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Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 19, pages 670–681 (2022)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal causes of cancer-related death worldwide. The treatment of HCC remains challenging and is largely predicated on early diagnosis. Surveillance of high-risk groups using abdominal ultrasonography, with or without serum analysis of α-fetoprotein (AFP), can permit detection of early, potentially curable tumours, but is limited by its insensitivity. Reviewed here are two current approaches that aim to address this limitation. The first is to use old re-emerged empirically derived biomarkers such as AFP, now applied within statistical models. The second is to use circulating nucleic acid biomarkers, which include cell-free DNA (for example, circulating tumour DNA, cell-free mitochondrial DNA and cell-free viral DNA) and cell-free RNA, applying modern molecular biology-based technologies and machine learning techniques closely allied to the underlying biology of cancer. Taken together, these approaches are likely to be complementary. Both hold considerable promise for achieving earlier diagnosis as well as offering additional functionalities including improved monitoring of therapy and prediction of response thereto.

Key points

  • The development of clinically useful biomarkers for hepatocellular carcinoma (HCC) management has been slow; α-fetoprotein (AFP), despite much controversy and many limitations, remains widely used.

  • Biomarkers predicting response to systemic therapy are urgently needed; AFP is the only biomarker to predict response, and only in a subset of patients receiving ramucirumab in the second-line setting.

  • Promising combinations of biomarkers in diagnostic, predictive and prognostic roles are largely based on case–control studies; judgment on these should be reserved until they are backed up by prospective studies.

  • Cell-free DNAs (cfDNA), based on their genomic and epigenetic changes, can serve as promising biomarkers for early HCC and monitoring of minimal residual disease.

  • The analysis of genetic changes in circulating tumour DNA (ctDNA) enables the deciphering of tumour heterogeneity, facilitating precision oncology in patients with advanced-stage HCC.

  • Liquid biopsy can go beyond genomic DNA molecules, with cell-free mitochondrial DNA, cell-free viral DNA, cfRNA and extracellular vesicles as potential biomarkers for HCC.

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Fig. 1: GALAD Performance in cohorts of patients with HCC at Mayo Clinic, Rochester, MN, USA. Panel.
Fig. 2: Overview of liquid biopsy in the management of HCC.

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Authors and Affiliations

  1. Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

    Philip Johnson

  2. Centre for Novostics, Hong Kong Science Park, New Territories, Hong Kong SAR, China

    Qing Zhou & Y. M. Dennis Lo

  3. State Key Laboratory for Translational Oncology and Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, New Territories, Hong Kong SAR, China

    Qing Zhou & Y. M. Dennis Lo

  4. Center of Excellence for Liver Disease in Vietnam, Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Doan Y Dao

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  1. Philip Johnson
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  2. Qing Zhou
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  3. Doan Y Dao
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  4. Y. M. Dennis Lo
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The authors contributed equally to all aspects of the article.

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Correspondence to Philip Johnson.

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Competing interests

Y.M.D.L. holds equities in Grail/Illumina, DRA and Take2, and has previously received research funding from Grail. Y.M.D.L. is a scientific cofounder of Grail. Y.M.D.L. receives patent royalties from Sequenom, Illumina, Xcelom, Grail, DRA and Take2. P.J, Q.Z. and D.Y.D. declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks Arndt Vogel, Thomas Decaens and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Johnson, P., Zhou, Q., Dao, D.Y. et al. Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 19, 670–681 (2022). https://doi.org/10.1038/s41575-022-00620-y

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