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Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

ABSTRACT: Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.

SUBMITTER: Sallman DA

PROVIDER: S-EPMC7864381 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

Sallman D A DA Komrokji R R Vaupel C C Cluzeau T T Geyer S M SM McGraw K L KL Al Ali N H NH Lancet J J McGinniss M J MJ Nahas S S Smith A E AE Kulasekararaj A A Mufti G G List A A Hall J J Padron E E

Leukemia 20151030 3

Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validatio ...[more]

PMID: 26514544

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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

Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

Publications

Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

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