Intratumoral heterogeneity and clonal evolution in liver cancer

Nat Commun. 2020 Jan 15;11(1):291. doi: 10.1038/s41467-019-14050-z.


Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology*
  • Carcinoma, Hepatocellular / virology
  • Clonal Evolution*
  • DNA Copy Number Variations
  • Epitopes / genetics
  • Epitopes / immunology
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genetic Heterogeneity
  • Hepatitis B Antigens / genetics
  • Hepatitis B virus / genetics
  • Hepatitis B virus / immunology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Kaplan-Meier Estimate
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / virology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Lymphocytes, Tumor-Infiltrating / virology
  • Polymorphism, Single Nucleotide
  • Single-Cell Analysis


  • Epitopes
  • Hepatitis B Antigens