Three permissiveness gates multiply to determine mutation realisation: age-specific incidence and the dialysis–transplant separation from one parameter set

Abstract Background Mutation realisation is set by the product of three permissiveness gates: intrinsic G1, tissue G2 and systemic G3. An expanded clone appears only when all three are non-zero. Age-specific incidence and the dialysis–transplant separation are two readouts of the same product. Methods We analysed published data. SEER 2010–2013 supplied the multistage-senescence parameters k and b for 20 non-reproductive cancers. ANZDATA supplied cancer SMRs for 52,936 dialysis patients and 16,820 transplant recipients. Driver-mutation clones in normal colon and oesophagus constrained G1. We estimated k, b and G2, compared the three-gate product with one-gate, two-gate and additive models, and tested the result against HALO-301 and the anti-CD47 phase III trial. Results k = 6.17, b = 0.0099 ± 0.0005 yr⁻¹, non-driver rate-limiting steps 4.43 (72%). Dialysis SMR 1.2, transplant SMR 2.6, ratio r = 2.17; with transplant set to 1, dialysis G2 = 0.46. Peak age about 85 years, matching the fitted SEER plateau. The product reproduces both the inverted-U incidence curve and the dialysis–transplant separation. The one-gate and two-gate models satisfy one of the two. The additive model returns output when a gate is zero. Both interventions improved technical endpoints without changing overall survival. Conclusions Permissiveness is a product gate. G2 sets the amplitude of incidence; G1 and G3 set the shape of the age curve. Screening and treatment are directed at the lowest gate.