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Urine DNA biomarkers for hepatocellular carcinoma screening

British Journal of Cancer volume 126, pages 1432–1438 (2022)Cite this article

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Abstract

Background

Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA (ctDNA) as a screening test.

Methods

Candidate markers in urine were selected from HCC and controls. We then enrolled 609 patients from five medical centres to test the selected urine panel. A two-stage model was developed to combine AFP and urine panel as a screening test.

Results

Mutated TP53, and methylated RASSF1a, and GSTP1 were selected as the urine panel markers. Serum AFP outperformed the urine panel among all cases of HCC, but the urine panel identified 49% of HCC cases with low AFP < 20 ng/ml. Using the two-stage model, the combined AFP and urine panel identified 148 of the 186 HCC cases (79.6% sensitivity at 90% specificity), which was 30% more than the cases detected with serum AFP alone. It also increased early-stage HCC detection from 62% to 92% (BCLC stage 0), and 40% to 77% (BCLC stage A).

Conclusion

Urine ctDNA has promising diagnostic utility in patients in HCC, especially in those with low AFP and can be used as a potential non-invasive HCC screening test.

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Fig. 1
Fig. 2: Detection of HCC-associated DNA markers in urine from patients with HCC and controls (hepatitis and cirrhosis).
Fig. 3: Performance of urine ctDNA markers for distinguishing HCC from non-HCC.
Fig. 4: Sensitivities of AFP ≥ 20 ng/ml, urine ctDNA and the two-stage model in different HCC stages per BCLC criteria.

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Data availability

The data generated and analysed during the study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dmitry Goryunov for the support in proofreading and editing of this manuscript.

Funding

This work is supported by R43CA165312, R44CA165312, R01CA202769 and K08CA237624.

Author information

Author notes

  1. These authors contributed equally: Amy K. Kim, James P. Hamilton.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Amy K. Kim, James P. Hamilton, Harry Luu & Michael G. Goggins

  2. JBS Science, Inc., Doylestown, PA, USA

    Selena Y. Lin, Jeremy Wang, Surbhi Jain & Wei Song

  3. Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Ting-Tsung Chang

  4. Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA

    Hie-Won Hann & Grace Park

  5. Division of Gastroenterology, Department of Internal Medicine, Hualien Tzu-Chi Hospital, Buddhist Tzu-Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan

    Chi-Tan Hu

  6. The Baruch S. Blumberg Institute, Doylestown, PA, USA

    Yue Lou, Tai-Jung Lee & Ying-Hsiu Su

  7. Department of Surgery, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan, Republic of China

    Yih-Jyh Lin

  8. Department of Radiology, University of Pennsylvania College of Medicine, Philadelphia, PA, USA

    Terence P. Gade

  9. ClinPharma Consulting, Inc, Phoenixville, PA, USA

    Dion Chen

  10. Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD, USA

    Michael G. Goggins

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Contributions

AKK and JPH contributed equally to this study. AKK contributed to formal analysis, original draft, patient recruitment and sample collection. JPH contributed to manuscript revision and editing, patient recruitment and sample collection. SYL contributed to conceptualisation, formal analysis, original draft and manuscript revision and editing. T-TC, H-WH, C-TH, Y-JL and TG contributed to patient recruitment and sample selection. YL contributed to formal analysis. GP and HL contributed to patient recruitment and sample selection and project administration. T-JL contributed to data curation. JW and DC contributed to data curation, formal analysis, and software support. MGG contributed to manuscript revision and editing. SJ contributed to conceptualisation, data curation, formal analysis and manuscript revision and editing. WS contributed to funding acquisition and project supervision. YHS contributed to lead conceptualisation, funding acquisition, original draft and manuscript revision and editing.

Corresponding author

Correspondence to Ying-Hsiu Su.

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Competing interests

AK is a consultant to AstraZeneca, WS, SJ and SL are shareholders of JBS Science Inc. YHS has received funding from JBS Science, Inc. The remaining authors declare no competing interests.

Ethics approval and consent to participate

The study received ethics approval from Heartland institutional review board (171201-173).

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Kim, A.K., Hamilton, J.P., Lin, S.Y. et al. Urine DNA biomarkers for hepatocellular carcinoma screening. Br J Cancer 126, 1432–1438 (2022). https://doi.org/10.1038/s41416-022-01706-9

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