Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma

作者：Jiabin Cai, Lei Chen, Zhou Zhang, Xinyu Zhang, Xingyu Lu, Weiwei Liu, Guo‐Ming Shi, Yang Ge, Pingting Gao, Yuan Yang, Ai‐Wu Ke, Linlin Xiao, Rui‐Zhao Dong, Yanjing Zhu, Xuan Yang, Jiefei Wang, Tongyu Zhu, Deping Yang, Xiaowu Huang, Chengjun Sui, Shuang‐Jian Qiu, Feng Shen, Hui‐Chuan Sun, Weiping Zhou, Jian Zhou, Ji Nie, Chang Zeng, Emily K. Stroup, Xu Zhang, Brian C.‐H. Chiu, Wan Yee Lau, Chuan He, Hongyang Wang, Wei Zhang, Jia Fan · 发表于：Gut · 年份：2019 · DOI：10.1136/gutjnl-2019-318882 · 被引用次数：298 · 研究领域：Cancer Genomics and Diagnostics、Hepatocellular Carcinoma Treatment and Prognosis、Genetic Associations and Epidemiology

OBJECTIVE: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC. DESIGN: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection. RESULTS: The 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic mo...