title: Genomic dynamics associated with malignant transformation in IDH1 mutated gliomas.
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.
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul, Korea.
authors.forename: Chul-Kee
authors.initials: CK
authors.lastname: Park
authors.affiliation: SD Genomics, Seoul, Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Park
authors.affiliation: Samsung SDS, Seoul, Korea.
authors.forename: Seungmook
authors.initials: S
authors.lastname: Lee
authors.affiliation: Samsung SDS, Seoul, Korea.
authors.forename: Choong-Hyun
authors.initials: CH
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Youngil
authors.initials: Y
authors.lastname: Koh
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Neurosurgery, Seoul National University Hospital, Seoul, Korea.
authors.forename: Ja Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Samsung SDS, Seoul, Korea.
authors.forename: Hongseok
authors.initials: H
authors.lastname: Yun
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D005260:Female; D023281:Genomics / Q000379:methods*; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: IDH1 mutation; clonal evolution; genomic sequencing; glioma; malignant transformation