Publication: Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients
Issued Date
2012
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eng
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Mahidol University
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BioMed Central
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Journal of Hematology & Oncology. Vol. 5, (2012), 5
Suggested Citation
Sadudee Chotirat, Wanna Thongnoppakhun, Orathai Promsuwicha, Chetsada Boonthimat, Chirayu U Auewarakul Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients. Journal of Hematology & Oncology. Vol. 5, (2012), 5. doi:10.1186/1756-8722-5-5 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/2655
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Title
Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients
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Abstract
Background: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and
mitochondrial enzymes that catalyze the conversion of isocitrate to a-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.