Joanna C Fowler, Giuseppina Arbore, Roshan K Sood, Irina Abnizova, Luca Albarello, Oliver Pickering, Kasumi Murai, Ujjwal Banerjee, Salomé Brunon, Swee Hoe Ong, Andrea Cossu, Ugo Elmore, Francesco Puccetti, David Fernandez-Antoran, Giovanni Tonon, Paolo Dellabona, Riccardo Rosati, Samuel Luke Hill, Tim Underwood, Benjamin A Hall, David Shorthouse, Philip H Jones
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.