Abstract
The genomic mechanism responsible for malignant transformation remains an open question for glioma researchers, where differing conclusions have been drawn based on diverse study conditions. Therefore, it is essential to secure direct evidence using longitudinal samples from the same patient. Moreover, malignant transformation of IDH1-mutated gliomas is of potential interest, as its genomic mechanism under influence of oncometabolite remains unclear, and even higher rate of malignant transformation was reported in IDH1-mutated low grade gliomas than in wild-type IDH1 tumors. We have analyzed genomic data using next-generation sequencing technology for longitudinal samples from 3 patients with IDH1-mutated gliomas whose disease had progressed from a low grade to a high grade phenotype. Comprehensive analysis included chromosomal aberrations as well as whole exome and transcriptome sequencing, and the candidate driver genes for malignant transformation were validated with public database. Integrated analysis of genomic dynamics in clonal evolution during the malignant transformation revealed alterations in the machinery regulating gene expression, including the spliceosome complex (U2AF2), transcription factors (TCF12), and chromatin remodelers (ARID1A). Moreover, consequential expression changes implied the activation of genes associated with the restoration of the stemness of cancer cells. The alterations in genetic regulatory mechanisms may be the key factor for the major phenotypic changes in IDH1 mutated gliomas. Despite being limited to a small number of cases, this analysis provides a direct example of the genomic changes responsible for malignant transformation in gliomas.
Highlights
One of the classic concepts of cancer progression includes an evolutionary process that results from stepwise mutations with sequential subclonal selection [1]
We studied 3 pairs of isocitrate dehydrogenase 1 (IDH1) mutated low grade gliomas and their high grade phenotype transformed after the lapse of time (Figure 1)
Case 1 is histologically classified as astrocytoma with IDH1 mutation and intact 1p19q status, which progressed to anaplastic astrocytoma followed by glioblastoma
Summary
One of the classic concepts of cancer progression includes an evolutionary process that results from stepwise mutations with sequential subclonal selection [1]. This evolutionary process in cancer is still applicable despite traditional cancer treatment strategies that involve artificial alterations in cancer-clone dynamics [2]. This concept did not have direct evidence until recent advances in next-generation sequencing and bioinformatics techniques allowed direct observation of this concept [3, 4]. Direct evidence of genomic dynamics of malignant transformation in glioma using longitudinal samples is rare
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