Journal Article

Genomics of lethal prostate cancer at diagnosis and castration resistance

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

2020

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: 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