title: Recurrent Glioblastomas Reveal Molecular Subtypes Associated with Mechanistic Implications of Drug-Resistance.
abstract: Previously, transcriptomic profiling studies have shown distinct molecular subtypes of glioblastomas. It has also been suggested that the recurrence of glioblastomas could be achieved by transcriptomic reprograming of tumors, however, their characteristics are not yet fully understood. Here, to gain the mechanistic insights on the molecular phenotypes of recurrent glioblastomas, gene expression profiling was performed on the 43 cases of glioblastomas including 15 paired primary and recurrent cases. Unsupervised clustering analyses revealed two subtypes of G1 and G2, which were characterized by proliferation and neuron-like gene expression traits, respectively. While the primary tumors were classified as G1 subtype, the recurrent glioblastomas showed two distinct expression types. Compared to paired primary tumors, the recurrent tumors in G1 subtype did not show expression alteration. By contrast, the recurrent tumors in G2 subtype showed expression changes from proliferation type to neuron-like one. We also observed the expression of stemness-related genes in G1 recurrent tumors and the altered expression of DNA-repair genes (i.e., AURK, HOX, MGMT, and MSH6) in the G2 recurrent tumors, which might be responsible for the acquisition of drug resistance mechanism during tumor recurrence in a subtype-specific manner. We suggest that recurrent glioblastomas may choose two different strategies for transcriptomic reprograming to escape the chemotherapeutic treatment during tumor recurrence. Our results might be helpful to determine personalized therapeutic strategy against heterogeneous glioma recurrence.
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea; Graduate School of Biomedical Science, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: So Mee
authors.initials: SM
authors.lastname: Kwon
authors.affiliation: Department of Neurosurgery, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Shin-Hyuk
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chul-Kee
authors.initials: CK
authors.lastname: Park
authors.affiliation: Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital & Medical School, Gwangju, Republic of Korea.
authors.forename: Shin
authors.initials: S
authors.lastname: Jung
authors.affiliation: Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Center, Houston, Texas, United States of America.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Se-Hyuk
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea; Graduate School of Biomedical Science, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Hyun Goo
authors.initials: HG
authors.lastname: Woo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000066673:Cell Self Renewal / Q000235:genetics; D016000:Cluster Analysis; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015203:Reproducibility of Results; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes