The Influence of Gene Aberrations on Survival in Resected IDH Wildtype Glioblastoma Patients: A Single-Institution Study

Abstract

This prospective population-based study on a group of 132 resected IDH-wildtype (IDH-wt) glioblastoma (GBM) patients assesses the prognostic and predictive value of selected genetic biomarkers and clinical factors for GBM as well as the dependence of these values on the applied therapeutic modalities. The patients were treated in our hospital between June 2006 and June 2015. Clinical data and tumor samples were analyzed to determine the frequencies of TP53, MDM2, EGFR, RB1, BCR, and CCND1 gene aberrations and the duplication/deletion statuses of the 9p21.3, 1p36.3, 19q13.32, and 10p11.1 chromosome regions. Cut-off values distinguishing low (LCN) and high (HCN) copy number status for each marker were defined. Additionally, MGMT promoter methylation and IDH1/2 mutation status were investigated retrospectively. Young age, female gender, Karnofsky scores (KS) above 80, chemoradiotherapy, TP53 HCN, and CCND1 HCN were identified as positive prognostic factors, and smoking was identified as a negative prognostic factor. Cox proportional regression models of the chemoradiotherapy patient group revealed TP53 HCN and CCND1 HCN to be positive prognostic factors for both progression-free survival and overall survival. These results confirmed the influence of key clinical factors (age, KS, adjuvant oncotherapy, and smoking) on survival in GBM IDH-wt patients and demonstrated the prognostic and/or predictive importance of CCND1, MDM2, and 22q12.2 aberrations.

The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

“…A whole exome sequencing for Jed66_GB indicated the presence of TC-rare damaging COSMIC variants detected in genes that were previously associated with glioblastoma including BCR activator of RhoGEF and GTPase ( BCR ) [ 43 , 44 ], TNF receptor associated protein 1 ( TRAP1 ) [ 45 – 47 ], DNA polymerase delta 1, catalytic subunit ( POLD1 ) [ 48 ], otopetrin 1 ( OTOP1 ) [ 49 ], tyrosine kinase 2 ( TYK2 ) [ 50 ], AT-rich interaction domain 1B ( ARID1B ) [ 51 ], CD48 molecule ( CD48 ) [ 52 ], ubiquitin specific peptidase 18 ( USP18 ) [ 53 ], nuclear receptor corepressor 1 ( NCOR1 ) [ 54 ], NFE2 Like BZIP Transcription Factor 2 ( NFE2L2 ) [ 55 ], and Kinesin Family Member 1A ( KIF1A ) [ 56 ]. For Jed41_GB, exome sequencing showed the presence of TC-rare damaging COSMIC variants detected in glioblastoma-associated genes including TP53 [ 43 , 44 , 57 ], LDL receptor related protein 1B ( LRP1B ) [ 44 , 58 ], adhesion G protein-coupled receptor E5 ( ADGRE5 ) [ 59 ], atrophin 1 ( ATN1 ) [ 60 ], autophagy related 2B ( ATG2B ) [ 61 , 62 ], MYC associated zinc finger protein ( MAZ ) [ 23 , 63 ], WNK lysine deficient protein kinase 1 ( WNK1 ) [ 64 , 65 ], UDP glucuronosyltransferase family 1 member A1 ( UGT1A1 ) [ 66 ], and UDP glucuronosyltransferase family 1 member A6 ( UGT1A6 ) [ 67 ]. Not surprisingly, differences in functional characteristics between the two cell lines were demonstrated, consistent with the high inter-patient heterogeneity seen for glioblastoma [ 6 – 9 , 15 ].…”

Effects of Reoperation Timing on Survival among Recurrent Glioblastoma Patients: A Retrospective Multicentric Descriptive Study

“…Isocitrate dehydrogenase (IDH) mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status were assessed using standard techniques employed at the three neuro-oncology centers described in detail in previous reports [19][20][21]. Briefly, immunohistochemistry (anti-IDH1R132H) and genotyping with Next-Generation Sequencing (Nextera XT kit, Illumina, San Diego, CA, USA) were employed for IDH mutation analyses and real-time methylation-specific PCRs or pyrosequencing analysis of MGMT promoter methylation.…”