IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients

Abstract

Mutations in the gene encoding isocitrate dehydrogenase enzyme isoforms 1 (IDH1) and 2 (IDH2) have recently been identified in a large proportion of glial tumors of the CNS, but their mechanistic role in tumor development remains unclear. Here, we assessed the actual impact of IDH1 and IDH2 mutations in patients harboring WHO grade II and III gliomas. We sequenced IDH1 at codon 132 and IDH2 at codon 172 in 33 patients with WHO grade II and III gliomas who benefited from a preoperative (18)F-FDG positron emission tomography (PET). Immunohistochemical expression of Hypoxia Inducible Factor-1alpha (HIF-1α), Carbonic Anhydrase IX (CAIX), Glucose Transporter 1 (GLUT1) and Caspase 3 active form (CASP3) along with the R132HIDH1 mutation was assessed in all cases as well as 1p/19q deletion status and p53 expression. HIF-1α expression was found in 15% of IDH-mutated compared to 7.7% of IDH-nonmutated tumors (P = 0.954). Also, GLUT-1 positive staining was found in 5% of IDH-mutated and in 7.1% of IDH-nonmutated tumors (P = 0.794). Finally, CA-IX expression was found in 15% of IDH-mutated and in 7.7% of IDH-nonmutated tumors (P = 0.484). The combined expression of these three hypoxic markers was found in two WHO grade III tumors, one of which was IDH-mutated whereas the other was IDH-nonmutated (P = 0.794). In IDH-mutated tumors, the median SUVmax ratio was 2.24 versus 2.15 in IDH-nonmutated tumors (P = 0.775). Together, these data question the actual relationship between IDH mutation status and in vivo hypoxic biomarkers expression in WHO grade II and III gliomas.

Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate

“…As an imaging-based technique, it has the benefit of posing minimal risk to the patients, can be performed repeatedly as many times as necessary, and can probe tumor heterogeneity without disturbing the internal milieu. To date, in vivo MRS is the only imaging method that is specific to IDH mutations -existing PET or SPECT radiotracers are not specific (56,57), IDH-targeted agents for in vivo molecular imaging do not yet exist, and the prohibitive cost of radiotracers will likely limit their clinical development.…”

CXCR7 and CXCR4 Expressions in Infiltrative Astrocytomas and Their Interactions with HIF1α Expression and IDH1 Mutation

“…IDH1mut related to a significantly lower expression of both receptors, CXCR4 and CXCR7, but presented no significant impact on the expression of HIF1α corroborating previous observations by others. [54] , [55] In fact, it have been demonstrated that 2HG, the oncometabolite generated by IDH1 mutation, inhibits α-KG-dependent dioxygenases. These enzymes modulate several pathways, including sensitization to hypoxia, demethylation of histones and DNA, fatty acid metabolism and modifications of collagen, contributing to tumorigenesis.…”

Oncometabolites: linking altered metabolism with cancer

“…Techniques for routine neuropathological detection of IDH mutations include DNAbased sequencing approaches and immunohistochemistry (IHC) staining using mutation-specific antibodies (94)(95)(96)(97). However, there are at least five reproducible cancer-associated mutations that can result in 2HG production, and further, con-ventional gene sequencing methods may lead to false positives due to genetic polymorphism and sequencing artifacts (98).…”