IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma.

Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur frequently in secondary glioblastoma. This study aimed to investigate their impact on temozolomide chemosensitivity and relationship with O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation in secondary glioblastoma. Searches for IDH1 and IDH2 mutations, 1p19q codeletion, MGMT promoter methylation, and p53 expression were carried out in a series of 86 secondary glioblastomas and correlated with progression-free survival and overall survival. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, then correlated with molecular alterations. IDH (IDH1 or IDH2) mutations were found in 58/79 patients (73.4%). IDH mutation, MGMT promoter methylation, and 1p19q codeletion were associated with prolonged progression-free survival in univariate (P < 0.001, P < 0.001, P = 0.003, respectively) and multivariate analysis (P < 0.001, P < 0.001, P = 0.035, respectively). IDH mutation (P = 0.001) and MGMT promoter methylation (P = 0.011) were correlated with a higher rate of objective response to temozolomide. Further analysis of response to temozolomide showed that patients with both IDH mutation and MGMT promoter methylation had the best response rate to temozolomide. IDH mutation appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. Use of IDH status combined with MGMT promoter status as a stratification factor seems appropriate in future clinical trials involving temozolomide for the treatment of patients with secondary glioblastoma.

SongTao Q ，Lei Y ，Si G ，YanQing D ，HuiXia H ，XueLin Z ，LanXiao W ，Fei Y ... -  《-》

IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas.

Houillier C ，Wang X ，Kaloshi G ，Mokhtari K ，Guillevin R ，Laffaire J ，Paris S ，Boisselier B ，Idbaih A ，Laigle-Donadey F ，Hoang-Xuan K ，Sanson M ，Delattre JY ... -  《-》

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》

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》