Gene expression profiling predicts response to temozolomide in malignant gliomas

Yoshino, Atsuo; Ogino, Akiyoshi; Yachi, Kazunari; Ohta, Takashi; Fukushima, Takao; Watanabe, Takao; Katayama, Yoichi; Okamoto, Yutaka; Naruse, Norio; Sano, Emiko; Tsumoto, Kouhei

doi:10.3892/ijo_00000621

Cited by 73 publications

(55 citation statements)

References 41 publications

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“…Our prior studies have shown that T98G, U-138MG and YH-13 had MGMT mRNA and protein expression, whereas A-172, AM-38, U-87MG and U-251 did not have them (3). Further, a synergistic antitumor effect of combination treatment with IFN-β and TMZ was observed in the TMZ-resistant glioma cells, T98G, due possibly to an attenuation of their MGMT mRNA levels (12).…”

Section: Discussionmentioning

confidence: 99%

“…Among the factors that may contribute to the TMZ resistance, O 6 -methylguanine-DNA methyltransferase (MGMT, a protein that removes drug-induced alkylguanine adducts from DNA created by TMZ) is thought to be involved in its principal mechanisms (1,2). In addition, we more recently reported a list of the most highly upregulated and downregulated genes which may be involved in conferring TMZ sensitivity/resistance in malignant gliomas employing a cDNA microarray, and suggested that an elevated level of the MGMT gene is one of the most robust predictors of the TMZ response in malignant glioma cells in vitro (3).…”

Section: Introductionmentioning

confidence: 99%

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Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

Yoshino

Tashiro²,

Ogino³

et al. 2011

Int J Oncol

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Abstract. Temozolomide (TMZ) is an alkylating agent that has yielded significant benefits and is a current standard agent in the treatment of malignant gliomas. However, its survival benefit remains unsatisfactory. Recently, a synergistic antitumor effect between TMZ and interferon-β (IFN-β) was reported in malignant glioma cells. The Japan Clinical Oncology Group (JCOG) brain tumor study group has recently began a randomized phase II study to evaluate the clinical effectiveness of combination therapy with TMZ and IFN-β in glioblastomas. However, it is not sufficient just to evaluate the mechanisms and establish an experimental basis for rational clinical therapy with IFN-β and TMZ. The precise mechanisms governing the direct effects of IFN-β and a combination of IFN-β and TMZ in gliomas are not yet fully understood. To gain insight into the mechanisms of sensitivity/resistance involving IFN-β and combination therapy with IFN-β and TMZ, and further to identify new marker(s) that could be used clinically to predict the response to such therapy and new target gene(s) for therapies related to malignant glioma patho genesis, we evaluated the gene expression profiles of human malignant glioma cell lines employing a high-density oligo nucleotide DNA array, GeneChip. We present a list of the most highly upregulated and downregulated genes which may be involved in conferring a response to IFN-β and synergistic effect between IFN-β and TMZ in malignant gliomas. Although the present study has several limitations, our reported candidate genes could represent not only potential molecular markers but also chemotherapy targets for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance in malignant gliomas.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

Yoshino

Tashiro²,

Ogino³

et al. 2011

Int J Oncol

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“…But at present, the underlying mechanism of IDH mutations in tumorigenesis and their prognostic significance is still not clear (39). Further research should be undertaken to open entire new horizon of potential individualized treatment tailored to gene expression profiling and clinical trials for glioma (40).…”

Section: Log-rankmentioning

confidence: 99%

IDH mutations occur frequently in Chinese glioma patients and predict longer survival but not response to concomitant chemoradiotherapy in anaplastic gliomas

et al. 2011

Oncol Rep

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Abstract. Mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) appear to occur frequently and selectively in gliomas. Our aim was to assess whether IDH mutations are common in Chinese glioma patients and whether the mutations predict good response to concomitant chemoradiotherapy. In this study IDH1 and IDH2 mutations were detected in a series of 203 gliomas. IDH1 mutations were present in 75 of the 203 cases (36.9%) while IDH2 mutations in 5 of the 203 cases (2.5%). No tumor was mutated in both IDH1 and IDH2. IDH1/2 mutations were associated with prolonged overall survival in the whole series of patients exclusive of pilocytic astrocytoma (P<0.001), WHO grade Ⅱ patients who received no adjuvant therapy after surgery (P= 0.014) and WHO grade Ⅲ patients who received concomitant chemoradiotherapy (standard schedule) after surgery (P=0.033). Furthermore, there was no correlation between IDH1/2 mutations and reponse to concomitant chemoradiotherapy in anaplastic gliomas. Our results suggest that IDH1 mutations also occur freuqently in Chinese glioma patients but the frequency of IDH1 mutations is below the findings reported by North American and European groups. Furthermore, we confirm the prognostic significance of IDH1/2 mutations in gliomas, but the mutations cannot predict a favorable response to concomitant chemoradiotherapy in anaplastic gliomas. IntroductionGliomas are the most frequent and lethal brain tumors and display a wide diversity with location, morphology, genetic status and response to therapy. These tumors have been classified as grade I to grade IV based on histopathological and clinical criteria established by the World Health Organization (WHO) (1). Despite intensive therapies, including surgery, radiotherapy (RT) and chemotherapy (CT), the outcome of glioma patients remain depressing (2,3). Especially, glioblastoma multiforme (GBM), the most prevalent form of brain tumors, has one of the worst prognosis among all types of gliomas with a median progression-free survival (PFS) of 6.9 months and a median overall survival (OS) of 14.6 months through surgery plus standard concomitant chemoradiotherapy (CCRT) (2,4).A combined understanding of the genetic basis and pathology of gliomas provides insight into biologically based tumor classification and identifies molecular prognostic biomarkers. In turn, this information is the route by which the most effective therapy can be focused (5). The latest breakthrough came in 2008, when the gene encoding isocitrate dehydrogenase 1 (IDH1) was initially found to be mutated in approximately 12% of GBM (6) followed by the observation that it was mutated in the majority of WHO grade II and III gliomas (7-11). IDH1 (encoded by IDH1 gene on chromosomal 2q33.3 and located in the cytoplasm and peroxisomes) or its mitochondrial counterpart IDH2, is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate thereby leading to NADPH (Nicotinamide Adenine Dinucleotide Phosphate) production (12). In the vast majority of the c...

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“…Survival-associated genes in gliomas have been reported in various studies (21)(22)(23)(24). Moreover, methylation microarray provides a more general, prognostic, genome-wide methylation profiling, which may have a role in individualized diagnosis and treatment.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis using methylation and gene expression microarrays reveals PDE4C as a prognostic biomarker in human glioma

et al. 2014

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Abstract. Hypermethylation of tumor suppressor promoters is generally accepted to indicate poor prognosis in glioma; however, the DNA methylation patterns associated with different glioma prognoses remain to be elucidated. In the present study, promoter methylation and gene expression microarrays were used to screen candidate genes between different grades of glioma. Survival analysis was performed using the Kaplan-Meier (KM) method. Promoter methylation and protein expression of phosphodiesterase 4C (PDE4C) was examined in different grade gliomas and the correlation between PDE4C and wild-type (WT) p53 was evaluated in glioma cell lines. In addition, gene ontology and gene set variation analysis were used to examine PDE4C function. We found PDE4C exhibited promoter hypermethylation in high-grade glioma samples and hypomethylation in low-grade glioma, with PDE4C expression levels showing the reverse. This indicated PDE4C may be a candidate glioma biomarker. Through studies of PDE4C methylation and expression status in an independent cohort of 124 patient samples (56 low-grade and 63 high-grade glioma and 5 normal brain), we identified PDE4C as having significant promoter methylation and lower expression in high-grade glioma. Hypermethylation and reduced PDE4C protein expression were associated with grade progression and overall survival. In glioma cell lines, PDE4C was upregulated by demethylation treatment with 5-Aza-2'-deoxycytidine and WT p53 expression was downregulated after PDE4C siRNA suppression. Finally, we found PDE4C promoted apoptosis and inhibited migration in a U87 cell line. On the basis of these observations and the results from subset analysis, it is reasonable to conclude that PDE4C may function as a tumor suppressor by promoting apoptosis through the WT p53 pathway and inhibiting cell migration. The data show that PDE4C is downregulated through promoter hypermethylation in glioma.

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Gene expression profiling predicts response to temozolomide in malignant gliomas

Cited by 73 publications

References 41 publications

Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

IDH mutations occur frequently in Chinese glioma patients and predict longer survival but not response to concomitant chemoradiotherapy in anaplastic gliomas

Integrated analysis using methylation and gene expression microarrays reveals PDE4C as a prognostic biomarker in human glioma

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