• Asian Pacific Journal of Cancer Prevention
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• v.16 no.9
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• pp.4095-4101
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• 2015

IDH1/2 mutations which result in alternation in DNA methylation pattern are one of the most common methylation associated mutations in Acute myeloid leukaemia. IDH1/2 mutations frequently associated with higher platelet level, normal cytogentics and NPM1 mutations. Here we analyzed IDH1/2 mutations in 200 newly diagnosed unselected Indian adult AML patients and investigated their correlation with clinical, cytogenetic parameters along with cooperating NPM1 mutation. We detected 5.5% and 4% mutations in IDH1/2 genes, respectively. Except IDH2 c.515_516GG>AA mutation, all the other identified mutations were reported mutations. Similar to reported c.515G>A mutation, the novel c.515_516GG>AA mutation replaces $172^{nd}$ arginine to lysine in the active site of the enzyme. Even though there was a preponderance of IDH1/2 mutations in NK-AML, cytogenetically abnormal patients also harboured IDH1/2 mutations. IDH1 mutations showed significant higher platelet count and NPM1 mutations. IDH2 mutated patients displayed infrequent NPM1 mutations and lower WBC count. All the NPM1 mutations in the IDH1/2 mutated cases showed type A mutation. The present data suggest that IDH1/2 mutations are associated with normal cytogenetics and type A NPM1 mutations in adult Indian AML patients.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3355-3360
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• 2015

Background: Zinc transporters have been considered as essential regulators in many cancers; however, their mechanisms remain unknown, especially in gliomas. Isocitrate dehydrogenase 1(IDH1) mutation is crucial to glioma. This study aimed to investigate whether zinc transporters are correlated with glioma grade and IDH1 mutation status. Materials and Methods: IDH1 mutation status and mRNA expression of four zinc transporters (ZIP4, ZIP9, ZIP11, and ZnT9) were determined by subjecting a panel of 74 glioma tissue samples to quantitative real-time PCR and pyrosequencing. The correlations between the expression levels of these zinc transporter genes and the grade of glioma, as well as IDH1 mutation status, were investigated. Results: Among the four zinc transporter genes, high ZIP4 expression and low ZIP11 expression were significantly associated with higher grade (grades III and IV) tumors compared with lower grade (grades I and II) counterparts (p<0.0001). However, only ZIP11 exhibited weak correlation with IDH1 mutation status (p=0.045). Samples with mutations in IDH1 displayed higher ZIP11 expression than those without IDH1 mutations. Conclusions: This finding indicated that zinc transporters may interact with IDH1 mutation by direct modulation or action in some shared pathways or genes to promote the development of glioma. Zinc transporters may play an important role in glioma. ZIP4 and ZIP11 are promising molecular diagnostic markers and novel therapeutic targets. Nevertheless, the detailed biological function of zinc transporters and the mechanism of the potential interaction between ZIP11 and IDH1 mutation in gliomagenesis should be further investigated.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10893-10898
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• 2015

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.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.12
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• pp.5195-5201
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• 2016

Background: Brain tumors, constituting one of the most deadly forms of cancer worldwide, result from the accumulation of multiple genetic and epigenetic alterations in genes and signaling pathways. Isocitrate dehydrogenase enzyme isoform 1 (IDH1) mutations are frequently identified in primary brain tumors and acute myeloid leukemia. Studies on IDH1 gene mutations have been extensively performed in various populations worldwide but not in Malaysia. This work was conducted to study the prevalence of IDH1 c.395G>A (R132H) hotspot mutations in a group of Malaysian patients with brain tumors in order to gain local data for the IDH1 mutation profile in our population. Methods: Mutation analysis of c.395G>A (R132H) of IDH1 was performed in 40 brain tumor specimens by the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) and then verified by direct sequencing. Associations between the IDH1 c.395G>A (R132H) mutation and clinicopathologic characteristics were also analyzed. Results: The IDH1 c.395G>A (R132H) mutation was detected in 14/40 patients (35%). A significant association was found with histological tumor types, but not with age, gender and race. Conclusions: IDH1 is frequently mutated and associated with histological subtypes in Malay brain tumors.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7261-7264
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• 2013

Recent genome wide sequencing has identified mutations in IDH1/IDH2 predominantly in grade II-III gliomas and secondary glioblastomas which are associated with favorable clinical outcome. These mutations have become molecular markers of significant diagnostic and prognostic relevance in the assessment of human gliomas. In the current study we evaluated IDH1 (R132) and IDH2 (R172) in 32 gliomas of various grades and tumor subtypes. Sequencing analysis revealed R132H mutations in 18.7% tumors, while none of the cases showed IDH2 (R172) mutations. The frequency of IDH1 mutations was higher in females (21.4%) than males (11.1%), and it was significantly higher in younger patients. Histological analyses demonstrated presence of necrosis and micro vascular proliferation in 69% and 75% respectively. Interestingly, IDH1 mutations were predominantly present in non-necrotic tumors as well as in cases showing microvascular proliferation. Of the six IDH1 positive cases, three were glioblastomas (IV), and one each were anaplastic oligoastrocytoma (III), anaplastic oligodendroglioma III (n=1) and diffuse astrocytoma. In conclusion, IDH1 mutations are quite frequent in Indian glioma patients while IDH2 mutations are not observed. Since IDH mutations are associated with good prognosis, their use in routine clinical practice will enable better risk stratification and management of glioma patients.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.427-432
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• 2014

Isocitrate dehydrogenase (IDH) is of great importance in cell metabolism and energy conversion. IDH mutation in glioma cells is reported to be associated with an increased overall survival. However, effects biological behavior of therapy of gliomas are unclear. Here, we investigated the influence of wild-type and mutated IDH genes on glioma cell biological behavior and response to chemotherapy. Relevant mechanisms were further explored. We designed our study on the background of the IDHR132H mutation. Stable cell lines were constructed by transfection. The CCK-8 method was used to assess cell proliferation, flow cytometry for the cell cycle and cell apoptosis, and the transwell method for cell invasion. Nude mouse models were employed to determine tumorigenesis and sensitivity to chemotherapy. Western blotting was used to detect relevant protein expression levels. We found that overexpression of wild IDH1 gene did not cause changes in the cell cycle, apoptosis and invasion ability. However, it resulted in chemotherapy resistance to a high dose of temozolomide (TMZ) in vivo and in vitro. The IDH1 mutation caused cell cycle arrest in G1 stage and a reduction of proliferation and invasion ability, while raising sensitivity to chemotherapy. This may provide an explanation for the better prognosis of IDH1 mutated glioma patients and the relative worse prognosis of their wild-type IDH1 counterparts. We also expect IDH1 mutations may be optimized as new targets to improve the prognosis of glioma patients.

• Investigative Magnetic Resonance Imaging
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• v.19 no.4
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• pp.218-223
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• 2015

Purpose: To investigate whether volumetric analysis based on T2WI and contrast-enhanced (CE) T1WI can distinguish between isocitrate dehydrogenase-1 mutation-positive ($IDH1^P$) and -negative ($IDH1^N$) glioblastomas (GBMs). Materials and Methods: We retrospectively enrolled 109 patients with histopathologically proven GBMs after surgery or stereotactic biopsy and preoperative MR imaging. We measured the whole-tumor volume in each patient using a semiautomatic segmentation method based on both T2WI and CE T1WI. We compared the tumor volumes between $IDH1^P$ (n = 12) and $IDH1^N$ (n = 97) GBMs using an unpaired t-test. In addition, we performed receiver operating characteristic (ROC) analysis for the differentiation of $IDH1^P$ and $IDH1^N$ GBMs using the tumor volumes based on T2WI and CE T1WI. Results: The mean tumor volume based on T2WI was larger for $IDH1^P$ GBMs than $IDH1^N$ GBMs ($108.8{\pm}68.1$ and $59.3{\pm}37.3mm^3$, respectively, P = 0.0002). In addition, $IDH1^P$ GBMs had a larger tumor volume on CE T1WI than did $IDH1^N$ tumors ($49.00{\pm}40.14$ and $22.53{\pm}17.51mm^3$, respectively, P < 0.0001). ROC analysis revealed that the tumor volume based on T2WI could distinguish $IDH1^P$ from $IDH1^N$ with a cutoff value of 90.25 (P < 0.05): 7 of 12 $IDH1^P$ (58.3%) and 79 of 97 $IDH1^N$ (81.4%). Conclusion: Volumetric analysis of T2WI and CE T1WI could enable $IDH1^P$ GBMs to be distinguished from $IDH1^N$ GBMs. We assumed that secondary GBMs with $IDH1^P$ underwent stepwise progression and were more infiltrative than those with $IDH1^N$, which might have resulted in the differences in tumor volume.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2649-2653
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• 2016

Background: Genetic alterations in gliomas have increasing importance for classification purposes. Thus, we are especially interested in studying IDH mutations which may feature potential roles in diagnosis, prognosis and response to treatment. Our aim was to investigate IDH mutations in diffuse glioma patients diagnosed in university hospital centre of Fez in Morocco. Materials and Methods: IDH1 codon 132 and IDH2 codon 172 were direct-sequenced in 117 diffuse glioma samples diagnosed and treated in University Hospital Hassan II between 2010 and 2014. Results: The R132H IDH1 mutation was identified in 43/117 tumor samples and R172K IDH2 mutation was detected in only one anaplastic oligodendroglioma. IDH mutations were observed in 63.2% of astrocytomas, 73.3% of diffuse oligodendrogliomas and 12.90% of glioblastomas. Conclusions: Our results confirmed other studies published earlier for other populations with some small discrepancies.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1247-1253
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• 2014

Mutations in the DNMT3A and IDH genes represent the most common genetic alteration after FLT3/NPM1 in acute myeloid leukemia (AML). We here analyzed the frequency and distribution pattern of DNMT3A and IDH mutations and their associations with other molecular markers in normal karyotype AML patients. Fortyfive patients were screened for mutations in DNMT3A (R882), IDH1 (R132) and IDH2 (R140 and R172) genes by direct sequencing. Of the 45 patients screened, DNMT3A and IDH mutations were observed in 6 (13.3%) and 7 (15.4%), respectively. Patients with isolated DNMT3A mutations were seen in 4 cases (9%), isolated IDH mutations in 5 (11.1%), while interestingly, two cases showed both DNMT3A and IDH mutations (4.3%). Nucleotide sequencing of DNMT3A revealed missense mutations (R882H and R882C), while that of IDH revealed R172K, R140Q, R132H and R132S. Both DNMT3A and IDH mutations were observed only in adults, with a higher frequency in males. DNMT3A and IDH mutations were significantly associated with NPM1, while trends towards higher coexistence with FLT3 mutations were observed. This is the first study to evaluate DNMT3A/IDH mutations in Indian patients. Significant associations among the various molecular markers was observed, that highlights cooperation between them and possible roles in improved risk stratification.

• Korean Journal of Radiology
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• v.22 no.2
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• pp.233-242
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• 2021

Objective: To evaluate the association of MRI features with the major genomic profiles and prognosis of World Health Organization grade III (G3) gliomas compared with those of glioblastomas (GBMs). Materials and Methods: We enrolled 76 G3 glioma and 155 GBM patients with pathologically confirmed disease who had pretreatment brain MRI and major genetic information of tumors. Qualitative and quantitative imaging features, including volumetrics and histogram parameters, such as normalized cerebral blood volume (nCBV), cerebral blood flow (nCBF), and apparent diffusion coefficient (nADC) were evaluated. The G3 gliomas were divided into three groups for the analysis: with this isocitrate dehydrogenase (IDH)-mutation, IDH mutation and a chromosome arm 1p/19q-codeleted (IDHmut1p/19qdel), IDH mutation, 1p/19q-nondeleted (IDHmut1p/19qnondel), and IDH wildtype (IDHwt). A prediction model for the genetic profiles of G3 gliomas was developed and validated on a separate cohort. Both the quantitative and qualitative imaging parameters and progression-free survival (PFS) of G3 gliomas were compared and survival analysis was performed. Moreover, the imaging parameters and PFS between IDHwt G3 gliomas and GBMs were compared. Results: IDHmut G3 gliomas showed a larger volume (p = 0.017), lower nCBF (p = 0.048), and higher nADC (p = 0.007) than IDHwt. Between the IDHmut tumors, IDHmut1p/19qdel G3 gliomas had higher nCBV (p = 0.024) and lower nADC (p = 0.002) than IDHmut1p/19qnondel G3 gliomas. Moreover, IDHmut1p/19qdel tumors had the best prognosis and IDHwt tumors had the worst prognosis among G3 gliomas (p < 0.001). PFS was significantly associated with the 95th percentile values of nCBV and nCBF in G3 gliomas. There was no significant difference in neither PFS nor imaging features between IDHwt G3 gliomas and IDHwt GBMs. Conclusion: We found significant differences in MRI features, including volumetrics, CBV, and ADC, in G3 gliomas, according to IDH mutation and 1p/19q codeletion status, which can be utilized for the prediction of genomic profiles and the prognosis of G3 glioma patients. The MRI signatures and prognosis of IDHwt G3 gliomas tend to follow those of IDHwt GBMs.