IDH1 and IDH2 Mutations in Gliomas

Abstract

Mutations in isocitrate dehydrogenase (IDH) 1 and 2, originally discovered in 2009, occur in the vast majority of low grade gliomas and secondary high grade gliomas. These mutations, which occur early in gliomagenesis, change the function of the enzymes, causing them to produce 2-hydroxyglutarate, a possible oncometabolite, and to not produce NADPH. IDH mutations are oncogenic, although whether the mechanism is through alterations in hydroxylases, redox potential, cellular metabolism, or gene expression is not clear. The mutations also drive increased methylation in gliomas. Gliomas with mutated IDH1 and IDH2 have improved prognosis compared to gliomas with wild-type IDH. Mutated IDH can now be detected by immunohistochemistry and magnetic resonance spectroscopy. No drugs currently target mutated IDH, although this remains an area of active research.

Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas

“…The first is the plausible hypothesis that IDH1-mutant GBMs represent malignant transformation of undiagnosed LGGs, and IDH1 wild-type GBM is, in many ways, a different disease sharing the same histological features. 11,13,37 This theory is supported by studies of serial biopsy samples obtained in patients with glioma, in which the IDH1 mutation appears to be a relatively early genetic event, 11,13,37 preceding other lineage-specific mutations, such as TP53 and ATRX mutations in astrocytomas and 1p19q codeletion, CIC, and telomerase reverse transcriptase (TERT) mutations in oligodendrogliomas. 13,34,37 In The Cancer Genome Atlas studies, IDH1-mutant GBMs cluster by gene expression in the proneural subtype.…”

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Известно, что мутации в генах метаболических ферментов IDH1/2 (наиболее распространена замена R132H гена IDH1) -практически уникальная характеристика патогенеза глиом, приводящая к превращению 2-оксоглутарата в онкометаболит 2-гидроксиглутарат и указывающая на более благоприятный прогноз исхода заболевания [18]. Используя специфические антитела к мутантной IDH1 [19] было установлено, что Hh-путь (экспрессия PTCH1, GLI1) активен в трансформированных клетках глиомы.…”

Advances in the Treatment of Primary Brain Tumors: The Realm of Immunotherapy

“…Well-characterized molecular alterations include isocitrate dehydrogenase (IDH) mutation, 1p and 19q codeletion, epidermal growth factor receptor variant III (EGFRvIII) rearrangement, and MGMT promoter methylation ( Table 1). Point mutations in isocitrate dehydrogenase (IDH) 1 and 2 have been associated with improved prognosis compared to patients with wild-type IDH [10]. The combined loss of chromosomal arms 1p and 19q has been shown to occur in oligodendrogliomas and oligoastrocytomas [11], but it is associated with better response to chemotherapy and radiation therapy leading to prolonged progression-free and overall survival [12,13].…”