Simona Alibrandi, Domenico Mordà, Concetta Scimone, Angela D’Ascola, Federica Aliquò, G Abate, Gianantonio Pozzato, Sergio Zaccaria Scalinci, Rosalia D’Angelo, Antonina Sidoti, Luigi Donato
Chimeric transcripts, long regarded as hallmarks of oncogenesis, are also generated in non-tumour cells under environmental stress, but remain poorly quantified in perturbation models. We profiled the chimeric transcriptome of retinal pigment epithelial (ARPE-19) cells across a balanced factorial design of 72 biological samples spanning oxidative stress, Quantum Molecular Resonance (QMR) therapy, a therapeutic secretome and their combination. Using a tiered pipeline and depth-normalised count models, oxidative stress increased the chimeric transcript burden by 33% (incidence-rate ratio 1.33, 95% CI 1.21-1.46, permutation p = 0.002). Modelling chimeric junctions jointly, therapy specifically reversed the stress-induced component (stress x therapy interaction IRR 0.52, 95% CI 0.32-0.84, p = 0.007), while constitutive chimeras, a negative control, showed no response (p = 0.49). The derailment was not random with respect to coding potential: oxidative stress preferentially induced chimeras preserving the reading frame, hence translatable (stress x frame ratio 2.59, 95% CI 1.11-6.04, p = 0.028). The effect was strongest for combined QMR+secretome treatment (IRR 0.40, q = 0.007). One junction, CTDNEP1 -ENSG00000262526, survived false-discovery-rate control and was confirmed by orthogonal callers, RT-qPCR and Sanger sequencing. The chimeric burden is thus a measurable, non-random and therapeutically reversible phenotype of oxidative stress; the generative mechanism remains undetermined.