasuriya, Semini; Bianchini, Diletta; Barrero, Maialen; Petermolo, Antonella; Zafeiriou, Zafeiris; Fontes, Mariane; Perez-Lopez, Raquel; Tunariu, Nina; Fulton, Ben; Jones, Robert; McGovern, Ursula; Ralph, Christy; Varughese, Mohini; Parikh, Omi; Jain, Suneil; Elliott, Tony; Sandhu, Shahneen; Porta, Nuria; Hall, Emma; Yuan, Wei; Carreira, Suzanne; de Bono, Johann S
- 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.
- Publication
The Journal of clinical investigation, 2020, Vol 130, Issue 4, p1743
- ISSN
1558-8238
- Publication type
Journal Article
- DOI
10.1172/JCI132031