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

// Monika Belickova 1 , Jitka Vesela 1 , Anna Jonasova 2 , Barbora Pejsova 1 , Hana Votavova 1 , Michaela Dostalova Merkerova 1 , Zuzana Zemanova 3 , Jana Brezinova 1 , Dana Mikulenkova 1 , Marie Lauermannova 1 , Jan Valka 1 , Kyra Michalova 1, 3 , Radana Neuwirtova 2 , Jaroslav Cermak 1 1 Institute of Hematology and Blood Transfusion, Prague, Czech Republic 2 First Department of Medicine, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic 3 Center of Oncocytogenetics, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic Correspondence to: Monika Belickova, email: monika.belickova@uhkt.cz Keywords: myelodysplastic syndrome, mutational status, TP53, prognosis, variant allele frequency Received: January 03, 2016 Accepted: April 16, 2016 Published: May 06, 2016 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.