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Tumour evolution in hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 17, pages 139–152 (2020)Cite this article

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Abstract

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, typically develops on the background of chronic liver disease and is an aggressive disease with dismal prognosis. Studies using next-generation sequencing of multiple regions of the same tumour nodule suggest different patterns of HCC evolution and confirm the high molecular heterogeneity in a subset of patients. Different hypotheses have been proposed to explain tumour evolution, including clonal selection or neutral and punctuated acquisition of genetic alterations. In parallel, data indicate a fundamental contribution of nonmalignant cells of the tumour microenvironment to cancer clonal evolution. Delineating these dynamics is crucial to improve the treatment of patients with HCC, and particularly to help understand how HCC evolution drives resistance to systemic therapies. A number of new minimally invasive techniques, such as liquid biopsies, could help track cancer evolution in HCC. These tools might improve our understanding of how systemic therapies affect tumour clonal composition and could facilitate implementation of real-time molecular monitoring of patients with HCC.

Key points

  • Hepatocellular carcinoma (HCC), the most frequent form of liver cancer, is a deadly disease that normally arises on the background of chronic liver disease (for example, cirrhosis).

  • Molecular studies have identified the most frequent alterations of HCC; these include mutations in the TERT promoter, TP53, and CTNNB1, copy number variations, and aberrations in DNA methylation.

  • Large studies on tumour evolution in HCC are lacking, but knowledge can be inferred from small sample studies in HCC utilizing multiregional or longitudinal sampling, including single-cell analysis, and from other tumour entities.

  • Potential drivers of tumour evolution are divided into intrinsic factors (that is, endogenous causes of DNA damage within the evolving tumour cell, such as genomic instability) and extrinsic factors from within the tumour microenvironment, such as immune cells (immunoediting of the tumour) and cancer-associated fibroblasts (remodelling).

  • Clonal tumour composition changes over time might be treatment-induced, and tumour evolution has wide clinical implications. For example, higher intratumoural heterogeneity is correlated with worse clinical outcomes.

  • For the implementation of personalized medicine and to truly understand the clinical effect of tumour evolution in HCC, noninvasive tracing of tumour evolution over time will be of fundamental importance.

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Fig. 1: Models of tumour evolution showing the progression of intratumoural heterogeneity over time.
Fig. 2: Hepatocarcinogenesis in cirrhotic and noncirrhotic (adenoma–carcinoma sequence) livers.
Fig. 3: Histological intratumoural heterogeneity in a small hepatocellular carcinoma nodule affecting cell differentiation and immune infiltrate.
Fig. 4: Intrinsic and extrinsic factors that drive tumour evolution.

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Acknowledgements

The work of A.V. is supported by the U.S. Department of Defense (CA150272P3). The work of J.v.F. is supported by Deutsche Forschungsgemeinschaft (FE1746/1-1). The work of T.G.-L is supported by Asociación Española para el Estudio del Hígado (AEEH).

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Authors and Affiliations

  1. 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

    Amanda J. Craig, Johann von Felden, Teresa Garcia-Lezana, Samantha Sarcognato & Augusto Villanueva

  2. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Johann von Felden

  3. Surgical Pathology & Cytopathology Unit, Department of Medicine — DIMED, University of Padova, Padova, Italy

    Samantha Sarcognato

  4. Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Augusto Villanueva

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  4. Samantha Sarcognato
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A.V. made a substantial contribution to discussion of content, and wrote and reviewed/edited the manuscript before submission. A.J.C., J.v.F., S.S. and T.G.-L. researched data for the article, made a substantial contribution to discussion of content, and wrote and reviewed/edited the manuscript before submission.

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Correspondence to Augusto Villanueva.

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Competing interests

A.V. has received consulting fees from Guidepoint and Fujifilm, advisory board fees from Exact Sciences, Nucleix and NGM, and lecture fees from Exelixis. The other authors declare no competing interests.

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Craig, A.J., von Felden, J., Garcia-Lezana, T. et al. Tumour evolution in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 17, 139–152 (2020). https://doi.org/10.1038/s41575-019-0229-4

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