TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas

Abstract

IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup.

Keywords: IDH; TERT promoter; chemotherapy; gliomas; radiation therapy.

Figure 1. Kaplan-Meier survival curves (univariate analysis) of IDH and TERT promoter mutations for OS and PFS in WHO grade II and III diffuse gliomas with and without adjuvant therapies

IDH mutations were associated with significantly longer OS A. and PFS B. in WHO grade II and III diffuse gliomas treated with genotoxic therapies after surgery but TERT promoter mutations were not significantly associated with longer PFS C. and were significantly associated with longer OS D. In the absence of genotoxic therapies after surgery, IDH mutations E and F. and TERT promoter mutations G and H. were not associated with significantly longer OS and PFS in WHO grade II and III diffuse gliomas.

Figure 2. Kaplan-Meier survival curves (univariate analysis) of adjuvant therapies for PFS in IDH mutated, IDH wild-type, TERT promoter mutated and TERT promoter wild-type WHO grade II and III diffuse gliomas

In IDH mutated WHO grade II and III diffuse gliomas, patients who received postoperative RT A. and CHT B. had significantly better PFS than those who did not. However, in IDH wild-type WHO grade II and III diffuse gliomas, PFS of patients who received postoperative RT C. or CHT D. did not differ significantly from PFS of those who did not. As for TERT promoter mutated and TERT promoter wild-type WHO grade II and III diffuse gliomas, patients who received postoperative RT E, G. and CHT F, H. had significantly better PFS than those who did not.

Figure 3. Kaplan-Meier survival curves (univariate analysis) of adjuvant therapies for PFS in subgroups of WHO grade II and III diffuse gliomas defined by IDH and TERT promoter mutations

In IDH mut/TERT mut A and B. IDH mut/TERT wt C and D. and IDH wt/TERT mut tumors E and F., patients who received post-operative RT and CHT had significantly better PFS than those who did not. However, in IDH wt/TERT wt tumors, PFS of patients who received postoperative RT G. and CHT H. did not differ significantly from PFS of those who did not.