TP53mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d660121e274">Background</h5> <p id="P1"> <i>TP53</i> gene mutations predict for poor prognosis in acute myeloid leukemia (AML). </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d660121e282">Methods</h5> <p id="P2">Peripheral blood or bone marrow samples from 293 newly diagnosed AML patients were analysed with targeted amplicon-based next-generation sequencing based mutation analysis. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d660121e287">Results</h5> <p id="P3">We found <i>TP53</i> mutations in 53 (18%; 45 were missense mutations; the most common pattern of amino acid substitution, in 13 of the 53 patients, was a substitution of arginine to histidine on different codons). The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML - <i>TP53</i>-mutated (n=53) vs. <i>TP53</i>-wildtype (n=240) were compared. <i>TP53</i>-mutations were significantly more likely in patients with complex karyotype, abnormalities of chromosome 5, 7, and 17, and therapy-related AML. <i>TP53</i>-mutated AMLs have significantly lower incidence of mutations in <i>FLT3, RAS,</i> and <i>NPM1</i> and higher incidence of coexisting <i>MPL</i> mutations compared to wild type. Distribution of <i>TP53</i>-mutations was equal in both age groups(<60 years vs ≥ 60 years). <i>TP53</i> mutated AML was associated with a lower response rate(CR 41% vs. 57%; p=0.04), significantly inferior complete remission duration (CRD) (at 2 yrs 30% vs. 55%; p=0.001) and overall survival (OS) (at 2 yrs 9% vs. 24%; p= <0.0001) irrespective of the age or the type of treatment used - high vs low intensity chemotherapies. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d660121e323">Conclusions</h5> <p id="P4">The type of treatment did not improve the outcome in younger or older patients with <i>TP53</i> mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with <i>TP53</i> mutations. </p> </div>

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Most cited references 26

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Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

Jay Patel, Mithat Gonen, María Figueroa … (2012)

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).

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Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.

S Gorina, Jun Cho, P Jeffrey … (1994)

Mutations in the p53 tumor suppressor are the most frequently observed genetic alterations in human cancer. The majority of the mutations occur in the core domain which contains the sequence-specific DNA binding activity of the p53 protein (residues 102-292), and they result in loss of DNA binding. The crystal structure of a complex containing the core domain of human p53 and a DNA binding site has been determined at 2.2 angstroms resolution and refined to a crystallographic R factor of 20.5 percent. The core domain structure consists of a beta sandwich that serves as a scaffold for two large loops and a loop-sheet-helix motif. The two loops, which are held together in part by a tetrahedrally coordinated zinc atom, and the loop-sheet-helix motif form the DNA binding surface of p53. Residues from the loop-sheet-helix motif interact in the major groove of the DNA, while an arginine from one of the two large loops interacts in the minor groove. The loops and the loop-sheet-helix motif consist of the conserved regions of the core domain and contain the majority of the p53 mutations identified in tumors. The structure supports the hypothesis that DNA binding is critical for the biological activity of p53, and provides a framework for understanding how mutations inactivate it.

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TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.

Frank Rücker, Richard F Schlenk, Lars Bullinger … (2012)

To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.