Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer.
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, AND PARTICIPANTS
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 STATISTICAL ANALYSIS
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 AND LIMITATIONS
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.


PATIENT SUMMARY
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.
['Hamid|Anis A|AA|', 'Gray|Kathryn P|KP|', 'Shaw|Grace|G|', 'MacConaill|Laura E|LE|', 'Evan|Carolyn|C|', 'Bernard|Brandon|B|', 'Loda|Massimo|M|', 'Corcoran|Niall M|NM|', 'Van Allen|Eliezer M|EM|', 'Choudhury|Atish D|AD|', 'Sweeney|Christopher J|CJ|']
D014408:Biomarkers, Tumor D016147:Genes, Tumor Suppressor D020022:Genetic Predisposition to Disease D059014:High-Throughput Nucleotide Sequencing D006801:Humans D008297:Male D008875:Middle Aged D009154:Mutation D009364:Neoplasm Recurrence, Local D009367:Neoplasm Staging D051059:PTEN Phosphohydrolase D011468:Prostatectomy D011471:Prostatic Neoplasms D056286:Retinoblastoma Binding Proteins D016019:Survival Analysis D016159:Tumor Suppressor Protein p53 D044767:Ubiquitin-Protein Ligases
Genomics TP53 PTEN RB1 Prostate cancer Tumor suppressor genes Next-generation sequencing Precision medicine Rb p53