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

doi:10.1093/noajnl/vdaa137

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

Neurooncol Adv. 2020 Oct 15;2(1):vdaa137. doi: 10.1093/noajnl/vdaa137. eCollection 2020 Jan-Dec.

Authors

Kristian Unger^{1

2

3}, Daniel F Fleischmann^{3

4

5}, Viktoria Ruf⁶, Jörg Felsberg^{7

8}, Daniel Piehlmaier¹, Daniel Samaga¹, Julia Hess^{1

2}, Marian Preetham Suresh⁹, Michel Mittelbronn^{10

11

12

13}, Kirsten Lauber^{2

3

4}, Wilfried Budach¹⁴, Michael Sabel⁹, Claus Rödel¹⁵, Guido Reifenberger^{7

8}, Jochen Herms⁶, Jörg-Christian Tonn¹⁶, Horst Zitzelsberger^{1

2

3}, Claus Belka^{2

3

4}, Maximilian Niyazi^{3

4}

Affiliations

¹ Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
² Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer," Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
³ Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.
⁴ German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.
⁵ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶ Center for Neuropathology and Prion Research LMU Munich, Munich, Germany.
⁷ Institute for Neuropathology, University Hospital Düsseldorf (UKD), Heinrich Heine University, Düsseldorf, Germany.
⁸ German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Department of Neurosurgery, University Hospital Düsseldorf (UKD), Heinrich Heine University, Düsseldorf, Germany.
¹⁰ National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg.
¹¹ Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
¹² Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
¹³ Luxembourg Center of Neuropathology (LCNP), Luxembourg, Luxembourg.
¹⁴ Department of Radiotherapy and Radiation Oncology, University Hospital Düsseldorf (UKD), Heinrich Heine University, Düsseldorf, Germany.
¹⁵ Department of Radiation Oncology, University Hospital, Frankfurt, Germany.
¹⁶ Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany.

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.

Keywords: MGMT promoter methylation; glioblastoma; miRNA; prognostic signature; risk stratification.