Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT

Abstract

The “integrated diagnosis” for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II–IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: 1-Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; 2- Astrocytoma, IDH-mutant; 3- Glioblastoma, IDH-mutant; 4- Glioblastoma, IDH-wildtype; and 5-Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95%CI: 1.05–7.04, p=0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI: 0.17–0.81, p=0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI: 0.27–0.87), p=0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.

Prognostic significance of genetic biomarkers in isocitrate dehydrogenase‐wild‐type lower‐grade glioma: the need to further stratify this tumor entity – a meta‐analysis

“…After screening the abstract, 150 potential articles were selected for full-text reading and, finally, we included 11 studies comprising 911 IDH-wt LGGs for final analyses (Fig. 1) [5,[7][8][9][10][11][12][13][14][15][16]. The characteristics of these studies are described in Tables 1 and 2.…”

“…The characteristics of these studies are described in Tables 1 and 2. The individual patient data were provided in eight studies [5,[8][9][10][11][12][13][14].…”

H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas

“…This is in contrast to H3.3 K27M DIPG where ATRX loss is rare (less than 10%) and subclonal (Nikbakht et al, 2016), potentially in accordance with our model. Furthermore, in adult HGG, ATRX loss associates with IDH mutations and TP53 loss and is also associated with improved prognosis (Pekmezci et al, 2017; Wiestler et al, 2013), potentially due to better resection of focal tumors during surgery. On the other hand, the addition of WT PDGFRA overexpression significantly decreases tumor latency while drastically promoting invasion when co-expressed with H3.3 K27M .…”

Mutant ATRX: uncovering a new therapeutic target for glioma

“…The ATRX protein is part of the SWI/SNF2 (SWItch/Sucrose Non Fermentable) family of chromatin remodeling proteins, and in combination with the transcription cofactor, DAXX (death domain associated protein), maintains genomic stability through its deposition of the replication-independent histone variant H3.3 at telomeres and pericentromeric heterochromatin [3]. There is a correlation between ATRX mutations and Alternative Lengthening of Telomeres (ALT), a non-telomerase-dependent telomere lengthening mechanism [4, 5, 6, 7, 8].…”