Abstract

ABSTRACTTo 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.Competing Interest StatementThe authors have declared no competing interest.View Full Text