Recursive mutational robustness in cancer through intra- and inter-genic compensation

Mutational robustness is a fundamental property of biological systems allowing phenotypic stability against genotypic perturbation. At the gene level, this is primarily attributed to inter-genic functional redundancy driven by paralogs. Here, we show that intra-genic functional redundancy, driven by alternatively spliced isoforms, is another prevalent source of mutational robustness. Integrating isoform-resolved pan-cancer genomics and transcriptomics data across tumors and cancer cell lines, we show that alternative isoforms often bypass deleterious somatic mutations. Mutation-skipping isoforms exhibit compensatory upregulation indicative of robustness against deleterious effects, especially in highly expressed genes. We found that intra-genic robustness is strongly associated with perturbation tolerance, is highly context-specific and, notably, can be complemented and augmented recursively by inter-genic robustness. Non-tumour-suppressor genes generally show higher robustness than tumour suppressor genes, and intra-genic compensation of their mutations is associated with worse disease outcome in most cancer types. Furthermore, intra-genic compensation by mutation-skipping isoforms associates with differential isoform usage among proximal interactors, suggesting restorative protein interaction rewiring at isoform-level. Mechanistically, self-transcriptional adaptation (self-TA) following nonsense-mediated decay of perturbed isoforms provides an explanation for the observed up-regulation of mutation-skipping isoforms. Overall, the proposed recursive mutational robustness framework opens new avenues for deeper mechanistic investigation into cancer evolution and identification of selective vulnerabilities in cancer cells.