Oncotarget

Research Papers:

Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents

Koichi Takahashi _, Keyur Patel, Carlos Bueso-Ramos, Jianhua Zhang, Curtis Gumbs, Elias Jabbour, Tapan Kadia, Michael Andreff, Marina Konopleva, Courtney DiNardo, Naval Daver, Jorge Cortes, Zeev Estrov, Andrew Futreal, Hagop Kantarjian and Guillermo Garcia-Manero

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Oncotarget. 2016; 7:14172-14187. https://doi.org/10.18632/oncotarget.7290

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Abstract

Koichi Takahashi1,3,4, Keyur Patel2, Carlos Bueso-Ramos2, Jianhua Zhang3, Curtis Gumbs3, Elias Jabbour1, Tapan Kadia1, Michael Andreff1, Marina Konopleva1, Courtney DiNardo1, Naval Daver1, Jorge Cortes1, Zeev Estrov1, Andrew Futreal3, Hagop Kantarjian1, Guillermo Garcia-Manero1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

3Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

4Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Correspondence to:

Guillermo Garcia-Manero, e-mail: [email protected]

Keywords: TP53, myelodysplastic syndromes, hypomethylating agents

Received: October 17, 2015     Accepted: January 09, 2016     Published: February 9, 2016

ABSTRACT

We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P <0.001). Further, TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed.


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