Functional classification of monoallelic TP53 mutations refines prognostic stratification in myelodysplastic neoplasms Free

Introduction

Myelodysplastic neoplasms (MDS) are a group of hematological disorders characterized by ineffective hematopoiesis. Mutations in the TP53 gene have emerged as one of the most significant negative prognostic factors. Despite the recognized negative impact of TP53 mutations, there is conflicting evidence in the literature regarding the prognostic significance of biallelic versus monoallelic mutation type. Some studies suggest that there is no significant difference in survival outcomes, while other research indicates that only biallelic mutations are associated with a worse prognosis. While many TP53 variants cause loss of function (LOF), others exert dominant-negative (DNE) or even gain-of-function effects on functional TP53 copies. The aim of this study was to explore the role of specific amino acid changes in TP53 in its monoallelic state as a negative prognostic factor in MDS.

Methods

To investigate the effect of individual TP53 variants, survival data from the IWG cohort (n=3,323) and the Japanese J-MDS cohort (n=1,384) were used. Functional annotation of each possible TP53 variant was based on published high-throughput saturation mutagenesis data obtained through a pooled screening approach in a human cell line. Variants were categorized as LOF or DNE based on their enrichment under selective conditions. A phenotypic score (PS) was derived from individual enrichment values to standardize the interpretation of each allele's functional impact (Giacomelli AO et al., 2018). This PS was then used to investigate the impact of each TP53 variant on patient prognosis.

Results

We found that MDS patients with a monoallelic TP53 mutation and a high PS (≥7; n=110) had a significantly worse overall survival (OS) compared to those with a lower score (<7; n=105; p=0.007; HR=1.66, 95% CI: 1.15–2.39). The median OS was 13.8 months for patients with a high PS (≥7) and 39.2 months for those with a low PS (<7). In comparison, TP53 wild-type patients (n=3,777) had a median OS of 42.4 months, while patients with biallelic TP53 mutations (n=517) had a median OS of 9.4 months. Notably, differences in allele frequency did not play a major role. This effect was observed in both low- and high-risk MDS patients, according to IPSS-R and IPSS-M. Furthermore, patients with long-term survival (≥24 months) had a significantly lower proportion (p<0.001) of monoallelic TP53 mutations with a high PS (19% vs. 43%).

Discussion

In this study, we demonstrated that the functional characteristics of TP53 mutations, as captured by a PS, have a significant prognostic impact in MDS patients with monoallelic TP53 mutations. This finding suggests that not only the allelic state but also the functional impact of the specific TP53 mutation plays a crucial role in determining patient prognosis. Notably, PS-based stratification identified higher risk patients among those considered as lower risk patients based on their allelic state alone according to IPSS-M. These results indicate that integrating functional mutation data may enhance current risk models and support more individualized treatment decisions.