Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia

Shen, Yang; Zhu, Yong‐Mei; Fan, Xing; Shi, Jingyi; Wang, Qinrong; Yan, Xiaojing; Gu, Zhaohui; Wang, Yanyan; Chen, Bing; Jiang, Chenyan; Han, Yu; Chen, Feifei; Chen, Haimin; Chen, Zhu; Jin, Jie; Chen, Sai‐Juan

doi:10.1182/blood-2011-03-343988

Cited by 289 publications

(268 citation statements)

References 52 publications

(114 reference statements)

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“…We and others 24,25,29 --31,44 found that DNMT3A mutations were strongly associated with FAB M4/M5 subtypes, and often co-occurred with NPM1 or IDH1 mutations in AML patients, suggesting that the oncogenic actions of these mutations are not redundant. DNMT3A mutations were reported to be associated with older age, 24,25,30,31 but this feature was not observed in our cohort of adult CN-AML. Nevertheless, a link between age and the incidence of DNMT3A mutations is likely as these mutations seem to be extremely rare (o1%) in pediatric AML.…”

Section: Discussioncontrasting

confidence: 76%

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

et al. 2012

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Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French --American --British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P ¼ 0.02) and overall survival (5-year OS: 23% vs 45%, P ¼ 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.

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Section: Discussioncontrasting

confidence: 76%

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

et al. 2012

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“…Cytogenetic analysis of BM samples was conducted as previously described (6). Gene mutations/fusions were detected as previously reported (6). Affymetrix Human Genome U133 Plus 2.0 Array GeneChip microarrays were used to assess the total RNA samples.…”

Section: Methodsmentioning

confidence: 99%

“…Of note, gene mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) were reported recently not only in gliomas but also in AML (4,5). The prognostic significance of these mutations appears controversial in AML (6)(7)(8)(9)(10), although a metaanalysis suggests a poor outcome in cases with IDH1 mutations (11).…”

mentioning

confidence: 99%

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

Wang

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The 2-hydroxyglutarate (2-HG) has been reported to result from mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes and to function as an "oncometabolite." To evaluate the clinical significance of serum 2-HG levels in hematologic malignancies, acute myeloid leukemia (AML) in particular, we analyzed this metabolite in distinct types of human leukemia and lymphoma and established the range of serum 2-HG in appropriate normal control individuals by using gas chromatograph-time-of-flight mass spectrometry. Aberrant serum 2-HG pattern was detected in the multicenter group of AML, with 62 of 367 (17%) patients having 2-HG levels above the cutoff value (2.01, log 2 -transformed from 4.03 μg/mL). IDH1/2 mutations occurred in 27 of 31 (87%) AML cases with very high 2-HG, but were observed only in 9 of 31 (29%) patients with moderately high 2-HG, suggesting other genetic or biochemical events may exist in causing 2-HG elevation. Indeed, glutamine-related metabolites exhibited a pattern in favor of 2-HG synthesis in the high 2-HG group. In AML patients with cytogenetically normal AML (n = 234), high 2-HG represented a negative prognostic factor in both overall survival and event-free survival. Univariate and multivariate analyses confirmed high serum 2-HG as a strong prognostic predictor independent of other clinical and molecular features. We also demonstrated distinct gene-expression/DNA methylation profiles in AML blasts with high 2-HG compared with those with normal ones, supporting a role that 2-HG plays in leukemogenesis.biomarker | prognosis

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“…101 On the other hand, we recently found DNMT3A mutations in a relapsed patient. 102 These results have prompted us to further identify the mechanisms of drug resistance in future work, so that the subset of patients who may develop resistance could be screened out earlier in the treatment, and specific therapeutic strategies can be given from the very beginning, to finally alter the prognosis of these patients.…”

Section: Future Perspectivesmentioning

confidence: 99%

How to manage acute promyelocytic leukemia

et al. 2012

Leukemia

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Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia

Cited by 289 publications

References 52 publications

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

How to manage acute promyelocytic leukemia

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