Dataset Information

Detection Of Mutations In The Isocitrate Dehydrogenase Genes (IDH1/IDH2) Using castPCRTM In Patients With AML And Their Clinical Impact In Mexico City.

ABSTRACT: Objective:Approximately 40-50% of patients with acute myeloid leukaemia (AML) have been reported to present with a normal karyotype and a variable disease-free period, most likely due to the molecular heterogeneity presented by these patients. A variety of mutations have been identified at the molecular level, such as those in the IDH1/2 gene, which causes a gain of function of the isocitrate dehydrogenase enzyme, generating high levels of the (R)-2-hydroxyglutarate oncometabolite, which competitively inhibits dioxygenase enzymes. Therefore, the objective of this study was to evaluate the incidence of IDH1/2 gene mutations in AML patients and their impact on survival. Materials and methods:A total of 101 patients with a diagnosis of AML were included; mononuclear cells were obtained for DNA extraction and purification. Mutations were detected using TaqMan™ competitive allele-specific probes (castPCR™). Overall survival curves were plotted using IBM SPSS Statistics 23 software. Results:The frequency of IDH gene mutations was 19.8%. For the IDH1 gene, 13.8% of the mutations identified included R132H, V178I, G105G and R132C. The frequency of mutations of the IDH2 gene was 5.9%; the variants included R172K and R140Q. The mean survival time in patients without IDH1 gene mutations was 173.15 days (120.20-226.10), while the mean survival time for patients with mutations was 54.95 days (9.7-100.18), p = 0.001. Conclusion:The frequency of IDH1 and IDH2 gene mutations in the sample was similar to that reported in other studies. The analysis of these mutations in AML patients is of great importance as a prognostic factor due to their impact on survival and their use as potential therapeutic targets or as targets of inhibitors of IDH1(Ivosidenib, Tibsovo) and IDH2 (Enasidenib, Idhifa).

SUBMITTER: Olarte I

PROVIDER: S-EPMC6781602 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Detection Of Mutations In The Isocitrate Dehydrogenase Genes (IDH1/IDH2) Using castPCR<sup>TM</sup> In Patients With AML And Their Clinical Impact In Mexico City.

Olarte Irma I García Anel A Ramos Christian C Arratia Brenda B Centeno Federico F Paredes Johanna J Rozen Etta E Kassack Juan J Collazo Juan J Martínez Adolfo A

OncoTargets and therapy 20191001

<h4>Objective</h4>Approximately 40-50% of patients with acute myeloid leukaemia (AML) have been reported to present with a normal karyotype and a variable disease-free period, most likely due to the molecular heterogeneity presented by these patients. A variety of mutations have been identified at the molecular level, such as those in the IDH1/2 gene, which causes a gain of function of the isocitrate dehydrogenase enzyme, generating high levels of the (R)-2-hydroxyglutarate oncometabolite, which ...[more]

PMID: 31632056

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Project description:BACKGROUND: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to ?-ketoglutarate. Acquired somatic mutations of IDH1 and IDH2 have recently been reported in some types of brain tumors and a small proportion of acute myeloid leukemia (AML) cases. METHODS: Two-hundred and thirty newly diagnosed AML patients were analyzed for the presence of IDH1 and IDH2 heterozygous mutations by polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing. Clinical and biological characteristics were analyzed and correlated to the IDH mutational status. Coexisting mutations such as FLT3, PML-RARA, RAS, AML1, and NPM1 mutations were additionally explored. RESULTS: The prevalence of IDH1 and IDH2 mutations was 8.7% (20/230) and 10.4% (24/230), respectively. Six missense mutations were identified among IDH1-mutated cases; p.R132H (n = 8), p.R132C (n = 6), p.R132S (n = 2), p.R132G (n = 2), p.R132L (n = 1), and p.I99M (n = 1). Two missense mutations were found in IDH2-mutated cases; p.R140Q (n = 20) and p.R172K (n = 4). No patients had dual IDH1 and IDH2 mutations. About 18% of AML with normal cytogenetics and 31% of acute promyelocytic leukemia had IDH mutations. Half of the IDH-mutated cohort had normal karyotype and the major FAB subtype was AML-M2. Interestingly, IDH1- and IDH2-mutated cases predominantly had NPM1 mutations (60-74%) as compared to the wild type (P < 0.001). Very few IDH-mutated cases had FLT3 and/or RAS abnormalities and none of them had AML1 mutations. Older age and higher median platelet counts were significantly associated with IDH2 mutations although the clinical impact of either IDH1 or IDH2 mutations on patients' overall survival could not be observed. CONCLUSION: Overall, 19% of newly diagnosed AML patients had alterations of IDH genes. No patients concurrently carried both IDH1 and IDH2 mutations suggesting that these mutations were mutually exclusive. NPM1 mutation appears as a major coexisting genetic mutation in IDH-mutated patients. Our present data failed to support the prognostic relevance of IDH mutations although alterations of these metabolic genes potentially have an important role in leukemia development.

Dataset Information

Detection Of Mutations In The Isocitrate Dehydrogenase Genes (IDH1/IDH2) Using castPCRTM In Patients With AML And Their Clinical Impact In Mexico City.

Publications

Detection Of Mutations In The Isocitrate Dehydrogenase Genes (IDH1/IDH2) Using castPCR<sup>TM</sup> In Patients With AML And Their Clinical Impact In Mexico City.

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