Combination genetic signature stratifies lower-grade gliomas better than histological grade

Abstract

We studied if combination genetic signature potentially stratifies lower-grade gliomas better than histology by investigating 214 lower-grade gliomas for IDH1/2 and TERTp mutations, 1p/19q codeletion and EGFR amplification as to their impact on prognostication. Prognostic association of grading was independent of other prognostic variables including age, histological type, IDH1/2, 1p/19q and TERTp status. No single marker, including IDH1/2, superseded grading in prognostication, indicating grading was still a very important tool. Prognosis was most favorable in 31.7% of patients with IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation (IDHmut-OT), intermediate in 45.8% of patients with IDH1/2 mutation only (IDHmut) and 16.9% of patients without any of the alterations (IDHwt), and poorest in 5.6% of patients with wild-type IDH1/2 and either TERTp mutation or EGFR amplification (IDHwt-ET). Our results suggested not all IDH1/2 wild-type lower-grade gliomas are aggressive and additional biomarkers are required to identify glioblastoma-equivalent tumors. Multivariate analysis revealed independent prognostic values of grading and genetic signature. Grade II IDHwt-ET gliomas exhibited shorter survival than IDH1/2 mutated grade III gliomas, suggesting combination genetic signature potentially superseded grading in prognostication. In summary, biomarker-based stratification is useful in the diagnosis and prognostication of lower-grade gliomas, and should be used together with grading.

Keywords: 1p/19q; EGFR; IDH1/2; Pathology Section; TERT; glioma.

Figure 1. Clinical and molecular data of 214 lower-grade gliomas in the study

1p/19q codeletion occurred exclusively in IDH1/2 mutated gliomas (p < 0.0001, Chi square test). EGFR amplification was mutually exclusive with IDH1/2 mutation (p < 0.0001, Fisher's exact test) and associated with TERTp mutation within the IDH1/2 wild-type gliomas (p = 0.002, Fisher's exact test). Tumors were assigned into genetic subgroups based on combinations of status of IDH1/2 mutation, 1p/19q codeletion, TERTp mutation and EGFR amplification. IDHmut-OT gliomas were defined as tumors harboring IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation. IDHmut gliomas were defined as tumors harboring IDH1/2 mutation only and without 1p/19q codeletion nor TERTp mutation. IDHwt gliomas were defined as tumors harboring none of the molecular markers. IDHwt-ET gliomas were defined as IDH1/2 wild-type tumors with either TERTp mutation or EGFR amplification. The cases were sorted by overall survival within each genetic signature subgroup. OS, overall survival.

Figure 2. Kaplan-Meier survival analysis by histological grade, age, histological type, IDH1/2 mutation, 1p/19q codeletion, TERTp mutation and EGFR amplification

Longer overall survival was associated with grade II gliomas a. patients at 50 years or younger b. oligodendroglial or oligoastrocytic tumors c. IDH1/2 mutated gliomas d. 1p/19q codeleted gliomas e. and EGFR non-amplified gliomas g. TERTp mutated gliomas trended to longer overall survival f. OS, overall survival; mut, mutant; wt, wild-type.

Figure 3. Kaplan-Meier survival analysis by co-evaluating histological grade with clinical and molecular variables

Histological grade showed prognostic relevance in patients of 50 years or younger and trend in patients above 50 years a. Prognostic relevance of histological grade was demonstrated in both astrocytic gliomas and oligodendroglial / oligoastrocytic gliomas b. Prognostic value of histological grade was independent of IDH1/2 mutation status c. 1p/19q codeletion status d. and TERTp mutation status e. No prognostic association was found for histological grade among EGFR amplified gliomas f. OS, overall survival; mut, mutant; wt, wild-type.

Figure 4. Kaplan-Meier survival analysis by genetic signature and co-evaluating genetic signature with clinical variables

The genetic signature showed prognostic relevance across the whole cohort a. The genetic signature was associated with overall survival in grade II gliomas b. and grade III gliomas c. Prognostic association of the genetic signature was demonstrated in patients at or younger than 50 years d. as well as patients above 50 years e. The genetic signature exhibited prognostic relevance in astrocytic gliomas g. and trend in oligodendroglial / oligoastrocytic gliomas f. OS, overall survival; mut, mutant; wt, wild-type.

Figure 5. Kaplan-Meier survival analysis of histological grade in each of the genetic signature subgroup

Histological grade showed prognostic association in IDHmut-OT gliomas a. IDHmut gliomas b. IDHwt gliomas c. as well as IDHwt-ET gliomas. Grade II IDHwt-ET gliomas demonstrated shorter overall survival than grade III IDHmut-OT gliomas and trend of shorter overall survival than grade III IDHmut gliomas e. OS, overall survival.