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

被引：5

作者：

Unger, Kristian ^{[1
,2
,3
]}

Fleischmann, Daniel F. ^{[3
,4
,5
]}

Ruf, Viktoria ^{[6
]}

Felsberg, Joerg ^{[7
,8
]}

Piehlmaier, Daniel ^{[1
]}

Samaga, Daniel ^{[1
]}

Hess, Julia ^{[1
,2
]}

Suresh, Marian Preetham ^{[9
]}

Mittelbronn, Michel ^{[10
,11
,12
,13
]}

Lauber, Kirsten ^{[2
,3
,4
]}

Budach, Wilfried ^{[14
]}

Sabel, Michael ^{[9
]}

Roedel, Claus ^{[15
]}

Reifenberger, Guido ^{[7
,8
]}

Herms, Jochen ^{[6
]}

Tonn, Joerg-Christian ^{[16
]}

Zitzelsberger, Horst ^{[1
,2
,3
]}

Belka, Claus ^{[2
,3
,4
]}

Niyazi, Maximilian ^{[3
,4
]}

机构：

[1] German Res Ctr Environm Hlth GmbH, Res Unit Radiat Cytogenet, Helmholtz Zentrum Munchen, Neuherberg, Germany

[2] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Clin Cooperat Grp Personalized Radiotherapy Head, Neuherberg, Germany

[3] Ludwig Maximilians Univ Munchen, Dept Radiat Oncol, Univ Hosp, Munich, Germany

[4] German Canc Consortium DKTK, Partner Site Munich, Munich, Germany

[5] German Canc Res Ctr, Heidelberg, Germany

[6] Ludwig Maximilians Univ Munchen, Ctr Neuropathol & Prion Res, Munich, Germany

[7] Heinrich Heine Univ, Univ Hosp Dusseldorf UKD, Inst Neuropathol, Dusseldorf, Germany

[8] German Canc Res Ctr, German Canc Consortium DKTK, Partner Site Essen Dusseldorf, Heidelberg, Germany

[9] Heinrich Heine Univ, Univ Hosp Dusseldorf UKD, Dept Neurosurg, Dusseldorf, Germany

[10] Natl Ctr Pathol NCP, Lab Natl Sante LNS, Luxembourg, Luxembourg

[11] Univ Luxembourg, Luxembourg Ctr Syst Biomed LCSB, Esch Sur Alzette, Luxembourg

[12] Luxembourg Inst Hlth LIH, Dept Oncol DONC, Luxembourg, Luxembourg

[13] Luxembourg Ctr Neuropathol LCNP, Luxembourg, Luxembourg

[14] Heinrich Heine Univ, Univ Hosp Dusseldorf UKD, Dept Radiotherapy & Radiat Oncol, Dusseldorf, Germany

[15] Univ Hosp, Dept Radiat Oncol, Frankfurt, Germany

[16] Ludwig Maximilians Univ Munchen, Dept Neurosurg, Univ Hosp, Munich, Germany

来源：

NEURO-ONCOLOGY ADVANCES | 2020年 / 2卷 / 01期

关键词：

glioblastoma; MGMT promoter methylation; miRNA; prognostic signature; risk stratification; NEWLY-DIAGNOSED GLIOBLASTOMA; ADJUVANT TEMOZOLOMIDE; RADIOTHERAPY; GENE; CONCOMITANT; EXPRESSION; PREDICTION; SURVIVAL; THERAPY;

D O I：

10.1093/noajnl/vdaa137

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 Dusseldorf (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 signatureassociated 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.

引用

页数：12

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