Oncotarget, Vol. 7, No. 12
www.impactjournals.com/oncotarget/
Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents 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 1
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4
Department 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 TP53mutated 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 T/A alteration was most common. Mutations in TP53 were predominantly detected in the core DNA-binding domain (93%), and only 2 mutations were detected in the tetramerization domain (Figure 1). The most frequently mutated codon was codon 272 (9%), followed by codons 273 (7%) and 248 (7%). Ninety-four percent of the detected missense mutations were predicted to be non-functional for transcriptional activity. [23] Ninety-five percent of them were predicted to be deleterious according to the SIFT algorithm. [24] The median variant allele frequency (VAF) of the TP53
Treatment response to HMA therapy Complete response (CR) and overall response (OR) were observed in 49 patients (29%) and 57 patients (34%), respectively. Table 3 summarizes the association between various clinical characteristics and response to HMA therapy. Patients with thrombocytopenia at baseline had a significantly
Figure 1: Lollipop figure of TP53 mutations detected in 168 patients with MDS and CMML. Green dots indicate missense mutations and red dots indicate nonsense mutations. The figure for was created using cBioPortal website (http://www.cbioportal.org/). www.impactjournals.com/oncotarget
14173
Oncotarget
Table 1: Baseline clinical characteristics of the 168 patients with MDS who were screened for TP53 mutation and were treated with HMA therapy Characteristics
N or median (% or range)
Median age, range, y
67 (17-89)
Female
64 (38)
Pathological classification
5q- syndrome
2 (1)
RA
16 (9)
RCMD
27 (16)
RCMD-RS
1 (
www.impactjournals.com/oncotarget/
Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents 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 1
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4
Department 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 TP53mutated 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 T/A alteration was most common. Mutations in TP53 were predominantly detected in the core DNA-binding domain (93%), and only 2 mutations were detected in the tetramerization domain (Figure 1). The most frequently mutated codon was codon 272 (9%), followed by codons 273 (7%) and 248 (7%). Ninety-four percent of the detected missense mutations were predicted to be non-functional for transcriptional activity. [23] Ninety-five percent of them were predicted to be deleterious according to the SIFT algorithm. [24] The median variant allele frequency (VAF) of the TP53
Treatment response to HMA therapy Complete response (CR) and overall response (OR) were observed in 49 patients (29%) and 57 patients (34%), respectively. Table 3 summarizes the association between various clinical characteristics and response to HMA therapy. Patients with thrombocytopenia at baseline had a significantly
Figure 1: Lollipop figure of TP53 mutations detected in 168 patients with MDS and CMML. Green dots indicate missense mutations and red dots indicate nonsense mutations. The figure for was created using cBioPortal website (http://www.cbioportal.org/). www.impactjournals.com/oncotarget
14173
Oncotarget
Table 1: Baseline clinical characteristics of the 168 patients with MDS who were screened for TP53 mutation and were treated with HMA therapy Characteristics
N or median (% or range)
Median age, range, y
67 (17-89)
Female
64 (38)
Pathological classification
5q- syndrome
2 (1)
RA
16 (9)
RCMD
27 (16)
RCMD-RS
1 (
