Intratumoral heterogeneity and clonal evolution in liver cancer

Bojan Losic; Amanda J. Craig; Carlos Villacorta-Martin; Sebastiao N. Martins-Filho; Nicholas Akers; Xintong Chen; Mehmet E. Ahsen; Johann von Felden; Ismail Labgaa; Delia DʹAvola; Kimaada Allette; Sergio A. Lira; Glaucia C. Furtado; Teresa Garcia-Lezana; Paula Restrepo; Ashley Stueck; Stephen C. Ward; Maria I. Fiel; Spiros P. Hiotis; Ganesh Gunasekaran; Daniela Sia; Eric E. Schadt; Robert Sebra; Myron Schwartz; Josep M. Llovet; Swan Thung; Gustavo Stolovitzky; Augusto Villanueva

doi:10.1038/s41467-019-14050-z

Intratumoral heterogeneity and clonal evolution in liver cancer

Bojan Losic, Amanda J. Craig, Carlos Villacorta-Martin, Sebastiao N. Martins-Filho, Nicholas Akers, Xintong Chen, Mehmet E. Ahsen, Johann von Felden, Ismail Labgaa, Delia DʹAvola, Kimaada Allette, Sergio A. Lira, Glaucia C. Furtado, Teresa Garcia-Lezana, Paula Restrepo, Ashley Stueck, Stephen C. Ward, Maria I. Fiel, Spiros P. Hiotis, Ganesh GunasekaranDaniela Sia, Eric E. Schadt, Robert Sebra, Myron Schwartz, Josep M. Llovet, Swan Thung, Gustavo Stolovitzky, Augusto Villanueva

Medicine

Research output: Contribution to journal › Article › peer-review

271 Citations (Scopus)

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.

Original language	English
Article number	291
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-14050-z
Publication status	Published - Dec 1 2020

Bibliographical note

Funding Information:
A.V. received consulting fees from Guidepoint and Fujifilm; advisory board fees from Exact Sciences, Nucleix and NGM Pharmaceuticals; and lecture fees from Exelixis. J.M.L. is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Roche, Genentech, Glycotest, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech, Sprink Pharmaceuticals, Nucleix and Can-Fite Bio-pharma. The remaining authors declare no competing interests.

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 Asociación Española Contra el Cáncer (AECC), Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2013-41027) and Grup de Recerca Consolidat – Recerca Translacional en Oncologia Hepàtica. 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 (Asociación Española para el Estudio del Hígado, 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:
© 2020, The Author(s).

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-14050-z

Cite this

Losic, B., Craig, A. J., Villacorta-Martin, C., Martins-Filho, S. N., Akers, N., Chen, X., Ahsen, M. E., von Felden, J., Labgaa, I., DʹAvola, D., Allette, K., Lira, S. A., Furtado, G. C., Garcia-Lezana, T., Restrepo, P., Stueck, A., Ward, S. C., Fiel, M. I., Hiotis, S. P., ... Villanueva, A. (2020). Intratumoral heterogeneity and clonal evolution in liver cancer. Nature Communications, 11(1), Article 291. https://doi.org/10.1038/s41467-019-14050-z

Losic, B, Craig, AJ, Villacorta-Martin, C, Martins-Filho, SN, Akers, N, Chen, X, Ahsen, ME, von Felden, J, Labgaa, I, DʹAvola, D, Allette, K, Lira, SA, Furtado, GC, Garcia-Lezana, T, Restrepo, P, Stueck, A, Ward, SC, Fiel, MI, Hiotis, SP, Gunasekaran, G, Sia, D, Schadt, EE, Sebra, R, Schwartz, M, Llovet, JM, Thung, S, Stolovitzky, G & Villanueva, A 2020, 'Intratumoral heterogeneity and clonal evolution in liver cancer', Nature Communications, vol. 11, no. 1, 291. https://doi.org/10.1038/s41467-019-14050-z

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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: A.V. received consulting fees from Guidepoint and Fujifilm; advisory board fees from Exact Sciences, Nucleix and NGM Pharmaceuticals; and lecture fees from Exelixis. J.M.L. is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Roche, Genentech, Glycotest, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech, Sprink Pharmaceuticals, Nucleix and Can-Fite Bio-pharma. The remaining authors declare no competing interests. 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).",

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doi = "10.1038/s41467-019-14050-z",

language = "English",

volume = "11",

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T1 - Intratumoral heterogeneity and clonal evolution in liver cancer

AU - Losic, Bojan

AU - Craig, Amanda J.

AU - Villacorta-Martin, Carlos

AU - Martins-Filho, Sebastiao N.

AU - Akers, Nicholas

AU - Chen, Xintong

AU - Ahsen, Mehmet E.

AU - von Felden, Johann

AU - Labgaa, Ismail

AU - DʹAvola, Delia

AU - Allette, Kimaada

AU - Lira, Sergio A.

AU - Furtado, Glaucia C.

AU - Garcia-Lezana, Teresa

AU - Restrepo, Paula

AU - Stueck, Ashley

AU - Ward, Stephen C.

AU - Fiel, Maria I.

AU - Hiotis, Spiros P.

AU - Gunasekaran, Ganesh

AU - Sia, Daniela

AU - Schadt, Eric E.

AU - Sebra, Robert

AU - Schwartz, Myron

AU - Llovet, Josep M.

AU - Thung, Swan

AU - Stolovitzky, Gustavo

AU - Villanueva, Augusto

N1 - Funding Information: A.V. received consulting fees from Guidepoint and Fujifilm; advisory board fees from Exact Sciences, Nucleix and NGM Pharmaceuticals; and lecture fees from Exelixis. J.M.L. is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Roche, Genentech, Glycotest, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech, Sprink Pharmaceuticals, Nucleix and Can-Fite Bio-pharma. The remaining authors declare no competing interests. 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 Asociación Española Contra el Cáncer (AECC), Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2013-41027) and Grup de Recerca Consolidat – Recerca Translacional en Oncologia Hepàtica. 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 (Asociación Española para el Estudio del Hígado, 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: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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Intratumoral heterogeneity and clonal evolution in liver cancer

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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