Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals
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 deve...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55428-y |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dimitrios V. Vavoulis |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e8180916444c4ebb9b244db737260b88 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e8180916444c4ebb9b244db737260b882025-01-12T12:31:07ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-024-55428-yMultimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signalsDimitrios V. Vavoulis0Anthony Cutts1Nishita Thota2Jordan Brown3Robert Sugar4Antonio Rueda5Arman Ardalan6Kieran Howard7Flavia Matos Santo8Thippesh Sannasiddappa9Bronwen Miller10Stephen Ash11Yibin Liu12Chun-Xiao Song13Brian D. Nicholson14Helene Dreau15Carolyn Tregidgo16Anna Schuh17Oxford Molecular Diagnostics Centre, Department of Oncology, University of OxfordOxford Molecular Diagnostics Centre, Department of Oncology, University of OxfordExact Sciences Innovation LTD, The Sherard Bldg, Edmund Halley Rd, LittlemoreExact Sciences Innovation LTD, The Sherard Bldg, Edmund Halley Rd, LittlemoreExact Sciences Innovation LTD, The Sherard Bldg, Edmund Halley Rd, LittlemoreExact Sciences Innovation LTD, The Sherard Bldg, Edmund Halley Rd, LittlemoreOxford Molecular Diagnostics Centre, Department of Oncology, University of OxfordOxford Molecular Diagnostics Centre, Department of Oncology, University of OxfordOxford Molecular Diagnostics Centre, Department of Oncology, University of OxfordExact Sciences Innovation LTD, The Sherard Bldg, Edmund Halley Rd, LittlemoreExact Sciences Innovation LTD, The Sherard Bldg, Edmund Halley Rd, LittlemoreLudwig Institute for Cancer Research, Nuffield Department of Medicine, University of OxfordCollege of Chemistry and Molecular Sciences, Wuhan UniversityLudwig Institute for Cancer Research, Nuffield Department of Medicine, University of OxfordNuffield Department of Primary Care Health Sciences, University of OxfordOxford Molecular Diagnostics Centre, Department of Oncology, University of OxfordExact Sciences Innovation LTD, The Sherard Bldg, Edmund Halley Rd, LittlemoreOxford Molecular Diagnostics Centre, Department of Oncology, University of OxfordAbstract 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.https://doi.org/10.1038/s41467-024-55428-y |
| spellingShingle | 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 Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals Nature Communications |
| title | Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals |
| title_full | Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals |
| title_fullStr | Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals |
| title_full_unstemmed | Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals |
| title_short | Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals |
| title_sort | multimodal cell free dna whole genome taps is sensitive and reveals specific cancer signals |
| url | https://doi.org/10.1038/s41467-024-55428-y |
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