DNMT3A mutation is a poor prognosis biomarker in AML: Results of a meta-analysis of 4500 AML patients

Shivarov, Velizar; Gueorguieva, Ralitza; Stoimenov, Angel; Tiu, Ramon V.

doi:10.1016/j.leukres.2013.07.032

Cited by 74 publications

(58 citation statements)

References 22 publications

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“…It was reported that SNP rs1550117 (A>G) was associated with DNMT3A promoter activity (Fan et al, 2010). Studies have also investigated the association between DNMT3A polymorphisms and cancer risk (Fan et al, 2010;Sun et al, 2012;Yang et al, 2012;Zhao et al, 2012;Mostowska et al, 2013;Shivarov et al, 2013;Cao et al, 2013;Xu et al, 2013;Zhao et al, 2013). However, the heterogeneity of data collection and statistical results remain inconclusive because of inadequate sample sizes.…”

Section: Introductionmentioning

confidence: 99%

DNMT3A -448A>G polymorphism and cancer risk: a meta-analysis

et al. 2015

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ABSTRACT. Cancer is a major public health problem worldwide that involves complex processes and factors. For instance, methylation is important in tumorigenesis. DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is the main de novo methyltransferase implicated in this process. In DNMT3A, the -448A>G polymorphism is associated with cancer; however, the results of various studies have been conflicting. To clarify the role of DNMT3A polymorphisms in cancer, we conducted a meta-analysis of 2014 cases and 3089 control subjects. Odds ratios with 95% confidence intervals were estimated to evaluate the association between the DNMT3A -448A>G polymorphism and cancer risk. The results showed that DNMT3A may be a protective factor against all cancer types and colorectal cancer groups. Further studies should be conducted including different ethnicities and large population sizes to generate a comprehensive conclusion.

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Section: Introductionmentioning

confidence: 99%

DNMT3A -448A>G polymorphism and cancer risk: a meta-analysis

et al. 2015

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“…3,9 Mutational profiles confer important prognostic information that is independent of other traditional risk factors, including karyotype, blast percentage, and patient clinical characteristics in both acute myeloid leukemia and myelodysplastic syndrome. [10][11][12][13][14][15][16][17][18] The prognostic significance of mutations in therapy-related myeloid neoplasms has not been extensively characterized. Point mutations of the tumor suppressor gene TP53 represent the most frequent single genetic abnormality in therapyrelated myeloid neoplasms and are detected in 20-40% of therapy-related myeloid neoplasm patients compared with 5-20% in de novo acute myeloid leukemia and myelodysplastic syndrome.…”

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confidence: 99%

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

Cleven

Nardi

et al. 2015

Modern Pathology

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Identification of p53-positive cells by immunohistochemistry in bone marrow from primary myelodysplastic syndrome patients correlates with the presence of TP53 mutations and poor prognosis. Mutations in the tumor suppressor gene TP53 are more frequent in therapy-related acute myeloid leukemia and myelodysplastic syndrome than in de novo disease, but the role of p53 immunohistochemistry in the therapy-related setting has not been specifically investigated. We studied p53 protein immunoreactivity in bone marrow biopsies of therapy-related myeloid neoplasms and correlated protein expression with TP53 mutation status, clinicopathologic features and outcome. We first studied 32 patients with therapy-related acute myeloid leukemia and 63 patients with therapy-related myelodysplastic syndrome/chronic myelomonocytic leukemia from one institution and then validated our results in a separate group of 32 patients with therapy-related acute myeloid leukemia and 56 patients with therapy-related myelodysplastic syndrome from a different institution. Strong p53 immunostaining in Z1% of bone marrow cells was highly predictive of a TP53 gene mutation (Po0.0001) and was strongly associated with a high-risk karyotype (Po0.0001). The presence of Z1% p53 strongly positive cells was associated with poorer overall and disease-specific survival, particularly in the subset of patients treated with stem-cell transplantation. In a multivariable Cox regression model, the presence of Z1% p53 strongly expressing cells was an independent prognostic marker for overall survival in both cohorts, with hazard ratios of 3.434 (CI: 1.751-6.735, Po0.0001) and 3.156 (CI: 1.502-6.628, P ¼ 0.002). Our data indicate that p53 protein expression, evaluated in bone marrow biopsies by a widely available immunohistochemical method, prognostically stratifies patients with therapy-related myeloid neoplasms independent of other risk factors. p53 immunostaining thus represents an easily applicable method to assess risk in therapy-related acute myeloid leukemia/myelodysplastic syndrome patients. Therapy-related myeloid neoplasms include acute myeloid leukemia, myelodysplastic syndrome, and less commonly myelodysplastic/myeloproliferative neoplasms such as chronic myelomonocytic leukemia. Therapy-related myeloid neoplasms occur as late complications of cytotoxic chemotherapy and/or radiotherapy given to treat malignancies or non-malignant conditions. 1,2 The etiology of therapy-related myeloid neoplasms is thought to be related to the mutagenic effect of cytotoxic therapy, including alkylating agents, ionizing radiation therapy, and topoisomerase inhibitors. 1 Typically, therapy-related myeloid neoplasms carry complex and usually unbalanced karyotypic abnormalities, particularly loss of material on the long arm of chromosomes 5 and 7 and rearrangements of the 11q23 region involving the MLL gene. 3 The prognosis of therapy-related myeloid neoplasms is poor, likely due at least in part to the high

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“…20 Although there were many studies, there was no definite conclusion about effect of DNMT3A mutations on AML prognosis (Table 1). [15][16][17][18][19][20][21]26 FLT3 is the most frequently mutated gene in AML (Table 1), with an approximately 28%»34%of AML cases harboring FLT3 mutations 28,29 FLT3 have 2 kinds of mutations: an internal tandem duplication (ITD) in the juxtamembrane domain and a point mutation of the tyrosine kinase domain (TKD). Estimated 20-25% of AML cases harbor FLT3-ITD mutations, 27 and FLT3-ITDmutations in adult AML are associated with clinical features such as having higher white blood cell count and higher peripheral blood blast cell count.…”

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confidence: 99%

“…Pre-LSCs can become fully transformed into fully transformed leukemic stem cells with the acquisition of additional driver mutations (e.g., FLT3-ITD). 45 CMML with [20] no influence on RFS in total population [18] [21] no influence on DFS in total population [19] no influence on RFS in the favorable genotype subgroup [18] CMML Shorter OS [22][26] [9] no influence on OS [32] OS: All Survival, RFS: relapse-free survival, DFS: disease-free survival DNMT3A mutation may quickly transform into AML after the mutation of FLT3-ITD happened. One case reported before gave the direct evidence that a pre-leukemic clone can evolve to AML.…”

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confidence: 99%

Chronic myelomonocytic leukemia with double-mutations in DNMT3A and FLT3-ITD treated with decitabine and sorafenib

Wang

Xiao

et al. 2017

Cancer Biology & Therapy

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Chronic myelomonocytic leukemia (CMML) is a heterogeneous neoplastic hematologic disorder with worse overall survival. Half of CMML have mutations, but case with concomitant mutations of DNA methyltransferase 3A (DNMT3A) and Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3-ITD) in CMML was not reported before. We reported a 51-year-old man who had CMML with concomitant mutations in DNMT3A and FLT3-ITD.The patient received decitabine and sorafenib combined treatment. In this report, we reviewed DNMT3A mutation and FLT3 mutation, and we reviewed treatment of decitabine and sorafenib. This report is significant. First: This is the first report on CMML with doublemutations of DNMT3A and FLT3-ITD. Second: It shows the importance of targeted drug in combined treatment of CMML.

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DNMT3A mutation is a poor prognosis biomarker in AML: Results of a meta-analysis of 4500 AML patients

Cited by 74 publications

References 22 publications

DNMT3A -448A>G polymorphism and cancer risk: a meta-analysis

DNMT3A -448A>G polymorphism and cancer risk: a meta-analysis

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

Chronic myelomonocytic leukemia with double-mutations in DNMT3A and FLT3-ITD treated with decitabine and sorafenib

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