TY - JOUR T1 - Single-cell and single-variant resolution analysis of clonal evolution in human liver cancer JF - bioRxiv DO - 10.1101/2020.12.30.424907 SP - 2020.12.30.424907 AU - Xianbin Su AU - Linan Zhao AU - Yi Shi AU - Rui Zhang AU - Qi Long AU - Shihao Bai AU - Qing Luo AU - Yingxin Lin AU - Xin Zou AU - Shila Ghazanfar AU - Kun Tao AU - Guoliang Yang AU - Lan Wang AU - Kun-Yan He AU - Xiaofang Cui AU - Jian He AU - Jiao-Xiang Wu AU - Bo Han AU - Na Wang AU - Xiaolin Li AU - Pengyi Yang AU - Shangwei Hou AU - Jielin Sun AU - Jean Y. H. Yang AU - Jinhong Chen AU - Ze-Guang Han Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/02/2020.12.30.424907.abstract N2 - Genetic heterogeneity of tumor is closely related to clonal evolution, phenotypic diversity and treatment resistance. Such heterogeneity has been characterized in liver cancer at single-cell sub-chromosomal scale, and a more precise single-variant resolution analysis is lacking. Here we employed a strategy to analyze both the single-cell genomic mutations and transcriptomic changes in 5 patients with liver cancer. Target sequencing was done for a total of 480 single cells in a patient-specific manner. DNA copy number status of point mutations was obtained from single-cell mutational profiling. The clonal structures of liver cancers were then uncovered at single-variant resolution, and mutation combinations in single cells enabled reconstruction of their evolutionary history. A common origin but independent evolutionary fate was revealed for primary liver tumor and intrahepatic metastatic portal vein tumor thrombus. The mutational signature suggested early evolutionary process may be related to specific etiology like aristolochic acids. By parallel single-cell RNA-Seq, the transcriptomic phenotype was found to be related with genetic heterogeneity in liver cancer. We reconstructed the single-cell and single-variant resolution clonal evolutionary history of liver cancer, and dissection of both genetic and phenotypic heterogeneity provides knowledge for mechanistic understanding of liver cancer initiation and progression.Competing Interest StatementThe authors have declared no competing interest.ADOallelic drop-outCNVcopy number variationHCChepatocellular carcinomaINDELinsertion or deletionPVTTportal vein tumor thrombusscRNA-Seqsingle-cell RNA-SeqSNVsingle-nucleotide variationVAFvariant allele frequencyWESwhole exome sequencingWGAwhole genome amplification. ER -