Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals
Dimitris Vavoulis, Anthony Cutts, Nishita Thota, J. Howard Brown, R. Sugar, Antonio Rueda, Arman Ardalan, Kieran Howard, Flavia Matos Santo, Thippesh Sannasiddappa, Bronwen Miller, Stephen Ash, Yibin Liu, Chun‐Xiao Song, Brian D Nicholson, Hélène Dreau, Carolyn Tregidgo, Anna Schuh
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.