Xu Yuyan, Cai Jianpeng, Zhong Kaihang, Wen Yaohong, Cai Lei, He Guolin, Liao Hangyu, Zhang Cheng, Fu Shunjun, Chen Tingting, Cai Jinping, Zhong Xuefeng, Chen Chunzhu, Huang Mengli, Cheng Yuan, Pan Mingxin
Department of Hepatobiliary Surgery II, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Front Oncol. 2023 Mar 7;13:1119744. doi: 10.3389/fonc.2023.1119744. eCollection 2023.
Minimal residual disease (MRD) is considered an essential factor leading to relapse within 2 years (early relapse) after radical surgery, which is challenging to be detected by conventional imaging. Circulating tumor DNA (ctDNA) provides a novel approach for detecting MRD and predicting clinical outcomes. Here, we tried to construct a fixed panel for plasma-only ctDNA NGS to enable tumor-uninformed MRD detection in hepatocellular carcinoma (HCC).
Here, we performed the followings: (i) profiling genomic alteration spectrum of ctDNA from the Chinese HCC cohort consisting of 493 individuals by NGS; (ii) screening of MRD monitoring genes; and (iii) performance evaluation of MRD monitoring genes in predicting early relapse in the ZJZS2020 cohort comprising 20 HCC patients who underwent curative resection.
A total of 493 plasma samples from the Chinese HCC cohort were detected using a 381/733-gene NGS panel to characterize the mutational spectrum of ctDNA. Most patients (94.1%, 464/493) had at least one mutation in ctDNA. The variants fell most frequently in (45.1%), (20.2%), (20.2%), (16.2%), and (13.4%). By customized filtering strategy, 13 MRD monitoring genes were identified, and any plasma sample with one or more MRD monitoring gene mutations was considered MRD-positive. In the ZJZS2020 cohort, MRD positivity presented a sensitivity of 75% (6/8) and a specificity of 100% (6/6) in identifying early postoperative relapse. The Kaplan-Meier analysis revealed a significantly short relapse-free survival (RFS; median RFS, 4.2 months . NR, P=0.002) in the MRD-positive patients versus those with MRD negativity. Cox regression analyses revealed MRD positivity as an independent predictor of poor RFS (HR 13.00, 95% CI 2.60-69.00, P=0.002).
We successfully developed a 13-gene panel for plasma-only MRD detection, which was effective and convenient for predicting the risk of early postoperative relapse in HCC.
微小残留病（MRD）被认为是导致根治性手术后2年内复发（早期复发）的重要因素，传统影像学检测难以发现。循环肿瘤DNA（ctDNA）为检测MRD和预测临床结果提供了一种新方法。在此，我们试图构建一个仅用于血浆ctDNA二代测序（NGS）的固定检测板，以实现肝细胞癌（HCC）中无需肿瘤信息的MRD检测。
在此，我们进行了以下操作：（i）通过NGS分析由493名个体组成的中国HCC队列中ctDNA的基因组改变谱；（ii）筛选MRD监测基因；（iii）在包含20例接受根治性切除的HCC患者的ZJZS2020队列中评估MRD监测基因预测早期复发的性能。
使用381/733基因NGS检测板对中国HCC队列中的493份血浆样本进行检测，以表征ctDNA的突变谱。大多数患者（94.1%，464/493）的ctDNA至少有一个突变。这些变异最常发生在（45.1%）、（20.2%）、（20.2%）、（16.2%）和（13.4%）。通过定制的筛选策略，鉴定出13个MRD监测基因，任何有一个或多个MRD监测基因突变的血浆样本被视为MRD阳性。在ZJZS2020队列中，MRD阳性在识别术后早期复发方面的敏感性为75%（6/8），特异性为100%（6/6）。Kaplan-Meier分析显示，与MRD阴性患者相比，MRD阳性患者的无复发生存期（RFS）显著缩短（中位RFS，4.2个月对未达到，P=0.002）。Cox回归分析显示，MRD阳性是RFS不良的独立预测因素（风险比13.00，95%置信区间2.60 - 69.00，P=0.002）。
我们成功开发了一个仅用于血浆MRD检测的13基因检测板，其对预测HCC术后早期复发风险有效且方便。
