Comprehensive Liquid Profiling of Circulating Tumor DNA and Protein Biomarkers in Long-Term Follow-Up Patients with Hepatocellular Carcinoma
Comprehensive Liquid Profiling of Circulating Tumor DNA and Protein Biomarkers in Long-Term Follow-Up Patients with Hepatocellular Carcinoma
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长期随访肝细胞癌患者循环肿瘤 DNA 和蛋白质生物标志物的综合液体分析
DOI：
10.1158/1078-0432.ccr-18-3477
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发表时间：
2019-09-01
影响因子：
11.5
通讯作者：
Liu, Jingfeng
中科院分区：
文献类型：
--
作者：
Cai, Zhixiong;Chen, Geng;Liu, Jingfeng
目的：循环肿瘤DNA（ctDNA）为检测肝细胞癌（HCC）的肿瘤负荷和预测临床结局提供了一种新的方法。在这里，我们进行了一个彻底的评估肝癌循环的遗传特征，并进一步充分整合它们，建立一个强大的战略肝癌监测和预后outcomeassessment.Experimental设计：我们进行了目标测序和低覆盖率的全基因组测序血浆样本收集34个长期随访的肝癌患者捕获肿瘤体细胞SNVs和CNVs，分别。临床信息也获得评估ctDNA的预后性能与临床应用的蛋白质生物标志物comparing.Results：所有血浆样本术前显示体细胞遗传变异类似于相应的肿瘤组织。在随访期间，SNV和CNV动态变化与患者的肿瘤负荷相关。我们整合了全面的ctDNA突变谱，以提供一种可靠的策略，与成像结果相比，准确评估患者的肿瘤负荷，具有高度一致性。该策略可以在成像前平均4.6个月发现肿瘤发生，并且表现出上级血清生物标志物AFP、AFP-L3%和Des-Gamma-Carboxy Prothrombin（DCP）的性能。此外，我们的策略可以精确地检测微小残留病（MRD）提前和预测患者的预后结果的无复发生存期（P = 0.001）和总生存期（P = 0.001）;进一步结合ctDNA与DCP可以增加MRD detection.Conclusions的敏感性：我们证明，血浆CNV和SNV水平动态相关的肝癌患者的肿瘤负荷。我们的综合突变谱整合策略可以准确和更好地评估患者的预后风险，并提前发现肿瘤的发生。
Purpose: Circulating tumor DNA (ctDNA) provides a novel approach for detecting tumor burden and predicting clinical outcomes of hepatocellular carcinoma (HCC). Here, we performed a thorough evaluation of HCC circulating genetic features and further fully integrated them to build a robust strategy for HCC monitoring and prognostic outcome assessment.Experimental Design: We performed target sequencing and low-coverage whole-genome sequencing on plasma samples collected from 34 long-term follow-up patients with HCC to capture tumor somatic SNVs and CNVs, respectively. Clinical information was also obtained to evaluate the prognostic performance of ctDNA comparing with clinically applied protein biomarkers.Results: All plasma samples before surgery showed somatic genetic variations resembling corresponding tumor tissues. During follow-up, SNVs and CNVs dynamically changed correlating to patients' tumor burden. We integrated the comprehensive ctDNA mutation profiles to provide a robust strategy to accurately assess patients' tumor burden with high consistence comparing with imaging results. This strategy could discover tumor occurrence in advance of imaging for an average of 4.6 months, and showed superior performance than serum biomarkers AFP, AFP-L3%, and Des-Gamma-Carboxy Prothrombin (DCP). Furthermore, our strategy could precisely detect minimal residual disease (MRD) in advance and predict patients' prognostic outcomes for both relapse-free survival (P = 0.001) and overall survival (P = 0.001); further combining ctDNA with DCP could increase the sensitivity for MRD detection.Conclusions: We demonstrated that plasma CNV and SNV levels dynamically correlated with patients' tumor burden in HCC. Our strategy of comprehensive mutation profile integration could accurately and better evaluate patients' prognostic risk and detect tumor occurrence in advance than traditional strategies.