Proteome-wide reanalysis identifies coverage and error-rate limits on acquired lysines in cancer

Abstract

Missense mutation in cancer creates acquired lysines, residues present in tumor cells and absent from normal cells in the same patient. The class holds 295,411 sites across 20,365 genes and falls on driver hotspots more often than other substitutions (odds ratio 1.68). Yet re-searching 42 proteomic experiments with a mutation-aware database recovers the mutant peptide in 0.63% of 8,470 site-in-cell-line observations, because a new lysine is a new cleavage site and the peptide it creates runs 6 residues against 13 for the wild type. Reported error rates do not hold either. Burden-matched entrapment puts the realized false-discovery proportion at 4.70% before score filtering, against 1% reported. Measured by competitive activity-based protein profiling across four cell lines, ligandability reproduces at the site level, no compound descriptor tested predicts it, and structure predicts it poorly at AUC 0.617. Acquired lysines are structurally ordinary, so the barrier is detection rather than chemistry.