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Hepatology
Original article
Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma
  1. Jiabin Cai1,2,3,
  2. Lei Chen4,5,
  3. Zhou Zhang6,
  4. Xinyu Zhang1,2,
  5. Xingyu Lu7,
  6. Weiwei Liu8,
  7. Guoming Shi1,2,
  8. Yang Ge9,
  9. Pingting Gao1,2,
  10. Yuan Yang10,
  11. Aiwu Ke1,2,
  12. Linlin Xiao11,
  13. Ruizhao Dong1,2,
  14. Yanjing Zhu4,
  15. Xuan Yang1,2,
  16. Jiefei Wang12,
  17. Tongyu Zhu12,
  18. Deping Yang13,
  19. Xiaowu Huang1,2,
  20. Chengjun Sui10,
  21. Shuangjian Qiu1,2,
  22. Feng Shen10,
  23. Huichuan Sun1,2,
  24. Weiping Zhou10,
  25. Jian Zhou1,2,3,
  26. Ji Nie14,
  27. Chang Zeng6,15,
  28. Emily Kunce Stroup15,
  29. Xu Zhang16,
  30. Brian C-H Chiu17,
  31. Wan Yee Lau18,
  32. Chuan He14,19,20,21,
  33. Hongyang Wang4,5,22,
  34. Wei Zhang6,23,
  35. Jia Fan1,2,3
  1. 1 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
  2. 2 Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China
  3. 3 Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences, Fudan University, Shanghai, China
  4. 4 The International Cooperation Laboratory on Signal Transduction, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
  5. 5 National Center for Liver Cancer, Shanghai, China
  6. 6 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  7. 7 Shanghai Epican Genetech Co. Ltd., Shanghai, China
  8. 8 Department of Laboratory Medicine, The Tenth People’s Hospital of Shanghai, Tongji University, Shanghai, China
  9. 9 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  10. 10 Department of Hepatobiliary Surgery, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
  11. 11 Department of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, China
  12. 12 Shanghai Public Health Clinic Center, Fudan University, Shanghai, China
  13. 13 Department of Laboratory Medicine, Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, China
  14. 14 Department of Chemistry, University of Chicago, Chicago, Illinois, USA
  15. 15 Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Chicago
  16. 16 Department of Medicine, University of Illinois, Chicago, Illinois, USA
  17. 17 Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA
  18. 18 Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong, China
  19. 19 Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA
  20. 20 Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA
  21. 21 The Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois, USA
  22. 22 Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, The Second Military Medical University & Ministry of Education, Shanghai, China
  23. 23 The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Dr Chuan He, Department of Chemistry, University of Chicago, Chicago, Illinois 60637, USA; chuanhe{at}uchicago.edu, Dr Hongyang Wang, The International Cooperation Laboratory on Signal Transduction, The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China; hywangk{at}vip.sina.com, Dr Wei Zhang, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; wei.zhang1{at}northwestern.edu and Dr Jia Fan, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; fan.jia{at}zs-hospital.sh.cn

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.

  • hepatobiliary cancer
  • hepatocellular carcinoma
  • cancer

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2019-318882

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    Footnotes

    • JC, LC, ZZ and XZ contributed equally.

    • CH, HW, WZ and JF contributed equally.

    • Contributors Conceptualisation: JF, WZ, HW and CH; Methodology: XL, JN and CH; Collection of samples and clinical data: JC, LC, XZ, WL, GS, YG, PG, YY, AK, LX, RD, YZ, XY, JW, TZ, DY, XH, HS, SQ, FS, CS, WZ and JZ; Formal data analysis: ZZ, CZ, XZ and WZ; Writing original draft: JC, LC, ZZ, XZ, XL, EKS, BCHC, CH, WZ and JF; Funding acquisition: GS, AK, JC, HW, and LC, CH, WZ, and JF.

    • Funding National Institutes of Health (U01CA217078 and R01CA223662); Chinese State Key Project for Liver Cancer (2018ZX10732202-001); National Natural Science Foundation of China (81790633, 91729303, 81672860, 81572061, 81602513, 81472840, 81530077 and 81672825); The University of Chicago Ludwig Center; and The Howard Hughes Medical Institute.

    • 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.

    • Ethics approval The human research ethics committees at The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China; Zhongshan Hospital, Fudan University, Shanghai, China; The Tenth People’s Hospital of Shanghai, Tongji University, Shanghai, China.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Patient consent for publication Not required.

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