RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2019-318882
DO 10.1136/gutjnl-2019-318882
A1 Jiabin Cai
A1 Lei Chen
A1 Zhou Zhang
A1 Xinyu Zhang
A1 Xingyu Lu
A1 Weiwei Liu
A1 Guoming Shi
A1 Yang Ge
A1 Pingting Gao
A1 Yuan Yang
A1 Aiwu Ke
A1 Linlin Xiao
A1 Ruizhao Dong
A1 Yanjing Zhu
A1 Xuan Yang
A1 Jiefei Wang
A1 Tongyu Zhu
A1 Deping Yang
A1 Xiaowu Huang
A1 Chengjun Sui
A1 Shuangjian Qiu
A1 Feng Shen
A1 Huichuan Sun
A1 Weiping Zhou
A1 Jian Zhou
A1 Ji Nie
A1 Chang Zeng
A1 Emily Kunce Stroup
A1 Xu Zhang
A1 Brian C-H Chiu
A1 Wan Yee Lau
A1 Chuan He
A1 Hongyang Wang
A1 Wei Zhang
A1 Jia Fan
YR 2019
UL http://gut.bmj.com/content/early/2019/07/28/gutjnl-2019-318882.abstract
AB 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.