The role of RB1 alteration and 4q12 amplification in IDH-WT glioblastoma

Abstract

Background Recent studies have identified that glioblastoma IDH-wild-type (GBM IDH-WT) might be comprised of molecular subgroups with distinct prognoses. Therefore, we investigated the correlation between genetic alterations and survival in 282 GBM IDH-WT patients, to identify subgroups with distinct outcomes. Methods We reviewed characteristics of GBM IDH-WT (2009-2019) patients analyzed by next-generation sequencing interrogating 205 genes and 26 rearrangements. Progression-free survival (PFS) and overall survival (OS) were evaluated with the log-rank test and Cox regression models. We validated our results utilizing data from cBioPortal (MSK-IMPACT dataset). Results Multivariable analysis of GBM IDH-WT revealed that treatment with chemoradiation and RB1-mutant status correlated with improved PFS (HR 0.25 p<0.001 and HR 0.47, p=0.002) and OS (HR 0.24 p<0.001 and HR 0.49, p=0.016). In addition, younger age (<55-years) was associated with improved OS. Karnofsky performance status <80 (HR=1.44, p=0.024) and KDR amplification (HR=2.51, p=0.008) were predictors of worse OS. KDR-amplified patients harbored coexisting PDGFRA and KIT amplification (p<0.001) and TP53-mutations (p=0.04). RB1-mutant patients had less frequent CDKN2A/B and EGFR alterations (p<0.001). Conversely, RB1-mutant patients had more frequent TP53 (p<0.001) and SETD2 (p=0.006) mutations. Analysis of the MSK-IMPACT dataset (n=551) validated the association between RB1 mutations and improved PFS (11.0-months vs. 8.7-months, p=0.009) and OS (34.7-months vs. 21.7-months, p=0.016). Conclusions RB1-mutant GBM IDH-WT is a molecular subgroup with improved PFS and OS. Meanwhile, 4q12 amplification (KDR/PDGFRA/KIT) denoted patients with worse OS. Identifying subgroups of GBM IDH-WT with distinct survival is important for optimal clinical trial design, incorporation of targeted therapies, and personalized neuro-oncological care.

Setd5, but not Setd2, is indispensable for retinal cell survival and proliferation

“…Setd2 is a tumour suppressor, and SETD2 mutations have been reported in multiple types of cancer [17,18]. While SETD2 and RB1 alternations are correlated in glioblastoma IDH-wildtype [19], SETD2 mutations have not been identified in retinoblastoma. Setd2 is a crucial regulator of the mouse oocyte and heart epigenome [20].…”

TERT Immunohistochemistry as a Surrogate Marker for TERT Promoter Mutations in Infiltrating Gliomas

“…The gliomas were diagnosed and classified by a board-certified neuropathologist according to the 2016 World Health Organization Classification of Central Nervous System Tumors 10. Demographic and clinical characteristics were obtained from the electronic medical record and stored in a REDCap database 9,13…”

“…Jamovi (v.1.8.1) was also utilized to generate Fagan nomograms and the receiver operating characteristic (ROC) curve to evaluate the probability of detecting TERT p mutations by TERT IHC. Survival analysis for glioblastoma IDH-WT was performed with the log-rank test in EZR 9,17…”

“…10 Demographic and clinical characteristics were obtained from the electronic medical record and stored in a REDCap database. 9,13…”

“…Infiltrating gliomas are the most common primary tumors of the central nervous system. Over the last decade, studies evaluating the genetic landscape of gliomas revealed a critical role of genomic alterations in classification, prognostication, and treatment 5–9. This led to the incorporation of IDH1/IDH2 mutations in the classification of gliomas in the 2016 updated World Health Organization (WHO) classification 10.…”