Single cell DNA sequencing reveals punctuated and gradual clonal evolution in hepatocellular carcinoma


Grant support

This work is jointly supported by National Natural Science Foundation of China (82173035, 81802813,82030079, 81972656, 81988101, and 81902401), the National Science and Technology Major Project of China (2018ZX10723204), the Michigan Medicine and Peking University Health Science Center Joint Institute for Translational and Clinical Research (BMU2020JI005), Natural Science Foundation of Tianjin (19JCQNJC09000), and China Scholarship Council (201906940003). We also thank the grant support from Sino-Russian Math Center and BioMap Inc.

Declaration of Interest

Z.Zhang. is a founder of Analytical BioSciences and is a consultant for InnoCare Pharma and ArsenalBio. Other authors declare no conflict of interest.

Author Contributions

Lin Guo, Ph.D (Conceptualization: Lead; Data curation: Lead; Methodology: Lead; Writing-original draft: Lead; Writing-review & editing: Equal) Xianfu Yi, Ph.D (Conceptualization: Equal; Formal analysis: Lead; Software: Lead; Visualization: Lead; Writing- review & editing: Equal) Lu Chen, MD (Resources: Lead; Validation: Equal) Ti Zhang, MD (Resources: Equal; Validation: Equal) Hua Guo, Ph.D (Resources: Supporting) Ziye Chen, Ph.D (Validation: Supporting) Jinghui Cheng, Ph.D (Formal analysis: Supporting) Qi Cao, Ph.D (Software: Supporting) Hengkang Liu, Ph.D (Formal analysis: Supporting) Chunyu Hou, Ph.D (Software: Supporting) Lisha Qi, MD (Methodology: Supporting) Zhiyan Zhu, Ph.D (Methodology: Supporting) Yucun Liu, MD (Resources: Supporting) Ruirui Kong, Ph.D (Methodology: Supporting) Chong Zhang, Ph.D (Formal analysis: Supporting) Xiaohua Zhou, Ph.D (Methodology: Supporting) Zemin Zhang, Ph.D (Writing-review & editing: Supporting) Tianqiang Song, MD (Resources: Supporting) Ruidong Xue, Ph.D (Conceptualization: Lead; Formal analysis: Lead; Methodology: Lead; Supervision: Lead; Validation: Lead; Visualization: Lead; Writing-original draft: Lead; Writing-review & editing: Lead) Ning Zhang, Ph.D (Conceptualization: Lead; Formal analysis: Lead; Funding acquisition: Lead; Investigation: Lead; Methodology: Lead; Supervision: Lead;Visualization: Lead; Writing-original draft: Lead; Writing-review & editing: Lead)

Data availability

Sequence data are deposited in the Genome Sequence Archive in Beijing Institute of Genomics (BIG) (, Chinese Academy of Sciences, under accession numbers HRA000094 and HRA000872. The data deposited and made public are compliant with the regulations of Ministry of Science and Technology of China.

What you need to know


The heterogeneity landscape and evolution pattern of CNAs in HCC at single cell resolution remain unknown.


CNA accumulation in HCC follows a novel DPCNE model. Prolonged gradual phase correlates with higher ITH and worse prognosis. CAD is a biomarker for early recurrence. Polyploid tumor cells have a diploid origin.


Only one case of scDNA-seq in this study has ploidy resolution. Further studies are needed to fully address ploidy heterogeneity in HCC.


Our DPCNE model provides new perspective on tumor clonal evolution and can be used to identify candidate genes that might be exploited as biomarkers or therapies.

Lay Summary

This study revealed that CNA accumulation in HCC follows a novel dual-phase copy number evolution model. HCC that rely most heavily on the gradual phase may be the most severe.

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