循环肿瘤 DNA (ctDNA) 是一种有前途的癌症非侵入性生物标志物。我们的目的是评估肝细胞癌 (HCC) 患者的 ctDNA 动态。我们分析了 173 名 HCC 患者在诊断或治疗时 (n=502) 以及局部治疗后 24 小时 (n=154) 收集的 772 份血浆以及随访期间（n=116）。作为对照，分析了来自无 HCC 的慢性肝病患者的 56 份血浆。通过测序和基于液滴的数字 PCR 分析所有样品的无细胞 DNA (cfDNA) 浓度以及 TERT 启动子、CTNNB1、TP53、PIK3CA 和 NFE2L2 的突变。将结果与 232 个相应肿瘤样本进行比较。在活动性 HCC 患者中，40.2% 的 ctDNA 发生突变，而非活动性 HCC 患者中这一比例为 14.6%，对照组为 1.8%（p<0.001）。在活动性 HCC 中，我们在 TERT 启动子中发现了 27.5% 的突变，在 TP53 中发现了 21.3%，在 CTNNB1 中发现了 13.1%，在 PIK3CA 中发现了 0.4%，在 NFE2L2 中发现了 0.2%，大多数情况下与相应肿瘤中发现的突变相似。 CtDNA 突变率随着肿瘤分期的进展而增加 (p<0.001)。在 103 名接受经皮消融治疗的患者中，治疗前 ctDNA 突变的存在和数量与较高的死亡风险 (p=0.001) 和复发风险 (p<0.001) 相关。有趣的是，局部治疗 24 小时后 cfDNA 浓度和可检测突变增加。在 53 名接受全身治疗的患者中收集的 356 份血浆中，我们在 60.4% 的病例中检测到基线突变。在接受 atezolizumab-bevacizumab 治疗的患者中，ctDNA 突变的持续存在与放射学进展相关（63.6% vs 消失的 36.4%，p=0.019）。在两名接受全身治疗取得进展的患者中，我们检测到血浆中 CTNNB1 突变的发生，其中一名患者的肿瘤中存在亚克隆，而另一名患者的肿瘤中则无法检测到。ctDNA 提供了反映肿瘤生物学的动态信息。它代表了一种可用于指导 HCC 临床管理的非侵入性工具。© 作者（或其雇主）2024。禁止商业重复使用。请参阅权利和权限。英国医学杂志出版。

Circulating tumour DNA (ctDNA) is a promising non-invasive biomarker in cancer. We aim to assess the dynamic of ctDNA in patients with hepatocellular carcinoma (HCC).We analysed 772 plasmas from 173 patients with HCC collected at the time of diagnosis or treatment (n=502), 24 hours after locoregional treatment (n=154) and during follow-up (n=116). For controls, 56 plasmas from patients with chronic liver disease without HCC were analysed. All samples were analysed for cell free DNA (cfDNA) concentration, and for mutations in TERT promoter, CTNNB1, TP53, PIK3CA and NFE2L2 by sequencing and droplet-based digital PCR. Results were compared with 232 corresponding tumour samples.In patients with active HCC, 40.2% of the ctDNA was mutated vs 14.6% in patients with inactive HCC and 1.8% in controls (p<0.001). In active HCC, we identified 27.5% of mutations in TERT promoter, 21.3% in TP53, 13.1% in CTNNB1, 0.4% in PIK3CA and 0.2% in NFE2L2, most of the times similar to those identified in the corresponding tumour. CtDNA mutation rate increased with advanced tumour stages (p<0.001). In 103 patients treated by percutaneous ablation, the presence and number of mutations in the ctDNA before treatment were associated with higher risk of death (p=0.001) and recurrence (p<0.001). Interestingly, cfDNA concentration and detectable mutations increased 24 hours after a locoregional treatment. Among 356 plasmas collected in 53 patients treated by systemic treatments, we detected mutations at baseline in 60.4% of the cases. In patients treated by atezolizumab-bevacizumab, persistence of mutation in ctDNA was associated with radiological progression (63.6% vs 36.4% for disappearance, p=0.019). In two patients progressing under systemic treatments, we detected the occurrence of mutations in CTNNB1 in the plasma that was subclonal in the tumour for one patient and not detectable in the tumour for the other one.ctDNA offers dynamic information reflecting tumour biology. It represents a non-invasive tool useful to guide HCC clinical management.© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.