TP53 mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes.

Monika Belickova,Anna Jonasova,Hana Votavova,Jan Valka,Jitka Vesela,Barbora Pejsova,Kyra Michalova,Marie Lauermannova,Jaroslav Cermak,Dana Mikulenkova,Jana Brezinova,Zuzana Zemanova,Michaela Dostalova Merkerova,Radana Neuwirtova

doi:10.18632/oncotarget.9200

Monika Belickova, Anna Jonasova + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.9200

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Abstract

TP53 mutations are frequently detected in patients with higher-risk myelodysplastic syndromes (MDS); however, the clinical impact of these mutations on the disease course of patients with lower-risk MDS is unclear. In this study of 154 lower-risk MDS patients, TP53 mutations were identified in 13% of patients, with prevalence in patients with del(5q) (23.6%) compared to non-del(5q) (3.8%). Two-thirds of the mutations were detected at the time of diagnosis, and one-third were detected during the course of the disease. Multivariate analysis demonstrated that a TP53 mutation was the strongest independent prognostic factor for overall survival (OS) (HR: 4.39) and progression-free survival (PFS) (HR: 3.74). Evaluation of OS determined a TP53 variant allele frequency (VAF) threshold of 6% as an optimal cut-off for patient stratification. The median OS was 43.5 months in patients with mutations detected at the time of diagnosis and a mutational burden of > 6% VAF compared to 138 months (HR 12.2; p = 0.003) in patients without mutations; similarly, the median PFS was 20.2 months versus 116.6 months (HR 79.5; p < 0.0001). In contrast, patients with a mutational burden of < 6% VAF were stable for long periods without progression and had no significant impact on PFS or OS. Additionally, we found a high correlation in the mutational data from cells of the peripheral blood and those of the bone marrow, indicating that peripheral blood is a reliable source for mutation monitoring. Our results indicate that the clinical impact of TP53 mutations in lower-risk MDS patients depends on the level of mutational burden.

Highlights

Myelodysplastic syndromes (MDS) are hematological malignancies characterized by ineffective hematopoiesis in one or more cell lineages, myelodysplasia and an increased risk of progression to acute myeloid leukemia (AML) [1,2,3]
Our results indicate that the clinical impact of TP53 mutations in lower-risk myelodysplastic syndromes (MDS) patients depends on the level of mutational burden
The median age of patients carrying mutation was years and those without mutations was years. 2 out of 154 patients had secondary MDS who were previously treated with chemotherapy

Summary

Introduction

Myelodysplastic syndromes (MDS) are hematological malignancies characterized by ineffective hematopoiesis in one or more cell lineages, myelodysplasia and an increased risk of progression to acute myeloid leukemia (AML) [1,2,3]. The IPSS is based on the number of cytopenias, the cytogenetic profile, and the percentage of blasts in the bone marrow (BM) and stratifies patients with MDS into one of four prognostic categories: low risk, intermediate 1 risk, intermediate 2 risk, and high risk. MDS are defined by the IPSS as low or intermediate 1 risk MDS with a lower risk of AML progression and longer survival. A subset of lower-risk patients shows a more aggressive disease course and shorter overall survival (OS) [6, 7]. Identification of these patients is important for risk prediction and the choice of the optimal therapeutic approach. The identification of new prognostic factors, such as mutations in relevant driver genes, is warranted

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