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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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.
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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.
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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.
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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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DOI: https://doi.org/10.1038/s41416-022-01706-9
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