Telomerase reverse transcriptase promoter mutation- and O(6)-methylguanine DNA methyltransferase promoter methylation-mediated sensitivity to temozolomide in isocitrate dehydrogenase-wild-type glioblastoma: is there a link?

Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wild-type glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma. MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH-wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302). In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter-unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07-2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter-methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes. Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH-wild-type glioblastoma.

Gramatzki D ，Felsberg J ，Hentschel B ，Wolter M ，Schackert G ，Westphal M ，Regli L ，Thon N ，Tatagiba M ，Wick W ，Schlegel U ，Krex D ，Matschke J ，Roth P ，Suresh MP ，Kamp MA ，Rushing EJ ，Pietsch T ，von Deimling A ，Sabel M ，Loeffler M ，Weller M ，Reifenberger G ... -  《-》

A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas.

Arita H ，Yamasaki K ，Matsushita Y ，Nakamura T ，Shimokawa A ，Takami H ，Tanaka S ，Mukasa A ，Shirahata M ，Shimizu S ，Suzuki K ，Saito K ，Kobayashi K ，Higuchi F ，Uzuka T ，Otani R ，Tamura K ，Sumita K ，Ohno M ，Miyakita Y ，Kagawa N ，Hashimoto N ，Hatae R ，Yoshimoto K ，Shinojima N ，Nakamura H ，Kanemura Y ，Okita Y ，Kinoshita M ，Ishibashi K ，Shofuda T ，Kodama Y ，Mori K ，Tomogane Y ，Fukai J ，Fujita K ，Terakawa Y ，Tsuyuguchi N ，Moriuchi S ，Nonaka M ，Suzuki H ，Shibuya M ，Maehara T ，Saito N ，Nagane M ，Kawahara N ，Ueki K ，Yoshimine T ，Miyaoka E ，Nishikawa R ，Komori T ，Narita Y ，Ichimura K ... -  《Acta Neuropathologica Communications》

Predictive value of MGMT promoter methylation on the survival of TMZ treated IDH-mutant glioblastoma.

O6methylguanine-DNA methyltransferase (MGMT) promoter methylation is a biomarker widely used to predict the sensitivity of IDH-wildtype glioblastoma to temozolomide therapy. Given that the IDH status has critical effects on the survival and epigenetic features of glioblastoma, we aimed to assess the role of MGMT promoter methylation in IDH-mutant glioblastoma. This study included 187 IDH-mutant glioblastomas and used 173 IDH-wildtype glioblastomas for comparison. Kaplan-Meier curves and multivariate Cox regression were used to study the predictive effects. Compared with IDH-wildtype glioblastomas, IDH-mutant glioblastomas showed significantly higher (P < 0.0001) MGMT promoter methylation. We demonstrated that MGMT promoter methylation status, as determined by a high cutoff value (≥30%) in pyrosequencing, could be used to significantly stratify the survival of 50 IDH-mutant glioblastomas receiving temozolomide therapy (cohort A); this result was validated in another cohort of 25 IDH-mutant glioblastomas (cohort B). The median progression-free survival and median overall survival in cohort A were 9.33 and 13.76 months for unmethylated cases, and 18.37 and 41.61 months for methylated cases, and in cohort B were 6.97 and 9.10 months for unmethylated cases, and 23.40 and 26.40 months for methylated cases. In addition, we confirmed that the MGMT promoter methylation was significantly (P = 0.0001) correlated with longer OS in IDH-mutant patients with GBM, independently of age, gender distribution, tumor type (primary or recurrent/secondary), and the extent of resection. MGMT promoter methylation has predictive value in IDH-mutant glioblastoma, but its cutoff value should be higher than that for IDH-wildtype glioblastoma.

Chai R ，Li G ，Liu Y ，Zhang K ，Zhao Z ，Wu F ，Chang Y ，Pang B ，Li J ，Li Y ，Jiang T ，Wang Y ... -  《Cancer Biology & Medicine》

IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry.

Yang P ，Zhang W ，Wang Y ，Peng X ，Chen B ，Qiu X ，Li G ，Li S ，Wu C ，Yao K ，Li W ，Yan W ，Li J ，You Y ，Chen CC ，Jiang T ... -  《Oncotarget》

Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy.

Promoter mutation in the human telomerase reverse transcriptase gene (hTERT) occurs in ~75% of primary glioblastoma (GBM). Although the mutation appears to upregulate telomerase expression and contributes to the maintenance of telomere length, its clinical significance remains unclear. We performed hTERT promoter genotyping on 303 isocitrate dehydrogenase 1 wild-type GBM tumors treated with standard chemoradiotherapy. We also stratified 190 GBM patients from the database of The Cancer Genome Atlas (TCGA) by hTERT gene expression. We analyzed overall and progression-free survival by Kaplan-Meier and Cox regression. We detected hTERT promoter mutation in 75% of the patients. When included as the only biomarker, hTERT mutation was not prognostic in our patient cohort by Cox regression analysis. However, when hTERT and O6-DNA methylguanine-methyltransferase (MGMT) were included together, we observed an interaction between these 2 factors. To further investigate this interaction, we performed pairwise comparison of the 4 patient subcohorts grouped by hTERT-MGMT status (MUT-M, WT-M, MUT-U, and WT-U). MGMT methylated patients showed improved survival only in the presence of hTERT promoter mutation: MUT-M versus MUT-U (overall survival of 28.3 vs 15.9 mos, log-rank P < .0001 and progression-free survival of 15.4 vs 7.86 mo, log-rank P < .0001). These results were confirmed by Cox analyses. Analogously, the cohort from TCGA demonstrated survival benefit of MGMT promoter methylation only in patients with high hTERT expression. In addition, hTERT mutation was negatively prognostic in our MGMT unmethylated patients, while the analogous association with high expression was not observed in the cohort from TCGA. The prognostic influence of MGMT promoter methylation depends on hTERT promoter mutation. This interaction warrants further mechanistic investigation.

Nguyen HN ，Lie A ，Li T ，Chowdhury R ，Liu F ，Ozer B ，Wei B ，Green RM ，Ellingson BM ，Wang HJ ，Elashoff R ，Liau LM ，Yong WH ，Nghiemphu PL ，Cloughesy T ，Lai A ... -  《-》