Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Department of Pathology, Weill Medical College of Cornell University, New York, NY 10021.
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11428-11436. doi: 10.1073/pnas.1902651116. Epub 2019 May 6.
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 () variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only alteration was significantly associated with poor survival, whereas alterations in , , and were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
通过几项全面的分析工作，转移性前列腺癌的基因组景观中的异质性已经变得明显，但是对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）患者的综合基因组和转录组分析，这些患者与纵向临床结果相关联，并整合了全外显子、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抑制剂（ARSI；阿比特龙或恩扎鲁胺）治疗的患者，我们检查了 18 种常见的基于 DNA 和 RNA 的基因组改变与临床结果的关联，包括雄激素受体（）变体表达、AR 转录输出和神经内分泌表达特征。在这些改变中，只有改变与不良生存显著相关，而改变与 ARSI 治疗时间较短相关。这项将 mCRPC 基因组学与组织学和临床结果相结合的大型分析确定了改变是不良预后的一个有力预测因子，并且是进一步研究临床和分子相关性的社区资源。
