Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer
Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer
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DOI：
10.1038/s41598-019-40719-y
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发表时间：
2019-03-11
影响因子：
4.6
通讯作者：
Akamatsu, Shusuke
中科院分区：
文献类型：
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作者：
Sumiyoshi, Takayuki;Mizuno, Kei;Akamatsu, Shusuke
去势抵抗性前列腺癌（CRPC）的治疗前景迅速扩大。需要开发非侵入性生物标志物来指导治疗。我们建立了一种高灵敏度的方法来分析血浆循环游离DNA（cfDNA）中雄激素受体基因（AR）拷贝数（CN）和突变，并评估CRPC患者的AR状态。通过数字PCR（dPCR）在稀释至1.0%的VCaP细胞系（AR扩增的）基因组DNA（gDNA）中可检测到AR扩增。在稀释至0.1%和1.0%的LNCaP细胞系（ART878A突变）gDNA中，分别通过dPCR和靶测序检测到AR突变。接下来，我们分析了来自102名患者的cfDNA中的AR状态。分别在47例和25例患者中检测到AR扩增和突变。作为一种生物标志物，治疗前cfDNA中的AR畸变与阿比特龙的不良反应相关，但与Enzalutamide无关。在来自41名患者的连续cfDNA分析中，基线时的大多数AR畸变随着有效治疗而减少，而在一些疾病进展的患者中，出现AR扩增或突变。cfDNA中AR的分析是治疗CRPC患者的可行且信息丰富的程序。cfDNA可能成为CRPC精准医疗的有用生物标志物。
The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (ART878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.