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Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas.

ABSTRACT: BACKGROUND:Previous studies addressing the influence of surgery on the outcome of patients with glioblastomas (GBM) have not addressed molecular markers. The value of surgery versus the tumor's major biological markers remains unclear. OBJECTIVE:We investigate the extent of resection as a prognosticator for patients with newly diagnosed primary GBM with the incorporation of molecular diagnostics as per the updated WHO 2016 diagnostic criteria for GBM. METHODS:Patients with newly diagnosed GBM who underwent resection were prospectively included within a database. We analyzed patients with newly diagnosed GBM and excluded patients who presented with IDH1 R132H mutations. Gross total resection (GTR) was defined as complete removal of enhancing disease. RESULTS:One hundred seventy-five patients were included within the analysis. One hundred four patients (59.4%) had GTR, 71 patients (40.6%) had subtotal or partial resection. Eighty patients (45.7%) displayed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, 95 patients (54.3%) showed no MGMT promoter methylation. In Cox regression analysis, MGMT promoter methylation (hazard ratio [HR] 1.55; 95% confidence interval [CI], 1.01-2.19; P = .0133) and GTR (HR 1.48; 95% CI, 1.06-2.07; P = .0206) were significantly associated with favorable progression-free survival. MGMT promoter methylation (HR 2.13; 95% CI, 1.45-3.12; P = .0001) and GTR (HR 1.81; 95% CI, 1.24-2.63; P = .002) were associated with favorable overall survival (OS). Of other risk factors analyzed, age (>60 vs ? 60 yr) was significantly associated with progression-free survival (HR 1.60; 95% CI, 1.14-2.24; P = .006) and OS (HR 2.19; 95% CI, 1.51-3.19; P < .0001). CONCLUSION:GTR and MGMT promoter methylation are independent prognosticators for improved overall and progression-free survival in a homogeneous cohort of newly diagnosed patients with IDH wild-type glioblastoma.

SUBMITTER: Gessler F

PROVIDER: S-EPMC6500906 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas.

Gessler Florian F Bernstock Joshua D JD Braczynski Anne A Lescher Stephanie S Baumgarten Peter P Harter Patrick N PN Mittelbronn Michel M Wu Tianxia T Seifert Volker V Senft Christian C

Neurosurgery 20190101 1

<h4>Background</h4>Previous studies addressing the influence of surgery on the outcome of patients with glioblastomas (GBM) have not addressed molecular markers. The value of surgery versus the tumor's major biological markers remains unclear.<h4>Objective</h4>We investigate the extent of resection as a prognosticator for patients with newly diagnosed primary GBM with the incorporation of molecular diagnostics as per the updated WHO 2016 diagnostic criteria for GBM.<h4>Methods</h4>Patients with ...[more]

PMID: 29617848

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Project description:Telomerase reverse transcriptase (TERT) promoter (pTERT) mutation has often been described as a late event in gliomagenesis and it has been suggested as a prognostic biomarker in gliomas other than 1p19q codeleted tumors. However, the characteristics of isocitrate dehydrogenase (IDH) wild type (wt) (IDHwt), pTERTwt glioblastomas are not well known. We recruited 72 adult IDHwt, pTERTwt glioblastomas and performed methylation profiling, targeted sequencing, and fluorescence in situ hybridization (FISH) for TERT structural rearrangement and ALT (alternative lengthening of telomeres). There was no significant difference in overall survival (OS) between our cohort and a the Cancer Genome Atlas (TCGA) cohort of IDHwt, pTERT mutant (mut) glioblastomas, suggesting that pTERT mutation on its own is not a prognostic factor among IDHwt glioblastomas. Epigenetically, the tumors clustered into classic-like (11%), mesenchymal-like (32%), and LGm6-glioblastoma (GBM) (57%), the latter far exceeding the corresponding proportion seen in the TCGA cohort of IDHwt, pTERTmut glioblastomas. LGm6-GBM-clustered tumors were enriched for platelet derived growth factor receptor alpha (PDGFRA) amplification or mutation (p = 0.008), and contained far fewer epidermal growth factor receptor (EGFR) amplification (p < 0.01), 10p loss (p = 0.001) and 10q loss (p < 0.001) compared with cases not clustered to this group. LGm6-GBM cases predominantly showed ALT (p = 0.038). In the whole cohort, only 35% cases showed EGFR amplification and no case showed combined chromosome +7/-10. Since the cases were already pTERTwt, so the three molecular properties of EGFR amplification, +7/-10, and pTERT mutation may not cover all IDHwt glioblastomas. Instead, EGFR and PDGFRA amplifications covered 67% and together with their mutations covered 71% of cases of this cohort. Homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A)/B was associated with a worse OS (p = 0.031) and was an independent prognosticator in multivariate analysis (p = 0.032). In conclusion, adult IDHwt, pTERTwt glioblastomas show epigenetic clustering different from IDHwt, pTERTmut glioblastomas, and IDHwt glioblastomas which are pTERTwt may however not show EGFR amplification or +7/-10 in a significant proportion of cases. CDKN2A/B deletion is a poor prognostic biomarker in this group.

Dataset Information

Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas.

Publications

Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas.

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