Cancer treatment alters mutant selection in normal esophagus

Cancer research · Esophageal cancer · TP53

Mutant TP53 and PPM1D clones are selectively expanded in esophageal epithelium of patients who undergo CROSS treatment, whereas FLOT treatment selectively expands RAC1, NFE2L2 and MTOR mutant clones.

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.

The findings reveal that different chemotherapeutic regimens impose distinct selective pressures on pre‑existing normal esophageal clonal populations, potentially influencing subsequent risk of clonal evolution and therapy‑related complications.

Evidence level: Korai humán adat. Kis vagy feltáró emberi adat.

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