Evidence map›Paper›PMID 31358576›Full record

ArticleGut2019

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

Jiabin Cai, Lei Chen, Zhou Zhang, Xinyu Zhang, Xingyu Lu, Weiwei Liu, Guoming Shi, Yang Ge, Pingting Gao, Yuan Yang and 25 more

Registry-linked trialAbstract readMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Gut, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07060001 (Evaluation of the Efficacy of Hypomethylating Agent Versus Standard Intensive Chemotherapy Induction Based on 5hmC - a Novel, Blood Epigenetic Marker for Assessing Measurable Residual Disease in Patients With Acute Myeloid Leukemia), which is not on this map. Cited by 174 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
174citing papers in PubMed, 5 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT07060001 phase2not yet recruitingnot on this mapstarted 2026, after this paper: background citation

Evaluation of the Efficacy of Hypomethylating Agent Versus Standard Intensive Chemotherapy Induction Based on 5hmC - a Novel, Blood Epigenetic Marker for Assessing Measurable Residual Disease in Patients With Acute Myeloid Leukemia

TypeinterventionalSponsorThe Methodist Hospital Research InstituteRan2026 to 2029Enrolled112ConditionsAcute Myeloid Leukemia (AML), Acute Myeloid Leukaemia (AML)Arms5hmC Biomarker, Venetoclax, Decitabine 20 mg/m²/day for 5 days, Azacitidine (AZA), Cytarabine (Ara-C)
3 · Its place in the literature

Who cites it

174 citing papers in PubMed, 5 syntheses or guidelines pooled it.

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  3. [Guideline for stratified screening and surveillance of primary liver cancer(2020 Edition)].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2021
    Guideline
  4. Utility of Liquid Biopsy Analysis in Detection of Hepatocellular Carcinoma, Determination of Prognosis, and Disease Monitoring: A Systematic Review.Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · 2020
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114 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

35 authors.

Jiabin Cai *Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Lei Chen *The International Cooperation Laboratory on Signal Transduction, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.ORCID 0000-0002-9380-9559
Zhou Zhang *Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Xinyu Zhang *Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Xingyu LuShanghai Epican Genetech Co. Ltd., Shanghai, China.
Weiwei LiuDepartment of Laboratory Medicine, The Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
Guoming ShiDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Yang GeSchool of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Pingting GaoDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Yuan YangDepartment of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
Aiwu KeDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Linlin XiaoDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, China.
Ruizhao DongDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Yanjing ZhuThe International Cooperation Laboratory on Signal Transduction, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
Xuan YangDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Jiefei WangShanghai Public Health Clinic Center, Fudan University, Shanghai, China.
Tongyu ZhuShanghai Public Health Clinic Center, Fudan University, Shanghai, China.
Deping YangDepartment of Laboratory Medicine, Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, China.
Xiaowu HuangDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Chengjun SuiDepartment of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
Shuangjian QiuDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Feng ShenDepartment of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
Huichuan SunDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Weiping ZhouDepartment of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
Jian ZhouDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Ji NieDepartment of Chemistry, University of Chicago, Chicago, Illinois, USA.
Chang ZengDepartment of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Emily Kunce StroupDriskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Chicago.
Xu ZhangDepartment of Medicine, University of Illinois, Chicago, Illinois, USA.
Brian C-H ChiuDepartment of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
Wan Yee LauFaculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong, China.
Chuan He *Department of Chemistry, University of Chicago, Chicago, Illinois, USA.
Hongyang Wang *The International Cooperation Laboratory on Signal Transduction, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.ORCID 0000-0002-4709-3334
Wei Zhang *Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Jia Fan *Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.ORCID 0000-0001-5158-629X

Funding

Epigenomic markers of circulating cell-free DNA and treatment outcome in multiple myelomaR01CA223662 · NCI · UNIVERSITY OF CHICAGO · PI CHIU, BRIAN C-H, ZHANG, WEI · 2018 to 2022
$3.2M
Development of 5hmC and 5mC biomarkers in cell-free circulating DNA for sensitive colon cancer detection and prognosisU01CA217078 · NCI · UNIVERSITY OF CHICAGO · PI BISSONNETTE, BRUCE MARC, ZHANG, WEI · 2017 to 2021
$3.2M
Predoctoral Training Program in Biomedical Data Driven Discovery (BD3)T32LM012203 · NLM · NORTHWESTERN UNIVERSITY AT CHICAGO · PI KLABJAN, DIEGO, STARREN, JUSTIN B. · 2015 to 2019
$1.1M
Howard Hughes Medical InstituteNCI NIH HHS R01 CA223662NCI NIH HHS U01 CA217078NLM NIH HHS T32 LM012203
6 · The paper itself

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.

Indexed as

5-MethylcytosineBiomarkers, TumorCarcinoma, HepatocellularCell-Free Nucleic AcidsDNA, NeoplasmEarly Detection of CancerFemaleGenome-Wide Association StudyHumansLiver NeoplasmsMaleMiddle AgedProspective StudiesROC Curve5-hydroxymethylcytosine5-MethylcytosineBiomarkers, TumorCell-Free Nucleic AcidsDNA, Neoplasmcancerhepatobiliary cancerhepatocellular carcinoma

Identifiers

PMID31358576
PMCPMC6872444

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.