<i>IDH</i> mutations predict longer survival and response to temozolomide in secondary glioblastoma

Qi, Songtao; Yu, Lei; Gui, Si; Ding, Yan‐Qing; Han, Hui-xia; Zhang, Xuelin; Lanxiao, Wu; Yao, Fei

doi:10.1111/j.1349-7006.2011.02134.x

Cited by 262 publications

(225 citation statements)

References 34 publications

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“…3). IDH1/2 mutations have been associated with overall better prognosis across all diffusely infiltrating malignant astrocytic entities (9,10,12,15,16) and their absence in elderly glioblastoma patients may explain in part why age is a negative prognostic factor in this disease (17). However, it has never been explored whether tumors with IDH1/2 mutations are enriched in long-term survivors of glioblastomas.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Hartmann¹,

Hentschel

Simon

et al. 2013

Clinical Cancer Research

175

108

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Purpose: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival.Experimental Design: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques.Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment.Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

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Section: Discussionmentioning

confidence: 99%

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Hartmann¹,

Hentschel

Simon

et al. 2013

Clinical Cancer Research

175

108

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“…The robustness of IDH1 mutation and MGMT methylation may drive other genetic changes in tumor cells, tumors accompanied by IDH1 mutation and methylated MGMT may consequently have different genetic characteristics compared to tumors unaccompanied by the alternations, which may lead to their varied biological features and patients' survival. As previous reported that the survival time of glioblastoma patients with only IDH1 mutation is shorter than that for patients with both IDH1 mutation and MGMT methylation (Hartmann et al, 2010;Juratli et al, 2012;SongTao et al, 2012). It is suggested that the IDH1-mutated patients is not homogeneous and that the prognosis is not only depend on IDH1 mutation but also on MGMT methylation, so there may be a underlying mechanistic link between IDH1 mutations and MGMT methylation and needs to be further explored (Wick et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of MGMT Promoter Methylation and TP53 Mutation in Glioblastomas Depends on IDH1 Mutation

Wang

Wang²,

Ma³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Asian Pac J Cancer Prev, 15 (24), 10893-10898 IntroductionGlioblastoma multiform (GBM), classified as World Health Organization (WHO) grade IV, is the most common malignant brain tumors in adults with an incidence rate of 23 per 100,000 persons (Stancheva et al., 2014). Their clinical course varies substantially, such that some patients succumb to progressive disease within weeks while others survive for a decade or more. Current treatments include surgery, radiation therapy and chemotherapy (Sathornsumetee et al., 2007;Koca et al., 2014;Pashaki et al., 2014). However, the median survival is still not optimistic. In spite of the existing classification, GBM subgroups are not homogeneous in terms of survival (Molenaar et al., 2014). Several prognostic factors have been established, including age, preoperative Karnofsky Performance Status (KPS), extent of resection, and also some molecular markers.Recently, molecular markers were shown to be helpful in predicting prognosis and treatment response. Three gene markers that have attracted most interest in this respect are mutations in the isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) gene (Stancheva et al., 2014), hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter, and complete deletion of both 1p and 19q. Abstract Several molecular markers have been proposed as predictors of outcome in patients with glioblastomas.We investigated the prognostic significance of O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation and TP53 mutation status dependent on isocitrate dehydrogenase 1 (IDH1) mutation in glioblastoma patients. A cohort of 78 patients with histologically confirmed glioblastomas treated with radiation therapy and chemotherapy were reviewed retrospectively. We evaluated the prognostic value of MGMT promoter methylation and TP53 mutation status with regard to progression-free survival (PFS) and overall survival (OS). It was revealed that mutations in IDH1, promoter methylation of MGMT, TP53 mutation, age, Karnofsky performance status (KFS), and extension of resection were independent prognostic factors. In patients with an IDH1 mutation, those with an MGMT methylation were associated with longer PFS (p=0.016) and OS (p=0.013). Nevertheless, the presence of TP53 mutation could stratify the PFS and OS of patients with IDH1 wild type (p=0.003 and 0.029 respectively, log-rank). The MGMT promoter methylation and TP53 mutation were associated with a favorable outcome of patients with and without mutant IDH1, respectively. The results indicate that glioblastomas with MGMT methylation or TP53 mutations have improved survival that may be influenced by IDH1 mutation status.

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“…29 Similarly, the presence of an IDH mutation predicts response to temozolomide in low-grade gliomas and secondary glioblastomas. 11,26 In contrast, little reliable information is available to demonstrate any difference in the impact of the extent of resection in glioma with a mutated and wild-type IDH1/IDH2 gene. If any difference between glioma with mutated or wild-type IDH genes can be demonstrated in the future, an intraoperative molecular diagnosis will provide useful information for designing the surgical strategy.…”

Section: Discussionmentioning

confidence: 99%

“…3 Additionally, the mutations have been shown to be prognostic 1,20,25 in high-grade gliomas and we can expect them to be present after radiation therapy and chemotherapy. 11,26,29 Based on these findings, we considered that the intraoperative detection of these mutations has potential for clinical application.…”

Section: Abstract • Glioma • Intraoperative Molecular Diagnosis • Idmentioning

confidence: 99%

Rapid and sensitive intraoperative detection of mutations in the isocitrate dehydrogenase 1 and 2 genes during surgery for glioma

Kanamori¹,

Kikuchi

Watanabe

et al. 2014

JNS

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Object Intraoperative diagnosis is important in determining the strategies during surgery for glioma. Because the mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes have diagnostic, prognostic, and predictive values, the authors assessed the feasibility and significance of a simplified method for the intraoperative detection of IDH1 and IDH2 gene mutations. Methods Rapid DNA extraction, amplification with conventional polymerase chain reaction (PCR) or co-amplification at lower denaturation temperature PCR (COLD-PCR), and fluorescence melting curve analysis with adjacent hybridization probes were performed for the intraoperative detection of IDH1 and IDH2 mutations in 18 cases of suspected nonneoplastic lesions and low- and high-grade gliomas and in 3 cases of radiation necrosis. Results DNA extraction for detection of the mutation took 60–65 minutes. The results of this assay showed complete correlation with that of Sanger sequencing. The sensitivity for detection of mutations in a background of wild-type genes was 12.5% and 2.5% in conventional PCR and COLD-PCR, respectively. The diagnosis of glioma was established in 3 of 5 cases in which definitive diagnosis was not obtained using frozen sections, and information was obtained for the discrimination of glioblastoma or glioblastoma with an oligodendroglioma component from anaplastic glioma or secondary glioblastoma. This assay also detected a small fraction of tumor cells with IDH1 mutation in radiation necrosis. Conclusions These methods provide important information for establishing the differential diagnosis between low-grade glioma and nonneoplastic lesions and the diagnosis for subtypes of high-grade glioma. Although tumor cells in radiation necrosis were detected with a high sensitivity, further investigation is necessary for clinical application in surgery for recurrent glioma.

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

Cited by 262 publications

References 34 publications

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Prognostic Value of MGMT Promoter Methylation and TP53 Mutation in Glioblastomas Depends on IDH1 Mutation

Rapid and sensitive intraoperative detection of mutations in the isocitrate dehydrogenase 1 and 2 genes during surgery for glioma

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