Cancer treatment alters mutant selection in normal esophagus
Abstract Aging epithelial tissues, including the esophagus, are colonized by somatic mutant clones under strong competitive selection. The effect of cancer treatment on mutant selection in normal epithelium is unknown. We hypothesized that some mutant clones may be selectively expanded during treatment. To test this, we sequenced normal esophageal epithelium removed from 70 patients after therapy for esophageal cancer. Patients received either no treatment, combination chemotherapy (FLOT, ECX or EOX) or chemotherapy and radiation therapy (CROSS). Mutant TP53 and PPM1D clones were expanded in patients undergoing CROSS. In the group undergoing FLOT, there was increased selection for RAC1 , NFE2L2 and MTOR mutations consistent with these mutants conferring 5-fluorouracil resilience in normal epithelium. Sequencing normal epithelia reveals treatment-specific selection of mutations and may identify genes implicated in cellular responses to therapy.
Authors
- Luca Albarello (ORCID: https://orcid.org/0000-0003-4846-5096)
- David Shorthouse (ORCID: https://orcid.org/0000-0002-3207-3584)
- Swee Hoe Ong (ORCID: https://orcid.org/0000-0002-3629-5387)
- Salomé Brunon
- Benjamin A. Hall (ORCID: https://orcid.org/0000-0003-0355-2946)
- Tim Underwood (ORCID: https://orcid.org/0000-0001-9455-2188)
- Philip H. Jones (ORCID: https://orcid.org/0000-0002-5904-795X)
- Joanna C. Fowler (ORCID: https://orcid.org/0000-0001-7546-369X)
- Giuseppina Arbore (ORCID: https://orcid.org/0000-0002-8318-7557)
- Giovanni Tonon (ORCID: https://orcid.org/0000-0003-2973-5038)
- Ujjwal Banerjee
- Samuel L. Hill (ORCID: https://orcid.org/0000-0002-9590-2116)
- Francesco Puccetti (ORCID: https://orcid.org/0000-0001-6638-6880)
- Roshan Sood (ORCID: https://orcid.org/0000-0002-1318-7025)
- Paolo Dellabona (ORCID: https://orcid.org/0000-0002-1414-633X)
- David Fernández‐Antorán (ORCID: https://orcid.org/0000-0003-1608-570X)
- Kasumi Murai
- Andrea Cossu
- Irina Abnizova
- Riccardo Rosati
- Oliver Pickering
- Ugo Elmore
Institutions
- Vita-Salute San Raffaele University (IT)
- University of Cambridge (GB)
- The Gurdon Institute (GB)
- Wellcome Sanger Institute (GB)
- Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo (ES)
- Hutchison/MRC Research Centre (GB)
- Instituto de Investigación Sanitaria Aragón (ES)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Southampton (GB)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- University College London (GB)
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-09-11
- DOI
- https://doi.org/10.1038/s41588-026-02738-0
- Primary Topic
- Esophageal Cancer Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- Cancer Research UK
- Royal Society