Acute Myeloid Leukemia With IDH1 or IDH2 Mutation Frequency and Clinicopathologic Features

Dept of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
American Journal of Clinical Pathology (Impact Factor: 2.51). 01/2011; 135(1):35-45. DOI: 10.1309/AJCPD7NR2RMNQDVF
Source: PubMed


Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are reported in acute myeloid leukemia (AML). We studied the frequency and the clinicopathologic features of IDH1 and IDH2 mutations in AML. Mutations in IDH1 (IDH1(R)¹³²) and IDH2 (IDH2(R)¹⁷²) were assessed by Sanger sequencing in 199 AML cases. Point mutations in IDH1(R)¹³² were detected in 12 (6.0%) of 199 cases and in IDH2(R)¹⁷² in 4 (2.0%) of 196 cases. Of the 16 mutated cases, 15 (94%) were cytogenetically normal, for an overall frequency in this group of 11.8%. IDH1(R)¹³² and IDH2(R)¹⁷² mutations were mutually exclusive. Concurrent mutations in NPM1, FLT3, CEBPA, and NRAS were detected only in AML with the IDH1(R)¹³² mutation. The clinical and laboratory variables of patients with AML with IDH mutations showed no significant differences compared with patients with wild-type IDH. We conclude that IDH1(R)¹³² and IDH2(R)¹⁷² mutations occur most often in cytogenetically normal AML cases with an overall frequency of approximately 11.8%.

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Available from: Farhad Ravandi, Mar 17, 2014
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    • " the clinical and molecular stand - points , with many distinct molecular subtypes defined by genetic abnormalities ; several of these target key epigenetic regulators . An estimated 20% - 25% of all AMLs are associated with heterozygous somatic mutations of isocitrate dehydrogenase 1 or 2 ( IDH1 or 2 ) , or ten - eleven translocation 2 ( TET2 ) ( Patel et al . , 2011 ) . Any one of these mutations results in an impairment of DNA demethylation pathways and leads to the establishment of a DNA hypermethylation phenotype ( Figueroa et al . , 2010a ) . A separate class of AMLs , con - stituting approximately 15% of all AML cases , are identified by the presence of the t ( 8 ; 21 ) translocation giving ri"
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    ABSTRACT: Motivation: DNA methylation plays critical roles in gene regulation and cellular specification without altering DNA sequences. The wide application of reduced representation bisulfite sequencing (RRBS) and whole genome bisulfite sequencing (bis-seq) opens the door to study DNA methylation at single CpG site resolution. One challenging question is how best to test for significant methylation differences between groups of biological samples in order to minimize false positive findings. Results: We present a statistical analysis package, methylSig, to analyse genome-wide methylation differences between samples from different treatments or disease groups. MethylSig takes into account both read coverage and biological variation by utilizing a beta-binomial approach across biological samples for a CpG site or region, and identifies relevant differences in CpG methylation. It can also incorporate local information to improve group methylation level and/or variance estimation for experiments with small sample size. A permutation study based on data from enhanced RRBS samples shows that methylSig maintains a well-calibrated type-I error when the number of samples is three or more per group. Our simulations show that methylSig has higher sensitivity compared with several alternative methods. The use of methylSig is illustrated with a comparison of different subtypes of acute leukemia and normal bone marrow samples. Availability: methylSig is available as an R package at Supplementary information: Supplementary data are available at Bioinformatics online.
    Bioinformatics 05/2014; 30(17). DOI:10.1093/bioinformatics/btu339 · 4.98 Impact Factor
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    • "This study sparked research into the field of IDH1 mutations within various AML populations, particularly the frequency of mutations and their clinical significance. To date there the approximate rate of IDH1 mutations in Western countries including the United States[3], [4], [5], Canada[6], France[7], Germany[8], [9], [10], [11], Netherlands[12] and England[13], [14] is 10–14%. However, there are limited reports regarding the rate of IDH1 mutations in Chinese AML patients suggest a mutation rate of 2–6.3%. "
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    PLoS ONE 12/2013; 8(12):e83334. DOI:10.1371/journal.pone.0083334 · 3.23 Impact Factor
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    • "For IDH1R132 mutations in AML, as in other tumors, five major different amino acid substitutions for arginine (R) have been detected: cysteine (R132C), leucine (R132L), glycine (R132G), histidine (R132H), and serine (R132S) (Mardis et al., 2009; Abbas et al., 2010; Chou et al., 2010; Ho et al., 2010; Marcucci et al., 2010; Schnittger et al., 2010; Wagner et al., 2010; Patel et al., 2011a). R132C (∼30%) and R132H (∼50%) are the most common mutations in AML. "
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    ABSTRACT: Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of α-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.
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