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Gut. 2019 Jul 29. pii: gutjnl-2019-318882. doi: 10.1136/gutjnl-2019-318882. [Epub ahead of print]

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

Cai J#1,2,3, Chen L#4,5, Zhang Z#6, Zhang X#1,2, Lu X7, Liu W8, Shi G1,2, Ge Y9, Gao P1,2, Yang Y10, Ke A1,2, Xiao L11, Dong R1,2, Zhu Y4, Yang X1,2, Wang J12, Zhu T12, Yang D13, Huang X1,2, Sui C10, Qiu S1,2, Shen F10, Sun H1,2, Zhou W10, Zhou J1,2,3, Nie J14, Zeng C6,15, Stroup EK15, Zhang X16, Chiu BC17, Lau WY18, He C#14,19,20,21, Wang H#4,5,22, Zhang W#6,23, Fan J#1,2,3.

Author information

1
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
2
Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China.
3
Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences, Fudan University, Shanghai, China.
4
The International Cooperation Laboratory on Signal Transduction, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
5
National Center for Liver Cancer, Shanghai, China.
6
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
7
Shanghai Epican Genetech Co. Ltd., Shanghai, China.
8
Department of Laboratory Medicine, The Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
9
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
10
Department of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
11
Department of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, China.
12
Shanghai Public Health Clinic Center, Fudan University, Shanghai, China.
13
Department of Laboratory Medicine, Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, China.
14
Department of Chemistry, University of Chicago, Chicago, Illinois, USA.
15
Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Chicago.
16
Department of Medicine, University of Illinois, Chicago, Illinois, USA.
17
Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
18
Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong, China.
19
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
20
Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA.
21
The Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois, USA.
22
Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, The Second Military Medical University & Ministry of Education, Shanghai, China.
23
The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
#
Contributed equally

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.

KEYWORDS:

cancer; hepatobiliary cancer; hepatocellular carcinoma

PMID:
31358576
DOI:
10.1136/gutjnl-2019-318882
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Conflict of interest statement

Competing interests: The 5hmC-Seal technology was invented by CH and was licensed by Shanghai Epican Genetech Co. Ltd. for clinical applications in human diseases from the University of Chicago. XL is a co-founder of Shanghai Epican Genetech Co. Ltd. CH and WZ are shareholders of Shanghai Epican Genetech Co. Ltd. CH is a scientific founder of Accent Therapeutics, Inc. and a member of its scientific advisory board. All other authors report no potential conflicts of interest.

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