TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution

Ha, Hou; Chou, Wen‐Chien; Kuo, Yueh‐Hsiung; Cy, Liu; Li, Lin; Mh, Tseng; Chiang, Yi-Te; Liu, MC; Liu, Cheng Wei; Tang, Jih-Luh; Yao, Ming; Cc, Li; Huang, Shang-Yi; Ko, Bor-Sheng; Sc, Hsu; Cy, Chen; Ct, Lin; Sj, Wu; Tsay, Woei; Yc, Chen; Tien, Hwei‐Fang

doi:10.1038/bcj.2015.59

Cited by 135 publications

(129 citation statements)

References 38 publications

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“…7, 9, 14, 16, 19, 25 In this study, we have made some important observations. First, the incidence of TP53 mutations in our cohort was 18% - higher than the 5-10% incidence previously reported 6,8,13,15,18 . This likely reflects the referral pattern to a tertiary referral cancer center.…”

Section: Discussioncontrasting

confidence: 70%

TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

Kadia

Jain

Ravandi

et al. 2016

Cancer

211

181

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Background TP53 gene mutations predict for poor prognosis in acute myeloid leukemia (AML). Methods Peripheral blood or bone marrow samples from 293 newly diagnosed AML patients were analysed with targeted amplicon-based next-generation sequencing based mutation analysis. Results We found TP53 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 -TP53-mutated (n=53) vs. TP53-wildtype (n=240) were compared. TP53-mutations were significantly more likely in patients with complex karyotype, abnormalities of chromosome 5, 7, and 17, and therapy-related AML. TP53-mutated AMLs have significantly lower incidence of mutations in FLT3, RAS, and NPM1 and higher incidence of coexisting MPL mutations compared to wild type. Distribution of TP53-mutations was equal in both age groups(<60 years vs ≥ 60 years). TP53 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. Conclusions The type of treatment did not improve the outcome in younger or older patients with TP53 mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with TP53 mutations.

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Section: Discussioncontrasting

confidence: 70%

TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

Kadia

Jain

Ravandi

et al. 2016

Cancer

211

181

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“…21,22 Anecdotal cases of late appearance of TP53 mutation in wtp53 AML patients during follow-ups might indicate emergence of t-AML. 23 The early location of TP53 mutation in the leukemic clonal hierarchy is of major relevance for disease pathogenesis and therapeutic response. AML with TP53 mutations in subclones only is thus expected to display differential susceptibility to p53-targeted therapies.…”

Section: Tp53 Mutations In Amlmentioning

confidence: 99%

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Prokocimer

Molchadsky

Rotter

2017

Blood

138

119

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The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices. (Blood. 2017; 130(6):699-712)

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“…2,3 Patients with AML and TP53 mutations tend to be older (median age, 61 to 67 years), and almost all have karyotypes that are associated with unfavorable risk; if they receive standard cytotoxic chemotherapy, these patients have especially poor outcomes (median survival, 4 to 6 months). 3-6 …”

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confidence: 99%

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Welch¹,

et al. 2016

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BACKGROUND The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine.

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TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution

Cited by 135 publications

References 38 publications

TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

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