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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\n                    <jats:italic>TP53<\/jats:italic>\n                    and\n                    <jats:italic>PPM1D<\/jats:italic>\n                    clones were expanded in patients undergoing CROSS. In the group undergoing FLOT, there was increased selection for\n                    <jats:italic>RAC1<\/jats:italic>\n                    ,\n                    <jats:italic>NFE2L2<\/jats:italic>\n                    and\n                    <jats:italic>MTOR<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02738-0","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:03:36Z","timestamp":1789117416000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cancer treatment alters mutant selection in normal esophagus"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7546-369X","authenticated-orcid":false,"given":"Joanna C.","family":"Fowler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Arbore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1318-7025","authenticated-orcid":false,"given":"Roshan K.","family":"Sood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Abnizova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4846-5096","authenticated-orcid":false,"given":"Luca","family":"Albarello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Pickering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasumi","family":"Murai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ujjwal","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salom\u00e9","family":"Brunon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3629-5387","authenticated-orcid":false,"given":"Swee Hoe","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cossu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugo","family":"Elmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6638-6880","authenticated-orcid":false,"given":"Francesco","family":"Puccetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1608-570X","authenticated-orcid":false,"given":"David","family":"Fernandez-Antoran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2973-5038","authenticated-orcid":false,"given":"Giovanni","family":"Tonon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Dellabona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Rosati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9590-2116","authenticated-orcid":false,"given":"Samuel Luke","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9455-2188","authenticated-orcid":false,"given":"Tim","family":"Underwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0355-2946","authenticated-orcid":false,"given":"Benjamin A.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3207-3584","authenticated-orcid":false,"given":"David","family":"Shorthouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5904-795X","authenticated-orcid":false,"given":"Philip H.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"2738_CR1","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1038\/s41586-018-0811-x","volume":"565","author":"A Yokoyama","year":"2019","unstructured":"Yokoyama, A. et al. 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