Genomics of lethal prostate cancer at diagnosis and castration-resistance

Joaquin Mateo, George Seed, Claudia Bertan, Pasquale Rescigno, David Dolling, Ines Figueiredo, Susana Miranda, Daniel Nava Rodrigues, Bora Gurel, Matthew Clarke, Mark Atkin, Rob Chandler, Carlo Messina, Semini Sumanasuriya, Diletta Bianchini, Maialen Barrero, Antonella Petremolo, Zafeiris Zafeiriou, Mariane Sousa Fontes, Raquel Perez-LopezNina Tunariu, Ben A Fulton, Robert Jones, Ursula B McGovern, Christy Ralph, Mohini Varughese, Omi Parikh, Suneil Jain, Tony Elliott, Shahneen Sandhu, Nuria Porta, Emma Hall, Wei Yuan, Suzanne Carreira, Johann S de Bono

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Genomics of primary prostate cancer differs from that 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-naïve, 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 significantly commoner than described in the TCGA cohort. Patients with RB1 loss in the primary tumour had a worse prognosis. Among 61 men with matched hormone-naïve 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 differs to that of the 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.

Original languageEnglish
JournalThe Journal of clinical investigation
Early online date24 Dec 2019
Publication statusEarly online date - 24 Dec 2019


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