Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade.
Four molecular subsets of the combined statuses of IDH and TERT-promoter mutations (double mutant, IDH only, TERT only, and double negative) were defined. Differences in age, anatomical location, molecular genetics, and survival rates in a surgical cohort of 299 patients with a total of 356 hemispheric diffuse gliomas (WHO Grade II, III, or IV) were analyzed.
TERTp-mut were present in 38.8% of IDH-mut and 70.2% of IDH-wt gliomas. The mutational status was stable in each patient at 57 recurrence events over a 2645-month cumulative follow-up period. Among patients with IDH-mut gliomas, those in the double-mutant subset had better survival and a lower incidence of malignant degeneration than those in the IDH-only subset. Of patients in the double-mutant subset, 96.3% were also positive for 1p/19q codeletions. All patients with 1p/19q codeletions had TERTp-mut. In patients with IDH-mut glioma, epidermal growth factor receptor or phosphatase and tensin homolog mutations were not observed, and copy-number variations were uncommon. Among IDH-wt gliomas, the TERT-only subset was associated with significantly higher age, higher Ki-67 labeling index, primary glioblastoma-specific oncogenic changes, and poor survival. The double-negative subset was genetically and biologically heterogeneous. Survival analyses (Kaplan-Meier, multivariate, and regression-tree analyses) confirmed that patients in the 4 molecular subsets had distinct prognoses.
Molecular subsets result in different tumor biology and clinical behaviors in hemispheric diffuse gliomas.
AritaHNaritaYFukushimaSTateishiKMatsushitaYYoshidaA: Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol126:267–2762013
KillelaPJReitmanZJJiaoYBettegowdaCAgrawalNDiazLAJr: TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A110:6021–60262013
LouisDNPerryABurgerPEllisonDWReifenbergerGvon DeimlingA: International Society Of Neuropathology–Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol24:429–4352014