Evolutionary Action Score of TP53 Mutations: Integrated Clinico-pathologic And Protein Structural Analysis in Myelodysplastic Syndromes

To determine the impact of TP53 mutations on the phenotype and outcome of myelodysplastic syndromes, we quantified the deleterious effects of missense TP53 mutations using the computationally-derived evolutionary action score (higher score indicates worse impact), based on the phylogenetic divergence of the sequence position and amino acid change perturbation, and correlated with clinico-pathologic-genomic features in 270 newly-diagnosed TP53-mutant patients primarily treated with hypomethylating agents. Using recursive partitioning and regression trees, we identified a subset of patients with low-EAp53 mutations (≤52) with improved overall survival (OS) (n=17, 6%) compared to high-EAp53 (n=253, 94%) [median OS, 48 vs. 10 months; p=0.01]. Compared to high-EAp53, low-EAp53 patients had lower cytogenetic complexity, lower TP53 protein expression, lacked multi-allelic TP53 alterations, but had more somatic mutations in other genes. There was no difference in median TP53 variant allele frequency or distribution of R-IPSS. 3D-protein modeling showed clustering of poor-outcome mutations, indicating structural location influences outcome.