Whole-exome tumor-agnostic ctDNA analysis enhances minimal residual disease detection and reveals relapse mechanisms in localized colon cancer
In stage 2-3 colon cancer (CC), postsurgery circulating tumor DNA (ctDNA) assessment is crucial for guiding adjuvant chemotherapy (ACT) decisions. While existing assays detect ctDNA and help identify high-risk persons with CC for recurrence, their limited sensitivity after surgery poses challenges in deciding on ACT. Additionally, a substantial portion of persons with CC fail to clear ctDNA after ACT, leading to recurrence. In this study, we performed whole-exome sequencing (WES) of ctDNA at different time points in participants with relapsed CC in two independent cohorts, alongside transcriptomic and proteomic analyses of metastases, to enhance comprehension of progression mechanisms. A plasma WES-based tumor-agnostic assay demonstrated higher sensitivity in detecting minimal residual disease (MRD) compared to current assays. Immune evasion appears to be the primary driver of progression in the localized CC setting, indicating the potential efficacy of immunotherapy for microsatellite stability in persons with CC. Organoid modeling further supports the promising potential of targeted therapy in eradicating MRD, surpassing conventional treatments.
Authors
- Blanca García-Micó (ORCID: https://orcid.org/0000-0002-9370-7966)
- Jorge Martín-Arana (ORCID: https://orcid.org/0000-0003-4554-5760)
- R. Tébar-Martínez (ORCID: https://orcid.org/0000-0001-8263-0513)
- David Casado
- Juan Antonio Carbonell‐Asins (ORCID: https://orcid.org/0000-0002-8449-5674)
- Tenna Vesterman Henriksen (ORCID: https://orcid.org/0000-0002-8541-1735)
- Stephanie García‐Botello (ORCID: https://orcid.org/0000-0001-6921-4902)
- Valentina Gambardella (ORCID: https://orcid.org/0000-0001-6081-8830)
- Claus L. Andersen (ORCID: https://orcid.org/0000-0002-7406-2103)
- José Martín‐Arévalo (ORCID: https://orcid.org/0000-0001-5337-9577)
- Brenda Palomar-De Lucas (ORCID: https://orcid.org/0000-0002-3094-2301)
- Alejandro Espí
- Tania Fleitas (ORCID: https://orcid.org/0000-0002-2789-9082)
- Daniel G. Camblor (ORCID: https://orcid.org/0000-0002-2449-9841)
- Susana Roselló (ORCID: https://orcid.org/0000-0003-3915-4130)
- Amanda Frydendahl (ORCID: https://orcid.org/0000-0001-9552-5421)
- Noelia Tarazona (ORCID: https://orcid.org/0000-0003-4888-1655)
- Kåre Andersson Gotschalck (ORCID: https://orcid.org/0000-0001-5119-2231)
- Francisco Gimeno-Valiente (ORCID: https://orcid.org/0000-0003-0544-9459)
- Desamparados Roda (ORCID: https://orcid.org/0000-0003-2657-9623)
- D Moro (ORCID: https://orcid.org/0009-0000-2674-6589)
- Leticia Pérez‐Santiago (ORCID: https://orcid.org/0000-0002-3090-8330)
- Carolina Martínez‐Ciarpaglini (ORCID: https://orcid.org/0000-0002-8797-2114)
- Andrés Cervantes (ORCID: https://orcid.org/0000-0003-3806-3691)
- B. Martínez-Castedo (ORCID: https://orcid.org/0009-0002-3629-8526)
- Vicente Pla
- Marisol Huerta
- M. Bartolomé
Institutions
- Cervantes Institute (ES)
- Universitat de València (ES)
- Aarhus University (DK)
- Instituto de Salud Carlos III (ES)
- Aarhus University Hospital (DK)
- London Cancer (GB)
- Regional Hospital Horsens (DK)
- INCLIVA Health Research Institute (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- University College London (GB)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1038/s43018-025-00960-z
- Citations
- 12
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 11.23
Funders
- American Concrete Institute Foundation
- Aarhus Universitet
- Aarhus Universitetshospital
- Generalitat Valenciana
- Novo Nordisk
- Novo Nordisk Fonden
- INCLIVA Instituto de Investigación Sanitaria
- Instituto de Salud Carlos III