Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns
Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns
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DOI：
10.1016/j.eururo.2017.01.011
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发表时间：
2017-08-01
期刊：
影响因子：
23.4
通讯作者：
Lindberg, Johan
中科院分区：
文献类型：
--
作者：
De laere, Bram;van Dam, Pieter-Jan;Lindberg, Johan
背景资料：雄激素受体剪接变异体7（AR-V7）的表达与去势抵抗性前列腺癌（CRPC）二线内分泌治疗的不良反应相关然而，很大一部分无反应的患者AR-V7-negative.Objective：为了调查，如果一个全面的液体活检为基础的AR配置文件可能会改善患者分层的背景下，二线endocrine therapy.Design，设置，和participants：外周血收集与CRPC患者（n = 30）开始一个新的线的系统治疗。我们通过低通全基因组测序和整个AR基因（包括内含子）的靶向测序对循环肿瘤DNA进行了分析。对富集的循环肿瘤细胞组分进行靶向RNA测序，以评估7种AR剪接变体（ARV）的表达水平。结果测量和统计分析：体细胞AR变异，包括拷贝数改变，结构变异和点突变，与ARV表达模式相结合，并与临床病理参数相关。令人惊讶的是，AR内结构变异存在于15/30例患者中，其中14例表达ARV。大多数ARV阳性患者表达多种ARV，其中AR-V3表达最丰富。任何抗逆转录病毒药物的存在与二线内分泌治疗后的无进展生存期相关（风险比4.53，95%置信区间1.424-14.41; p = 0.0105）。六出17个不良反应者AR-V7阴性，但四个进行其他AR perturbation.Conclusions：全面的AR分析，这是可行的，使用液体活检，是必要的，以增加我们的了解的机制的基础抵抗内分泌治疗。患者总结：雄激素受体的改变与内分泌治疗结局相关。这项研究表明，通过简单的抽血可以识别不同类型的改变。需要进行后续研究，以确定这种改变对激素治疗的影响。(C)2017年欧洲泌尿外科协会。Elsevier B. V.出版，保留所有权利。
Background: Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative.Objective: To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy.Design, setting, and participants: Peripheral blood was collected from patients with CRPC (n = 30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs). Outcome measurements and statistical analysis: Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters.Results and limitations: Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424-14.41; p = 0.0105). Six out of 17 poor responders were AR-V7-negative, but four carried other AR perturbations.Conclusions: Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment. Patient summary: Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of such alterations on hormonal therapy. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.