Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma. Issue 12 (29th July 2019)

• Record Type: Journal Article
• 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;
• Is Part Of: Gut. Volume 68:Issue 12(2019)
• Page Start: 2195
• Page End: 2205
• Publication Date: 2019-07-29
• Subjects: hepatobiliary cancer -- hepatocellular carcinoma -- cancer; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2019-318882
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.