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

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.DesignA...

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Published inGut 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
LanguageEnglish
Published England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.12.2019
BMJ Publishing Group LTD
BMJ Publishing Group
SeriesOriginal 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
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Abstract 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.
AbstractList 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.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.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.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.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).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).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.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.
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.
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. 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. 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). 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.
Author 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
AuthorAffiliation 6 Department of Preventive Medicine , Northwestern University Feinberg School of Medicine , Chicago , Illinois , USA
8 Department of Laboratory Medicine, The Tenth People’s Hospital of Shanghai , Tongji University , Shanghai , China
22 Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer , The Second Military Medical University & Ministry of Education , Shanghai , China
15 Driskill Graduate Program in Life Sciences , Northwestern University Feinberg School of Medicine , Chicago , Illinois , Chicago
23 The Robert H. Lurie Comprehensive Cancer Center , Northwestern University Feinberg School of Medicine , Chicago , Illinois , USA
21 The Howard Hughes Medical Institute , University of Chicago , Chicago , Illinois , USA
19 Department of Biochemistry and Molecular Biology , University of Chicago , Chicago , Illinois , USA
11 Department of Laboratory Medicine , Shanghai Jiao Tong University , Shanghai , China
12 Shanghai Public Health Clinic Center , Fudan University , Shanghai ,
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– name: 20 Institute for Biophysical Dynamics , University of Chicago , Chicago , Illinois , USA
– name: 9 School of Public Health , Shanghai Jiao Tong University School of Medicine , Shanghai , China
– name: 14 Department of Chemistry , University of Chicago , Chicago , Illinois , USA
– name: 2 Key Laboratory of Carcinogenesis and Cancer Invasion , Fudan University & Ministry of Education , Shanghai , China
– name: 10 Department of Hepatobiliary Surgery , The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
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– name: 19 Department of Biochemistry and Molecular Biology , University of Chicago , Chicago , Illinois , USA
– name: 23 The Robert H. Lurie Comprehensive Cancer Center , Northwestern University Feinberg School of Medicine , Chicago , Illinois , USA
– name: 5 National Center for Liver Cancer , Shanghai , China
– name: 13 Department of Laboratory Medicine , Zhoupu Hospital, Shanghai University of Medicine & Health Sciences , Shanghai , China
– name: 18 Faculty of Medicine , The Chinese University of Hong Kong , New Territories , Hong Kong , China
– name: 3 Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences , Fudan University , Shanghai , China
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– name: 8 Department of Laboratory Medicine, The Tenth People’s Hospital of Shanghai , Tongji University , Shanghai , China
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/31358576$$D View this record in MEDLINE/PubMed
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Issue 12
Keywords hepatobiliary cancer
cancer
hepatocellular carcinoma
Language English
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Snippet ObjectiveThe lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma...
The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We...
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StartPage 2195
SubjectTerms 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
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Title Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma
URI https://gut.bmj.com/content/68/12/2195.full
https://www.ncbi.nlm.nih.gov/pubmed/31358576
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https://pubmed.ncbi.nlm.nih.gov/PMC6872444
Volume 68
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