Driver mutations in CTNNB1 are a hallmark of hepatoblastoma and offer a common biomarker for a liquid biopsy approach based on the presence of CTNNB1 circulating tumor DNA (ctDNA). We developed and investigated the utility of a quantitative universal next-generation sequencing (NGS) ctDNA assay for hepatoblastoma (QUENCH) to detect CTNNB1 ctDNA and assessed the links between ctDNA and current clinical indicators/biomarkers in hepatoblastoma. Applied to patients with hepatoblastoma, we demonstrate quantitation of various variants including single base substitutions and deletions down to 0.3% variant allele frequency, with 65% sensitivity and 100% specificity at the patient level, to allow biopsy-free tumor genotyping and sensitive ctDNA quantitation. CtDNA positivity correlates with tumor burden and ctDNA levels correlate with macroscopic residual disease and treatment response, thus providing promising evidence for the utility of quantitative ctDNA detection in hepatoblastoma.

The authors have declared no competing interest.

This research was funded by the Tour de Cure grant RSP-191-2020 (JK, SKE, SAV), U.S. Department of Defense Career Development Award grant CA201061 (SEW), and Cancer Prevention and Research Institute of Texas (CPRIT) Multi-Investigator Research Award grant RP180674 (SAV). SKE salary was supported by the Royal Australasian College of Surgeons (RACS) grant 170287 (JK). JT, DTPS, AEM, SK, and LDG acknowledge funding from the Kinghorn Foundation.

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The study was conducted under research protocols approved by the Sydney Children's Hospitals Network Human Research Ethics Committee, and Baylor College of Medicine (reference numbers: HREC/17/SCHN/302, and BCM IRB H-38834, respectively), with informed consent obtained from all participants.

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