Experiment‐Anchored Abundance–Coverage Frontiers Define Conditional RHSVV Exposure Requirements in TP53‐Missense Tumors

ABSTRACT Mutant p53 accumulation may complement conformation‐sensitive RHSVV recognition, but the required exposure discrimination depends on tumor coverage and normal‐cell stress. We analyzed 809 tumors and 523 adjacent‐normal specimens from eight CPTAC cohorts. R denotes p53 abundance relative to the cohort‐normal median; q denotes high‐state target/background epitope‐exposure contrast; and π is the assumed target mixture weight in the high‐exposure state. Native exposure was not measured. Among 268 quantified sequence‐compatible missense tumors, requiring R ≥ 3 retained 90 (33.6%), whereas R ≥ 4 retained 54 (20.1%). At π = 0.90 and a primary 2.1‐fold normal‐p53 stress multiplier derived from a western blot in irradiated wild‐type mouse embryonic fibroblasts, R ≥ 3 required q = 1.25 for both the pooled target criterion and the criterion requiring every one of seven fixed cohorts to pass. At R ≥ 4, abundance alone passed ( q = 1), showing that exposure discrimination expands modeled coverage rather than being required at every landmark. For R ≥ 3, the required contrast under the seven‐cohort criterion increased to 2.00, 3.00, and 6.00 at normal‐stress multipliers of 3, 5, and 10. In an exploratory comparison restricted to selected hotspots, observed median R was lower in the conformational‐proxy group than in the DNA‐contact‐proxy group (2.39 versus 3.22; n = 38 and 31). This subset‐specific association does not establish a general mutation‐class difference; class labels could not identify native exposure or π. Internal resampling revealed threshold sensitivity and cohort attrition and did not constitute validation. The resulting frontier specifies conditional experimental requirements across stress scenarios, not evidence of tumor killing or clinical safety.