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


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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Figure 1: Workflow chart of data generation and analysis.
Figure 2: cfDNA methylation analysis of HCC diagnosis.
Figure 3: cfDNA methylation analysis and tumour burden, treatment response, and staging.
Figure 4: cfDNA methylation analysis for prognostic prediction HCC survival.

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The results published here are in part based upon data generated by the TCGA Research Network: 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.

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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.

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Correspondence to Rui-hua Xu or Kang Zhang.

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The authors declare no competing financial interests.

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Xu, Rh., Wei, W., Krawczyk, M. et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nature Mater 16, 1155–1161 (2017).

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