Journal Article

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

Zhou, Jian, Yang, Xuan, Gao, Pingting, Nie, Ji, Liu, Weiwei, Ke, Aiwu, Chiu, Brian C-H, Zeng, Chang, Ge, Yang, Sun, Huichuan, Dong, Ruizhao, Yang, Deping, Stroup, Emily Kunce, Zhang, Zhou, Fan, Jia, Yang, Yuan, Zhu, Yanjing, Zhang, Wei, Chen, Lei, Zhang, Xu, He, Chuan, Lau, Wan Yee, Wang, Jiefei, Qiu, Shuangjian, Zhu, Tongyu, Sui, Chengjun, Shen, Feng, Zhang, Xinyu, Cai, Jiabin, Shi, Guoming, Wang, Hongyang, Lu, Xingyu, Xiao, Linlin, Zhou, Weiping, Huang, Xiaowu

2019

Overview

ObjectiveThe 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.DesignApplying 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.ResultsThe 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).ConclusionWe 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: 5-Methylcytosine - analogs & derivatives / 5-Methylcytosine - blood / Biomarkers / Biomarkers, Tumor - blood / Biopsy / cancer / Carcinoma, Hepatocellular - blood / Carcinoma, Hepatocellular - diagnosis / Carcinoma, Hepatocellular - genetics / Cell-Free Nucleic Acids - blood / Chronic infection / Cirrhosis / Clinical outcomes / Deoxyribonucleic acid / DNA / DNA, Neoplasm - analysis / Early Detection of Cancer - methods / Epigenetics / Female / Gastroenterology / Gene expression / Gene mapping / Generalized linear models / Genome-Wide Association Study - methods / Genomes / Health care / Hepatitis / Hepatitis B / hepatobiliary cancer / Hepatocellular carcinoma / Hepatology / Hospitals / Humans / Liver cancer / Liver cirrhosis / Liver Neoplasms - blood / Liver Neoplasms - diagnosis / Liver Neoplasms - genetics / Male / Medical prognosis / Middle Aged / Patients / Prospective Studies / ROC Curve / Signal transduction / Surveillance / Tumors / α-Fetoprotein