Restoring Cancer Genomes: Functional Mutation Correction as a Platform for Precision Oncology

Abstract

Cancer genome sequencing has uncovered an extensive landscape of somatic mutations. However, determining which of these alterations are biologically consequential and therapeutically actionable remains a central challenge in oncology. CRISPR-based genome editing now enables precise correction of oncogenic mutations within their endogenous genomic context. Recent work demonstrates that repairing cancer hotspot mutations restores conserved tumor-relevant transcriptional programs across diverse tumor types, revealing tumor-agnostic dependencies. Beyond therapeutic implications, this mutation-correction framework provides a scalable functional platform to stratify drivers, interrogate variants of uncertain significance, and refine precision diagnostics. This perspective discusses how programmable mutation correction advances (i) mechanistic cancer biology, (ii) personalized cancer diagnostics, and (iii) next-generation precision gene therapies. We propose that systematic reversal of cancer mutations represents a conceptual shift from observing mutational landscapes to actively testing their biological necessity.