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, Anna Schuh
Nat Commun . 2025 Jan 8;16(1):430. doi: 10.1038/s41467-024-55428-y.
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.