Variant-Level Functional Classification of Monoallelic TP53 Mutations Refines Prognostic Stratification in Myelodysplastic Neoplasms Beyond Allelic Status

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Abstract
TP53 mutations represent one of the strongest adverse prognostic factors in myelodysplastic neoplasms (MDS). While multi-hit TP53 ( TP53 multiHit ) alterations uniformly lead to very poor outcomes, the prognostic relevance of monoallelic TP53 ( TP53 mono ) mutations remains controversial. TP53 variants can cause loss-of-function, dominant-negative, or gain-of-function effects. We hypothesized that functional heterogeneity among TP53 variants contributes to the variable clinical behavior observed in monoallelic TP53 -mutated MDS. Therefore, we analyzed pretreatment samples from 4,505 patients with MDS from two independent cohorts (IWG, n=3,173; J-MDS, n=1,332), including 271 patients with TP53 mono and 499 with TP53 multiHit . Functional annotation of TP53 variants was performed using a previously published phenotype score (PS) derived from saturation mutagenesis screens, capturing dominant-negative and loss-of-function effects. Median overall survival (OS) differed significantly by TP53 allelic state ( TP53 wild-type ( TP53 wt ) 42.4 months; TP53 mono 22.9 months; TP53 multiHit 9.2 months; p < 0.001). Within the TP53 mono subgroup, functional annotation identified marked heterogeneity. Patients with high PS (≥7) showed significantly inferior OS compared with those with low PS (median OS: 13.8 vs. 39.2 months; HR 1.68, 95% CI 1.16-2.42; p = 0.006), particularly for IPSS-R and IPSS-M low-risk cases. Combining PS and variant allele frequency (VAF) further improved risk stratification. TP53 mono patients with PS ≥7 and VAF ≥22% had outcomes comparable to TP53 multiHit (median OS: 8.8, p = 0.2), whereas those with PS TP53 wt (median OS: 49.7, p = 0.9). Overall, functional annotation of TP53 variants refines prognostication in TP53 mono -mutated MDS and may enhance individualized risk assessment.

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