Intratumoral heterogeneity and clonal evolution in liver cancer

• Published in: Nature communications Vol. 11; no. 1; pp. 291 - 15
• Main Authors: Losic, Bojan, Craig, Amanda J., Villacorta-Martin, Carlos, Martins-Filho, Sebastiao N., Akers, Nicholas, Chen, Xintong, Ahsen, Mehmet E., von Felden, Johann, Labgaa, Ismail, DʹAvola, Delia, Allette, Kimaada, Lira, Sergio A., Furtado, Glaucia C., Garcia-Lezana, Teresa, Restrepo, Paula, Stueck, Ashley, Ward, Stephen C., Fiel, Maria I., Hiotis, Spiros P., Gunasekaran, Ganesh, Sia, Daniela, Schadt, Eric E., Sebra, Robert, Schwartz, Myron, Llovet, Josep M., Thung, Swan, Stolovitzky, Gustavo, Villanueva, Augusto
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38/23; 45; 45/91; 631/250; 631/67; 692/4020; 692/4028; Adaptive immunity; Adaptive systems; Antigens; Biopsy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - virology; Clonal Evolution; Deoxyribonucleic acid; DNA; DNA Copy Number Variations; DNA sequencing; Epitopes; Epitopes - genetics; Epitopes - immunology; Evolution; Gene expression; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genetic Heterogeneity; Hepatitis B; Hepatitis B Antigens - genetics; Hepatitis B virus - genetics; Hepatitis B virus - immunology; Hepatocellular carcinoma; Heterogeneity; High-Throughput Nucleotide Sequencing; Humanities and Social Sciences; Humans; Immune response; Immune system; Kaplan-Meier Estimate; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Liver Neoplasms - virology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Lymphocytes, Tumor-Infiltrating - virology; multidisciplinary; Mutation; Polymorphism, Single Nucleotide; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Single-Cell Analysis; Single-nucleotide polymorphism; Substrates; Survival; T cell receptors; Transcriptomics; Tumors; Viruses
• ISSN: 2041-1723; 2041-1723
• 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. Immune-mediated selection pressures impact the clonal evolution of tumours. Here, in hepatocellular carcinoma the authors map spatio-temporal interactions between tumor and immune cells, highlighting the regulatory substrate of intra-tumoural heterogeneity that correlates with regional adaptive immune responses.