RNA-Centric Tumour Evolution: Transcriptional Reinforcement, Reversibility, and Clinical Plasticity Beyond Genetics

Cancer progression is traditionally interpreted through genetic mutation and clonal selection. While this framework explains tumour initiation, it does not fully account for prolonged dormancy, late relapse, spatial heterogeneity, or metastasis occurring without new driver mutations. Increasing evidence instead implicates reversible regulatory layers operating downstream of DNA sequence. We propose an RNA-centric framework in which transcriptional reinforcement and RNA fate control jointly shape tumour evolution across time and space. Weak or context-dependent promoters-common in cancer-can generate sustained transcriptional output through exon-dependent reinforcement without promoter mutation, enhancer hijacking, or immediate protein production. The resulting RNA output is then filtered through RNA fate checkpoints that govern decay, nuclear retention, export, or persistence, functionally uncoupling transcription from translation. Within this model, non-coding and non-canonical RNAs act as spatiotemporal reporters of tumour state, reflecting when and where transcriptional programmes are engaged rather than which proteins are produced. RNA persistence enables tumours to remain transcriptionally primed under hypoxia, therapy, or immune pressure, supporting dormancy and rapid reactivation without irreversible genetic change. Reframing tumour evolution around RNA state regulation provides a coherent explanation for relapse and resistance and highlights RNA states as clinically tractable biomarkers and therapeutic targets that complement DNA-based oncology.