Isocitrate Dehydrogenase 1 and 2 (IDH1/IDH2) Mutation Analysis (IDH1 and IDH2 Mutation)

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2), encoded by the IDH1 and IDH2 genes, respectively, catalyze oxidative decarboxylation of isocitrate into α-ketoglutarate (α-KG). Gain-of-function mutations in the IDH genes are associated with aberrant conversion of α-KG to 2-hydroxyglutarate (2-HG), which is an oncogenic metabolite, and are recurrent in myeloid malignancies and glioma.^1-3 

Mutations in IDH1 exon 4 (7%-14%) and IDH2 exon 4 (8%-19%) are relatively common in patients with acute myeloid leukemia (AML) and have been associated with an unfavorable prognosis and inferior overall survival in some studies.^1,2 IDH inhibitors have been approved by the US Food and Drug Administration (FDA) for treatment of adult patients with relapsed or refractory AML who have an IDH mutation.^4,5

Quest Diagnostics sequences exon 4 of the IDH1 gene and exon 4 of the IDH2 gene. These exons harbor over 90% of all reported IDH1/IDH2 cancer-associated mutations,^{6, 7} including the most frequently encountered IDH1 R132, IDH2 R140, and IDH2 R172 mutations.

The patient report will include a list of mutations resulting in an amino acid change. If a rare mutation with an unknown clinical significance is detected, the report will include an interpretive comment based on a review of the available literature.

Results are typically reported within 3 to 5 days of specimen submission.

DNA is extracted from whole blood or bone marrow specimens. PCR is used to amplify DNA fragments covering the entire coding regions of IDH1 exon 4 and IDH2 exon 4. PCR products are subsequently purified and sequenced. We perform both forward and reverse dye-terminator Sanger sequencing and gel capillary electrophoresis on an automated platform.

The analytical sensitivity is 20% tumor cells in the background of normal cells.

The preferred specimen type is whole blood or bone marrow aspirate in an EDTA tube. Heparin tubes may be submitted but are not preferred. DNA extracted in a CLIA laboratory is also acceptable.