Genomics of lethal prostate cancer at diagnosis and castration resistance.
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Authors
Mateo, J
Seed, G
Bertan, C
Rescigno, P
Dolling, D
Figueiredo, I
Miranda, S
Nava Rodrigues, D
Gurel, B
Clarke, M
Atkin, M
Chandler, R
Messina, C
Sumanasuriya, S
Bianchini, D
Barrero, M
Petermolo, A
Zafeiriou, Z
Fontes, M
Perez-Lopez, R
Tunariu, N
Fulton, B
Jones, R
McGovern, U
Ralph, C
Varughese, M
Parikh, O
Jain, S
Elliott, T
Sandhu, S
Porta, N
Hall, E
Yuan, W
Carreira, S
de Bono, JS
Seed, G
Bertan, C
Rescigno, P
Dolling, D
Figueiredo, I
Miranda, S
Nava Rodrigues, D
Gurel, B
Clarke, M
Atkin, M
Chandler, R
Messina, C
Sumanasuriya, S
Bianchini, D
Barrero, M
Petermolo, A
Zafeiriou, Z
Fontes, M
Perez-Lopez, R
Tunariu, N
Fulton, B
Jones, R
McGovern, U
Ralph, C
Varughese, M
Parikh, O
Jain, S
Elliott, T
Sandhu, S
Porta, N
Hall, E
Yuan, W
Carreira, S
de Bono, JS
Document Type
Journal Article
Date
2020-04-01
Date Accepted
2019-12-18
Date Available
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.
Citation
The Journal of clinical investigation, 2020, 130 (4), pp. 1743 - 1751
Source Title
Publisher
AMER SOC CLINICAL INVESTIGATION INC
ISSN
0021-9738
eISSN
1558-8238
Collections
Research Team
Cancer Biomarkers
Clinical Trials & Statistics Unit
ICR-CTSU Urology and Head and Neck Trials Team
Prostate Cancer Targeted Therapy Group
Clinical Trials & Statistics Unit
ICR-CTSU Urology and Head and Neck Trials Team
Prostate Cancer Targeted Therapy Group