Dataset Information

Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes.

ABSTRACT: TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate (ORR) (odds ratio, 0.3; P = .021), and lower TP53 VAF correlated with higher ORR to HMAs. Increase in TP53 VAF at the time of transformation was observed in 13 patients (61%), and previously undetectable mutations were observed in 15 patients (65%). TP53 VAF was associated with worse prognosis (hazard ratio, 1.02 per 1% VAF increase; 95% confidence interval, 1.01-1.03; P < .001). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups within TP53-mutant MDS. We developed a multivariable model for overall survival that included the revised International Prognostic Scoring System (IPSS-R) categories and TP53 VAF. Total score for each patient was calculated as follows: VAF TP53 + 13 × IPSS-R blast score + 16 × IPSS-R cytogenetic score + 28 × IPSS-R hemoglobin score + 46 × IPSS-R platelet score. Use of this model identified 4 prognostic subgroups with median survival times of not reached, 42.2, 21.9, and 9.2 months. These data suggest that outcomes of patients with TP53-mutated MDS are heterogeneous and that transformation may be driven not only by TP53 but also by other factors.

SUBMITTER: Montalban-Bravo G

PROVIDER: S-EPMC7013259 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes.

Montalban-Bravo Guillermo G Kanagal-Shamanna Rashmi R Benton Christopher B CB Class Caleb A CA Chien Kelly S KS Sasaki Koji K Naqvi Kiran K Alvarado Yesid Y Kadia Tapan M TM Ravandi Farhad F Daver Naval N Takahashi Koichi K Jabbour Elias E Borthakur Gautham G Pemmaraju Naveen N Konopleva Marina M Soltysiak Kelly A KA Pierce Sherry R SR Bueso-Ramos Carlos E CE Patel Keyur P KP Kantarjian Hagop H Garcia-Manero Guillermo G

Blood advances 20200201 3

TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex kary ...[more]

PMID: 32027746

Similar Datasets

Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders for which allogeneic hematopoietic cell transplantation (HCT) is currently the sole curative treatment. Epigenetic lesions are considered a major pathogenetic determinant in many cancers, and in MDS, epigenetic-based interventions have emerged as life-prolonging therapies. However, the impact of epigenomic aberrations on HCT outcomes among patients with MDS are not well understood. We hypothesized that epigenomic signatures in MDS patients before undergoing HCT serve as a novel prognostic indicator of the risk of post-HCT MDS relapse. To evaluate these epigenomic signatures in MDS patients, we analyzed reduced representation bisulfite sequencing profiles in a matched case-control population of 94 patients. Among these HCT recipients, 47 patients with MDS who relapsed post-HCT (cases) were matched 1:1 to patients with MDS who did not relapse (controls). Only patients with wild-type TP53, RAS pathway, and JAK2 mutations were included in this study to promote the discovery of novel factors. Cases were matched with controls based on conditioning regimen intensity, age, sex, Revised International Prognostic Scoring System, Karnofsky Performance Status, graft type, and donor type. Pre-HCT whole-blood samples from cases and matched controls were obtained from the Center for International Blood and Marrow Transplant Research repository. We comprehensively identified differentially methylated regions (DMRs) by comparing the methylation patterns among matched cases and controls. Our findings show that cases displayed more hyper-DMRs pretransplantation compared with controls, even after adjusting for pre-HCT use of hypomethylating agents. Hyper-DMRs specific to cases were mapped to the transcription start site of 218 unique genes enriched in 5 different signaling pathways that may serve as regions of interest and factors to consider as prognostic determinants of post-HCT relapse in MDS patients. Interestingly, although patients selected for this cohort were wild-type for the TP53 gene, cases showed significantly greater levels of methylation at TP53 compared with controls. These findings indicate that previously identified prognostic genes for MDS, such as TP53, may affect disease relapse not only through genetic mutation, but also through epigenetic methylation mechanisms.

Dataset Information

Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes.

Publications

Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets