Pan‐Cancer Quantification of Driver Alteration Transmission Across Molecular Layers Reveals Limited Propagation to Protein Abundance

ABSTRACT Precision oncology relies primarily on DNA‐level alterations for therapeutic decisions, but the extent to which driver mutations propagate to protein abundance has not been systematically evaluated. Here, I developed a regression‐based transmission score (TS_ R 2 ) to quantify driver alteration signal propagation across DNA, mRNA, and protein layers. Applying this framework to matched genomic, transcriptomic, proteomic, and phosphoproteomic data from 754 Clinical Proteomic Tumor Analysis Consortium (CPTAC) tumors across seven cancer types, I analyzed 86 driver gene–cancer type pairs, of which 83 were evaluable for the full two‐layer transmission score. I employed covariate‐adjusted regression for each molecular transition, assessing significance via permutation testing ( n = 1000). Mixed‐effects modeling then partitioned gene‐intrinsic from cancer‐type‐dependent effects. Only 5 of 83 evaluable pairs (6%) demonstrated high transmission (TS_ R 2 > 0.05), with receptor tyrosine kinases ( EGFR , FGFR2 ) exemplifying this class. The primary bottleneck occurred at the mutation–mRNA transition, not mRNA–protein translation. Gene identity accounted for 49% of transmission efficiency variance, nearly double the contribution of cancer type (29%). Copy number alterations transmitted signals 13.8‐fold more efficiently than point mutations, and truncating mutations showed higher transmission than missense variants (Wilcoxon p = 0.005). Microsatellite instability attenuated mRNA–protein transmission in UCEC and COAD. These findings demonstrate that many driver alterations show limited propagation to protein abundance. This challenges DNA‐only interpretations in precision oncology and provides a framework for integrated functional driver prioritization.