Improved risk stratification in younger IDH wild-type glioblastoma patients by combining a 4-miRNA signature with MGMT promoter methylation status

Kristian Unger*, Daniel F. Fleischmann, Viktoria Ruf, Jörg Felsberg, Daniel Piehlmaier, Daniel Samaga, Julia Hess, Marian Preetham Suresh, Michel Mittelbronn, Kirsten Lauber, Wilfried Budach, Michael Sabel, Claus Rödel, Guido Reifenberger, Jochen Herms, Jörg Christian Tonn, Horst Zitzelsberger, Claus Belka, Maximilian Niyazi

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: The potential benefit of risk stratification using a 4-miRNA signature in combination with MGMT promoter methylation in IDH1/2 wild-type glioblastoma patients was assessed.

Methods: Primary tumors from 102 patients with comparable treatment from the LMU Munich (n = 37), the University Hospital Düsseldorf (n = 33), and The Cancer Genome Atlas (n = 32) were included. Risk groups were built using expressions of hsa-let-7a-5p, hsa-let-7b-5p, hsa-miR-615-5p, and hsa-miR-125a-5p to assess prognostic performance in overall survival (OS). MGMT promoter methylation and age were considered as cofactors. Integrated miRNA, DNA methylome, and transcriptome analysis were used to explore the functional impact of signature miRNAs.

Results: The 4-miRNA signature defined high-risk (n = 46, median OS: 15.8 months) and low-risk patients (n = 56, median OS: 20.7 months; univariable Cox proportional hazard analysis: hazard ratio [HR]: 1.8, 95% confidence interval [CI]: 1.14-2.83, P = .01). The multivariable Cox proportional hazard model including the 4-miRNA signature (P = .161), MGMT promoter methylation (P < .001), and age (P = .034) significantly predicted OS (Log-rank P < .0001). Likewise to clinical routine, analysis was performed for younger (≤60 years, n = 50, median OS: 20.2 months) and older patients (>60 years, n = 52, median OS: 15.8) separately. In younger patients, the 4-miRNA signature had prognostic value (HR: 1.92, 95% CI: 0.93-3.93, P = .076). Particularly, younger, MGMT methylated, 4-miRNA signature low-risk patients (n = 18, median OS: 37.4 months) showed significantly improved survival, compared to other younger patients (n = 32, OS 18.5 months; HR: 0.33, 95% CI: 0.15-0.71, P = .003). Integrated data analysis revealed 4-miRNA signature-associated genes and pathways.

Conclusion: The prognostic 4-miRNA signature in combination with MGMT promoter methylation improved risk stratification with the potential for therapeutic substratification, especially of younger patients.

Original languageEnglish
Article numbervdaa137
JournalNeuro-Oncology Advances
Volume2
Issue number1
DOIs
Publication statusPublished - 15 Oct 2020

Keywords

  • glioblastoma
  • MGMT promoter methylation
  • miRNA
  • prognostic signature
  • risk stratification

Fingerprint

Dive into the research topics of 'Improved risk stratification in younger IDH wild-type glioblastoma patients by combining a 4-miRNA signature with MGMT promoter methylation status'. Together they form a unique fingerprint.

Cite this