An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive ‘liquid biopsy’ for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.

尚未开发出一种有效的基于血液的肝细胞癌（HCC）诊断和预后方法。循环携带肿瘤特异性遗传和表观遗传畸变的肿瘤DNA（ctDNA）可以实现无创性“液体活检”，以诊断和监测癌症。在这里，我们通过比较肝癌组织和正常血液白细胞来鉴定肝癌特异性甲基化标记物组，并显示肝癌肿瘤DNA和匹配的血浆ctDNA的甲基化谱高度相关。使用来自1,098名HCC患者和835名正常对照的大样本人群的cfDNA样本，我们构建了诊断预测模型，该模型显示出较高的诊断特异性和敏感性（P<0.001），并且与肿瘤负担，治疗反应和分期高度相关。此外，我们构建了可有效预测预后和生存率的预后预测模型（P <0.001）。总之，这些发现在一个大型临床队列中证明了ctDNA甲基化标记物在HCC的诊断，监测和预后中的实用性。