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Nat Commun. 2020 Jan 15;11(1):291. doi: 10.1038/s41467-019-14050-z.
Intratumoral heterogeneity and clonal evolution in liver cancer.
Losic B1,2,3, Craig AJ4, Villacorta-Martin C4, Martins-Filho SN4,5, Akers N1,6, Chen X1, Ahsen ME1, von Felden J4,7, Labgaa I4,8, DʹAvola D4,9, Allette K1,2, Lira SA10, Furtado GC10, Garcia-Lezana T4, Restrepo P1, Stueck A11, Ward SC12, Fiel MI12, Hiotis SP13, Gunasekaran G13, Sia D4, Schadt EE2,14, Sebra R1,2,14, Schwartz M13, Llovet JM4,15,16, Thung S12, Stolovitzky G1,17, Villanueva A18,19.
Author information
1
Department of Genetics and Genomic Sciences, Cancer Immunology Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
Department of Pathology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
6
Adaptive Biotechnologies, Seattle, WA, USA.
7
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
8
Department of Visceral Surgery, Lausanne University Hospital CHUV, Lausanne, Switzerland.
9
Liver Unit and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Clínica Universidad de Navarra, Pamplona, Spain.
10
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
12
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
13
Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
14
Sema4, a Mount Sinai venture, Stamford, CT, USA.
15
Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Hospital Clinic, Universitat de Barcelona, Barcelona, Catalonia, Spain.
16
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
17
IBM T. J. Watson Research Center, Yorktown Heights, New York, NY, USA.
18
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
19
Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
Abstract
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.
PMID:
31941899
DOI:
10.1038/s41467-019-14050-z
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