Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer
Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer
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DOI：
10.1016/j.eururo.2018.11.045
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发表时间：
2019-07-01
期刊：
影响因子：
23.4
通讯作者：
Sweeney, Christopher J.
中科院分区：
文献类型：
--
作者：
Humid, Anis A.;Gray, Kathryn P.;Sweeney, Christopher J.
背景：TP 53、PTEN和RB 1肿瘤抑制基因（TSGs）在治疗抵抗性前列腺癌中反复改变。合作损失的两个或两个以上的TSGs可能会驱动更多的侵略性diseases.Objective：以确定单一和复合TSG的改变在整个频谱的prostate cancer.Design，设置，和参与者的临床结局：大规模平行靶向测序使用去势敏感性前列腺癌（CSPC;局部[L]和转移性[M1]）和去势抵抗性前列腺癌（CRPC）标本（n = 285）。TSG改变（TSG-alt）是一种或多种TSG（TP 53、PTEN和RB 1）的任何拷贝数丢失或有害突变。结果测量和统计分析：对于L-CSPC，估计无事件生存期（EFS）和至CRPC的时间。对于M1 -CSPC和M1 -CRPC，估计了总生存期（OS）。考克斯回归模型评估之间的关联累积TSG命中（零命中与一个命中与两至三个命中）和多变量分析的结果调整clinical pathologicalfactors.Results和限制：TSG变异增加与先进的疾病（L-CSPC：39%; M1-CSPC：63%，M1 -CRPC：92%）。TSG-alt L-CSPC的EFS（中位数2.6年，风险比[HR] 1.95，95%置信区间[CI] 1.22-3.13）和至CRPC的时间（中位数9.5个月，HR 3.36，95% CI 1.01-11.16）较短。累积的基因命中导致复发风险增加（EFS：1个基因，HR 1.69，95% CI 0.99-2.87; 2 - 3个基因，HR 2.70，95% CI 1.43-5.08;均对零个基因，p = 0.004）。有证据表明，随着转移性队列中TSG命中率的增加，OS较差。M1 -CRPC队列中只有4例（8%）患者为TSG阴性，其中1例在5.2年后死亡。多变量分析调整突变和拷贝数负担没有表现出显着的独立关联增加基因命中和较差outcomes.Conclusions：有害的TSG变异与复发（L）和死亡（M1）的风险增加在CSPC。在早期和晚期疾病中都可以看到复合基因命中的可能结果，这可能部分反映了全球基因组不稳定性的增加。患者摘要：前列腺肿瘤复合肿瘤抑制基因突变的男性预后较差。这些发现有助于识别可能从强化治疗中受益的具有侵袭性特征的患者。(C)2018年欧洲泌尿外科协会。Elsevier B. V.出版，保留所有权利。
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 2.6 yr, hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.22-3.13) and time to CRPC (median 9.5 mo, 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 5.2 yr. 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. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.