Genomic correlates of clinical outcome in advanced prostate cancer
Genomic correlates of clinical outcome in advanced prostate cancer
复制标题
DOI：
10.1073/pnas.1902651116
复制
发表时间：
2019-06-04
影响因子：
11.1
通讯作者：
Sawyers, Charles L.
中科院分区：
文献类型：
--
作者：
Abida, Wassim;Cyrta, Joanna;Sawyers, Charles L.
转移性前列腺癌基因组景观中的异质性通过几次全面的分析工作已经变得明显，但关于这种异质性对临床结果的影响知之甚少。在这里，我们报告了429例转移性去势抵抗性前列腺癌（mCRPC）患者的全面基因组和转录组分析，这些患者与纵向临床结局相关，整合了全外显子组，转录组和组织学分析的结果。对于128例接受一线下一代雄激素受体信号传导抑制剂（ARSI;阿比特龙或恩杂鲁胺）治疗的患者，我们检查了18种复发性基于DNA和RNA的基因组改变（包括雄激素受体（AR）变体表达、AR转录输出和神经内分泌表达特征）与临床结局的相关性。其中，只有RB 1的改变与不良生存率显著相关，而RB 1、AR和TP 53的改变与ARSI治疗时间缩短相关。这项将mCRPC基因组学与组织学和临床结局相结合的大型分析将RB 1基因组改变确定为不良结局的有效预测因子，并且是进一步询问临床和分子相关性的社区资源。
Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA-and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.