Article

Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma

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Abstract

An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive ‘liquid biopsy’ for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.

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Acknowledgements

The results published here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov. We thank staff at Kang Zhang and Ruihua Xu laboratories for technical assistance. This study was funded by Richard Annesser Fund, Michael Martin Fund, Dick and Carol Hertzberg Fund, SYSUCC, Xijing Hospital, and West China Hospital.

Author information

Author notes

    • Rui-hua Xu
    • , Wei Wei
    • , Michal Krawczyk
    • , Wenqiu Wang
    •  & Huiyan Luo

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

    • Rui-hua Xu
    • , Wei Wei
    • , Huiyan Luo
    • , Qi Zhao
    •  & Rongping Guo
  2. Moores Cancer Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Wei Wei
    • , Michal Krawczyk
    • , Wenqiu Wang
    • , Huiyan Luo
    • , Ken Flagg
    • , Shaohua Yi
    • , William Shi
    • , Bennett A. Caughey
    • , Jiayi Hou
    • , Runze Zhang
    • , Zheng Zhong
    • , Danni Lin
    • , Xin Fu
    • , Jie Zhu
    • , Yaou Duan
    • , Edward Zhang
    • , Charlotte Zhang
    • , Oulan Li
    • , Hannah Carter
    •  & Kang Zhang
  3. Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China

    • Qingli Quan
    • , Kang Li
    • , Yanxin Xu
    • , Huimin Cai
    • , Gen Li
    • , Meixing Yu
    • , Wengeng Zhang
    •  & Kang Zhang
  4. Guangzhou Youze Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, China

    • Lianghong Zheng
    • , Huimin Cai
    • , Gen Li
    •  & Rui Hou
  5. Shanghai Center for Plant Stress Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 210602, China

    • Heng Zhang
    •  & Jian-kang Zhu
  6. Department of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China

    • Binwu Ying
  7. Department of Clinical Laboratory Medicine, Xijing Hospital, the Fourth Military Medical University, Xi’an, Shanxi 710032, China

    • Juan Wang
    •  & Xiaoke Hao
  8. Veterans Administration Healthcare System, San Diego, California 92093, USA

    • Kang Zhang

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Contributions

W.Wei, M.K., W.Wang, H.L., K.F., W.S., S.Y., L.Z., H.Z., R.Z., Y.X., K.L., H.Cai, G.L., L.Z., R.-h.X., Z.Z., D.L., E.Z. and C.Z. performed the experiments; M.K. W.Wang, H.L., K.F., B.A.C., Q.Q., Q.Z., L.Z., R.-h.X., J.Z., X.F., J.-k.Z., Y.D., H.Carter, M.Y., W.Z., R.G. and X.H. collected and analysed the data. K.Z. and R.-h.X. conceived the project, designed the experiments, and wrote the manuscript; All authors discussed the results and reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Rui-hua Xu or Kang Zhang.

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