TP53 Combined Phenotype Score Is Associated with the Clinical Outcome of TP53-Mutated Myelodysplastic Syndromes.

Mariko Yabe,Hannah May,Virginia M Klimek,Robert P Hasserjian,Ahmet Dogan,Maria E Arcila,Aidana Z Omarbekova,Andrew M Brunner,Meier Hsu,Valentina Nardi,Ying Liu

doi:10.3390/cancers13215502

Abstract

Simple SummaryTP53 is the most frequently mutated genes in cancer, and mutations of TP53 are observed in 5–10% of patients in myelodysplastic syndrome (MDS). In patients with MDS, TP53 mutations are associated with adverse outcomes; however, there is still significant heterogeneity in these disease courses. We performed retrospective review of 107 patients with untreated TP53-mutated MDS, and identified that the functional impact of TP53 mutations, represented by phenotypic annotation of TP53 mutations (PHANTM) combined phenotype score is associated with prognosis. In patients with TP53-mutated MDS, we found that a higher PHANTM combined phenotype score is associated with poorer clinical outcome, and this has independent influence on prognosis accounting for IPSS-R and other risk variables. Our findings suggest that TP53-mutated MDS is heterogeneous and not all TP53 mutations harbor the same impact on prognosis. The PHANTM combined score adds to prognostic precision in MDS beyond previously reported TP53 allelic state.Mutations of TP53 are observed in 5–10% of patients in myelodysplastic syndrome (MDS) and are associated with adverse outcomes. Previous studies indicate that the TP53 allelic state and variant allele frequency of TP53 mutation impact patient outcomes, but there is significant heterogeneity within this MDS subgroup. We performed retrospective review of clinicopathologic and genomic information of 107 patients with TP53-mutated MDS. We assessed each mutation according to the phenotypic annotation of TP53 mutations (PHANTM) and analyzed the associations between predicted TP53 mutant function, represented by the PHANTM combined phenotype score, and overall survival (OS) using the log rank test and Cox regression. Our results indicated that patients with PHANTM combined phenotype score above the median (>1) had significantly shorter OS compared to those with scores below the median (median OS: 10.59 and 16.51 months, respectively, p = 0.025). This relationship remained significant in multivariable analysis (HR (95%CI): 1.62 (1.01–2.58), p = 0.044) and identified to have an independent prognostic influence, accounting for known risk such as IPSS-R and other standard risk variables. Our results suggest that the functional information of TP53 mutations, represented by PHANTM combined phenotype score, are associated with the clinical outcome of patients with TP53-mutated MDS.

Highlights

Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid disorders characterized by ineffective hematopoiesis leading to cytopenias and risk of transformation to acute myeloid leukemia (AML) [1]
Whether these functional differences translate into distinct clinical features and outcomes and how the type, number, and size of TP53 mutations influence the prognosis of patients with TP53-mutated MDS remains unclear
Our data suggest that the functional information of TP53 mutations, represented by phenotypic annotation of TP53 mutations (PHANTM) combined phenotype score independently influence the clinical outcome in TP53-mutated myelodysplastic syndromes

Summary

Introduction

Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid disorders characterized by ineffective hematopoiesis leading to cytopenias and risk of transformation to acute myeloid leukemia (AML) [1]. It has previously been argued that loss of p53 function is the critical determinant in cancer, yet the preponderance of missense mutations relative to truncation mutations argues that full-length mutant p53 actively promotes tumor development [14,15]. To determine the function of each missense or nonsense TP53 mutations, Giacomelli et al created a comprehensive library of p53 mutants and evaluated the function of these alleles in the presence or absence of endogenous p53 [15]. From these data, they developed a classifier which provides functional classification for any missense and nonsense variant of TP53 (phenotypic annotation of TP53 mutations (PHANTM); http://mutantp53.broadinstitute.org, accessed on 4 February 2020) [15]

Methods

Discussion

Conclusion