Abstract
Recurrence and progression to higher grade lesions are characteristic behaviorsof gliomas. Though IDH1 mutation frequently occurs and is considered as an early event in gliomagenesis, little is known about its role in the recurrence and progression of gliomas. We therefore analysed IDH1 and IDH2 statusat codon 132 of IDH1 and codon 172 of IDH2 by direct sequencing and anti-IDH1-R132H immunohistochemistry in 53 paired samples and their recurrences, including 29 low- grade gliomas, 16 anaplastic gliomas and 8 Glioblastomas. IDH1/IDH2 mutation was detected in 32 primarytumors, with 25 low- grade gliomas and 6 anaplastic gliomas harboring IDH1 mutation and 1 low- grade glioma harboring IDH2 mutation. All of the paired tumors showed consistent IDH1 and IDH2 status. Patients were analyzed according to IDH1 status and tumor-related factors. Malignant progression at recurrence was noted in 22 gliomas and was not associated with IDH1 mutation. Survival analysis revealed patients with IDH1 mutated gliomas had a significantly longer progression-free survival (PFS) and overall survival (OS). In conclusion, this study demonstrated a strong tendency of IDH1/IDH2 status being consistent during progression of glioma. IDH1 mutation was not a predictive marker for malignant progression and it was a potential prognostic marker for gliomas of Chinese patients.
Highlights
Gliomas are the most common primary brain tumors, accounting for 80% of malignant central nervous system neoplasms [1].Recent genome-wide mutational analysis has demonstrated that the incidence of IDH1 mutations in gliomas ranges from 5% in primary glioblastoma (GBM) to 70% in anaplastic astrocytomas (AA) and 80% in secondary GBM [2,3,4,5,6]
Primary Tumors The primary tumor cohort consisted of 29 low grade gliomas (WHO grade II) (17 diffuse astrocytomas, 7 oligoastrocytomas and 5 oligodendrogliomas), 16 anaplastic gliomas (WHO grade III) (8 anaplastic astrocytomas, 3 anaplastic oligodendrogliomas, 1 anaplastic oligoastrocytoma, 1 anaplastic ganglioglioma and 3 anaplastic ependymomas) and 8 glioblastomas (GBM) (WHO grade IV)
WHO grade II was defined as low grade glioma (LGG), while WHO grade III and IV were defined as high grade.The mean and median age of the patients was39.5and 38 years, respectively
Summary
Gliomas are the most common primary brain tumors, accounting for 80% of malignant central nervous system neoplasms [1].Recent genome-wide mutational analysis has demonstrated that the incidence of IDH1 mutations in gliomas ranges from 5% in primary glioblastoma (GBM) to 70% in anaplastic astrocytomas (AA) and 80% in secondary GBM [2,3,4,5,6]. Patients with high-grade astrocytomas with IDH1 mutations were reported to have a better survival [6]. IDH1 mutation has been shown to occur in early stage of gliomagenesis [5]. Does loss of function occur with reduced production of a-ketoglutarate (a-KG) from isocitrate, the R132H mutation confers a gain of function to the mutant IDH1, which converts a-KG to 2hydroxyglutarate (2-HG) [11]. Accumulation of this oncometabolite induce sextensive DNA hypermethylation, leading to genomewide epigenetic changes and predisposing cells toward neoplastic transformation [12]
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