AUTHOR=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 TITLE=Plasma-only circulating tumor DNA analysis detects minimal residual disease and predicts early relapse in hepatocellular carcinoma patients undergoing curative resection JOURNAL=Frontiers in Oncology VOLUME=13 YEAR=2023 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1119744 DOI=10.3389/fonc.2023.1119744 ISSN=2234-943X ABSTRACT=Background

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).

Methods

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.

Results

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 TP53 (45.1%), LRP1B (20.2%), TERT (20.2%), FAT1 (16.2%), and CTNNB1 (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 vs. 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).

Conclusions

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.