@article{532bc21aefae4498a226eca1e80fb9a7,
title = "Intratumoral heterogeneity and clonal evolution in liver cancer",
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.",
author = "Bojan Losic and Craig, {Amanda J.} and Carlos Villacorta-Martin and Martins-Filho, {Sebastiao N.} and Nicholas Akers and Xintong Chen and Ahsen, {Mehmet E.} and {von Felden}, Johann and Ismail Labgaa and Delia DʹAvola and Kimaada Allette and Lira, {Sergio A.} and Furtado, {Glaucia C.} and Teresa Garcia-Lezana and Paula Restrepo and Ashley Stueck and Ward, {Stephen C.} and Fiel, {Maria I.} and Hiotis, {Spiros P.} and Ganesh Gunasekaran and Daniela Sia and Schadt, {Eric E.} and Robert Sebra and Myron Schwartz and Llovet, {Josep M.} and Swan Thung and Gustavo Stolovitzky and Augusto Villanueva",
note = "Funding Information: The authors thank the office of Scientific Computing and the Genomics Core Facility at the Icahn School of Medicine at Mount Sinai (ISMMS) for providing computational resources and staff expertise, as well as the ISMMS Tissue Biorepository for providing the samples. TCGA data were downloaded as part of a general data use application to NIH via dbGaP for the project “Utilizing In-Silico Prediction Tools to Identify Mutation-derived Neoantigens and their Effect on Survival in TCGA cohort” granted to B.L. A.V. is the recipient of the American Association for the Study of Liver Diseases Foundation (AASLDF) Alan Hofmann Clinical and Translational Award, and he is supported by the U.S. Department of Defense (CA150272P3) and the Tisch Cancer Institute (Cancer Center Grant P30 CA196521). A.J.C. is supported by the National Cancer Institute Ruth L. Kirschstein NRSA Institutional Research Training Grant (CA078207). J.M.L. is supported by grants from the U.S. Department of Defense (CA150272P3), European Commission Framework Program 7 (HEPTROMIC, proposal number 259744) and Horizon 2020 Program (HEPCAR, proposal number 667273-2), the Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (AECC), Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2013-41027) and Grup de Recerca Consolidat – Recerca Translacional en Oncologia Hep{\`a}tica. AGAUR (Generalitat de Catalunya), SGR 1162. J.v. F. is supported by the German Research Foundation (FE1746/1-1). I.L. is supported by a grant from the Swiss National Science Foundation, from Foundation Roberto & Gianna Gonella and Foundation SICPA. S.A.L. is supported by the National Institutes of Health R01CA161373. D.D. is supported by the Grant for Studies Broadening from the Spanish Association for the Study of the Liver (Asociaci{\'o}n Espa{\~n}ola para el Estudio del H{\'i}gado, AEEH) and the Cancer Research Grant from Nuovo Soldati Foundation. B.L., N.A. and X.C. were all supported by the Icahn Institute of Genomics and Multiscale Biology. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-019-14050-z",
language = "English (US)",
volume = "11",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}