IDH mutation is associated with higher risk of malignant transformation in low-grade glioma

Abstract

Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HR(DEATH) = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HR(MT) = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HR(DEATH) versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HR(MT) versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation.

Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide

“…In this study, 33 patients underwent malignant transformation after therapy, though it is unclear what fraction of these patients developed a hypermutated state attributable to TMZ use. The rate of malignant transformation observed was comparable to those previously published, 32,33 and there was not a higher rate of malignant transformation based on molecular subtype or pretreatment tumor volume. Work is ongoing to determine which patients are most at risk for TMZ-induced mutagenesis, the frequency of this phenomenon, and whether this event adversely affects patient outcomes.…”

Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells

“…We explored a similarly predicted role for CD11b + /GR1 + cells mediating tumor progression within the glioma microenvironment and via JAK/STAT signaling with our PDGF-driven RCAS murine glioma model. This model lacks IDH alterations often seen in a majority of diffuse astrocytomas (35, 36),however given that we are not studying the molecular pathways of gliomagenesis, rather the tumor microenvironment-immune system modulation, we believe this is a useful model given its wide utilization and our internal controls using other non-spontaneous mouse models (20). …”

Magnetic Resonance Spectroscopy for Detection of 2-Hydroxyglutarate as a Biomarker for IDH Mutation in Gliomas

“…Mutations in IDH1/2 within LGGs are highly prevalent, and can be observed at a rate of 70–80% in all tumours within this subgroup. The influence of IDH mutation on LGG patients has been highlighted in the stratification of oligodendroglioma, astrocytoma and mixed glioma [31]. The study evaluated the accumulation of a number of additional genetic aberrations alongside IDH mutation, including hypermethylation of O -6-methylguanine DNA methyltransferase (MGMT) promotor region, 1p/19q co-deletion and TP53 mutation.…”