Genomics of lethal prostate cancer at diagnosis and castration resistance

• Published in: The Journal of clinical investigation Vol. 130; no. 4; pp. 1743 - 1751
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2020
• Subjects: 1-Phosphatidylinositol 3-kinase; Abiraterone; AKT protein; Biomedical research; Biopsy; BRCA2 protein; Cancer genetics; Cancer metastasis; Cancer patients; Cancer research; Cancer treatment; Care and treatment; Castration; Copy number; Defects; Deoxyribonucleic acid; Diagnosis; Disease-Free Survival; DNA; DNA sequencing; Enzalutamide; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genetic research; Genomes; Genomics; Hormones; Humans; Male; Medical diagnosis; Medical prognosis; Medical research; Metastases; Metastasis; Mutation; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; p53 Protein; Patients; Pharmaceutical industry; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - mortality; Prostatic Neoplasms, Castration-Resistant - pathology; PTEN protein; Software industry; Survival Rate; Tumor proteins; Tumors; Whole genome sequencing; United States; United Kingdom; Oncology; Molecular biology; Prostate cancer; Cancer; Cell Biology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci132031

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.