IDH1 and IDH2 Mutations Identified, Characterized in AML

Laurie Barclay, MD

December 30, 2010

December 30, 2010 — Isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations are found in approximately 11.8% of cases of cytogenetically normal acute myeloid leukemia (AML), according to the results of a study reported in the January 2011 issue of the American Journal of Clinical Pathology.

"Mutations in the [IDH1] and IDH2 genes are reported in [AML]," write Keyur P. Patel, MD, PhD, from the Department of Hematopathology at the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues. "Identification of somatically acquired gene mutations has provided critical insights into the pathogenesis of [AML]. Gene mutations in AML provide useful markers for diagnosis and for monitoring response to therapy and also provide information useful in assessing prognosis and making therapeutic decisions."

The investigators determined the frequency and the clinicopathologic features of IDH1 and IDH2 mutations in 199 patients with AML. Sanger sequencing was used to identify mutations in IDH1 (IDH1R132 ) and in IDH2 (IDH2R172 ).

Twelve (6.0%) of the 199 patients had point mutations in IDH1R132 , and 4 (2.0%) of 196 patients tested had point mutations in IDH2R172 . These mutations were mutually exclusive. Most (15/16; 94%) of the cases with identified mutations were cytogenetically normal, and overall frequency in this group was 11.8%.

Concurrent mutations in NPM1, FLT3, CEBPA, and NRAS were identified only in patients with AML who had the IDH1R132 mutation. Compared with patients with AML with wild-type IDH, those with IDH mutations had similar clinical features and laboratory test results.

"We conclude that IDH1R132 and IDH2R172 mutations occur most often in cytogenetically normal AML cases with an overall frequency of approximately 11.8%," the study authors write.

The authors further describe these mutations as a novel class of point mutations that are heterozygous and mutually exclusive and that lead to overproduction of an oncometabolite, 2-hydroxyglutarate. Most AML cases with an IDH mutation are morphologically classified as AML with or without myeloid maturation (French-American-British classification M1 or M2), have morphologic evidence of dysplasia, and have a nondistinctive myeloid immunophenotype. Molecularly and clinically, IDH1R132 and IDH2R172 may represent distinct subgroups.

"The details of a possible pathogenic role of IDH mutations are just beginning to emerge," the study authors conclude. "Traditionally, up-regulation of a cancer-associated transcription factor, hypoxia-induced factor, has been considered to be a major pathogenic mechanism. More recently, accumulation of 2-hydroxyglutarate in the cells and the serum of patients with glioma and with AML with the IDH1 mutation has been shown, [which] could be used as a potential diagnostic test in the management of patients with IDH mutations."

The study authors have disclosed no relevant financial relationships.

Am J Clin Pathol. 2011;135:35-45. Abstract

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