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

• Published in: Gut Vol. 68; no. 12; pp. 2195 - 2205
• Main Authors: Cai, Jiabin, Chen, Lei, Zhang, Zhou, Zhang, Xinyu, Lu, Xingyu, Liu, Weiwei, Shi, Guoming, Ge, Yang, Gao, Pingting, Yang, Yuan, Ke, Aiwu, Xiao, Linlin, Dong, Ruizhao, Zhu, Yanjing, Yang, Xuan, Wang, Jiefei, Zhu, Tongyu, Yang, Deping, Huang, Xiaowu, Sui, Chengjun, Qiu, Shuangjian, Shen, Feng, Sun, Huichuan, Zhou, Weiping, Zhou, Jian, Nie, Ji, Zeng, Chang, Stroup, Emily Kunce, Zhang, Xu, Chiu, Brian C-H, Lau, Wan Yee, He, Chuan, Wang, Hongyang, Zhang, Wei, Fan, Jia
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.12.2019; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original article
• Subjects: 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; Chicago Illinois; United States > US; Illinois; China; hepatobiliary cancer; cancer; hepatocellular carcinoma
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2019-318882

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.