TY - JOUR T1 - Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma JF - Gut JO - Gut SP - 2195 LP - 2205 DO - 10.1136/gutjnl-2019-318882 VL - 68 IS - 12 AU - Jiabin Cai AU - Lei Chen AU - Zhou Zhang AU - Xinyu Zhang AU - Xingyu Lu AU - Weiwei Liu AU - Guoming Shi AU - Yang Ge AU - Pingting Gao AU - Yuan Yang AU - Aiwu Ke AU - Linlin Xiao AU - Ruizhao Dong AU - Yanjing Zhu AU - Xuan Yang AU - Jiefei Wang AU - Tongyu Zhu AU - Deping Yang AU - Xiaowu Huang AU - Chengjun Sui AU - Shuangjian Qiu AU - Feng Shen AU - Huichuan Sun AU - Weiping Zhou AU - Jian Zhou AU - Ji Nie AU - Chang Zeng AU - Emily Kunce Stroup AU - Xu Zhang AU - Brian C-H Chiu AU - Wan Yee Lau AU - Chuan He AU - Hongyang Wang AU - Wei Zhang AU - Jia Fan Y1 - 2019/12/01 UR - http://gut.bmj.com/content/68/12/2195.abstract N2 - 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 model appeared to be independent from potential confounders (eg, smoking/alcohol intake history).Conclusion We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals. ER -