Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals

Dimitrios V. Vavoulis (), Anthony Cutts, Nishita Thota, Jordan Brown, Robert Sugar, Antonio Rueda, Arman Ardalan, Kieran Howard, Flavia Matos Santo, Thippesh Sannasiddappa, Bronwen Miller, Stephen Ash, Yibin Liu, Chun-Xiao Song, Brian D. Nicholson, Helene Dreau, Carolyn Tregidgo and Anna Schuh ()
Additional contact information
Dimitrios V. Vavoulis: University of Oxford
Anthony Cutts: University of Oxford
Nishita Thota: Littlemore
Jordan Brown: Littlemore
Robert Sugar: Littlemore
Antonio Rueda: Littlemore
Arman Ardalan: University of Oxford
Kieran Howard: University of Oxford
Flavia Matos Santo: University of Oxford
Thippesh Sannasiddappa: Littlemore
Bronwen Miller: Littlemore
Stephen Ash: University of Oxford
Yibin Liu: Wuhan University
Chun-Xiao Song: University of Oxford
Brian D. Nicholson: University of Oxford
Helene Dreau: University of Oxford
Carolyn Tregidgo: Littlemore
Anna Schuh: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The analysis of circulating tumour DNA (ctDNA) through minimally invasive liquid biopsies is promising for early multi-cancer detection and monitoring minimal residual disease. Most existing methods focus on targeted deep sequencing, but few integrate multiple data modalities. Here, we develop a methodology for ctDNA detection using deep (80x) whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive approach than bisulphite sequencing, which permits the simultaneous analysis of genomic and methylomic data. We conduct a diagnostic accuracy study across multiple cancer types in symptomatic patients, achieving 94.9% sensitivity and 88.8% specificity. Matched tumour biopsies are used for validation, not for guiding the analysis, imitating an early detection scenario. Furthermore, in silico validation demonstrates strong discrimination (86% AUC) at ctDNA fractions as low as 0.7%. Additionally, we successfully track tumour burden and ctDNA shedding from precancerous lesions post-treatment without requiring matched tumour biopsies. This pipeline is ready for further clinical evaluation to extend cancer screening and improve patient triage and monitoring.

Date: 2025
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DOI: 10.1038/s41467-024-55428-y

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