Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer.
Eur Urol
; 76(1): 89-97, 2019 07.
Article
em En
| MEDLINE
| ID: mdl-30553611
ABSTRACT
BACKGROUND:
TP53, PTEN, and RB1 tumor suppressor genes (TSGs) are recurrently altered in treatment-resistant prostate cancer. Cooperative loss of two or more TSGs may drive more aggressive disease.OBJECTIVE:
To determine clinical outcomes of single and compound TSG alterations across the spectrum of prostate cancer. DESIGN, SETTING, ANDPARTICIPANTS:
Massively parallel targeted sequencing using castration-sensitive prostate cancer (CSPC; localized [L] and metastatic [M1]) and castration-resistant prostate cancer (CRPC) specimens (n=285). TSG altered (TSG-alt) was any copy number loss or deleterious mutation of one or more TSGs (TP53, PTEN, and RB1). OUTCOME MEASUREMENTS AND STATISTICALANALYSIS:
For L-CSPC, event-free survival (EFS) and time to CRPC were estimated. For M1-CSPC and M1-CRPC, overall survival (OS) was estimated. Cox regression models assessed the association between cumulative TSG hits (zero hits vs one hit vs two to three hits) and outcomes with multivariable analyses adjusted for clinicopathological factors. RESULTS ANDLIMITATIONS:
TSG variants increased with advanced disease (L-CSPC 39%; M1-CSPC 63%, M1-CRPC 92%). TSG-alt L-CSPC had shorter EFS (median 2.6yr, hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.22-3.13) and time to CRPC (median 9.5mo, HR 3.36, 95% CI 1.01-11.16). Cumulative gene hits led to an incremental risk of relapse (EFS one gene, HR 1.69, 95% CI 0.99-2.87; two to three genes, HR 2.70, 95% CI 1.43-5.08; both versus zero genes, p=0.004). There was evidence of inferior OS with increasing TSG hits in the metastatic cohorts. Only four (8%) patients in the M1-CRPC cohort were TSG-neg, one of whom died after 5.2yr. Multivariable analyses adjusting for mutational and copy number burden did not demonstrate a significant independent association of increasing gene hits and poorer outcomes.CONCLUSIONS:
Deleterious TSG variants are associated with an increased risk of relapse (L) and death (M1) in CSPC. Poorer outcomes are seen with compound gene hits in both early and advanced disease, and this may in part reflect increasing global genomic instability. PATIENTSUMMARY:
Men with prostate tumors with compound tumor suppressor gene mutations have poorer outcomes. These findings help identify patients with aggressive features who may benefit from intensified treatment.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Prostatectomia
/
Neoplasias da Próstata
/
Proteína Supressora de Tumor p53
/
Ubiquitina-Proteína Ligases
/
PTEN Fosfo-Hidrolase
/
Proteínas de Ligação a Retinoblastoma
/
Recidiva Local de Neoplasia
Tipo de estudo:
Prognostic_studies
Limite:
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Eur Urol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos