A DNA repair and cell cycle gene expression signature in primary and recurrent glioblastoma: prognostic value and clinical implications

Gobin, M. et al. (2019) A DNA repair and cell cycle gene expression signature in primary and recurrent glioblastoma: prognostic value and clinical implications. Cancer Research, 79(6), pp. 1226-1238. (doi: 10.1158/0008-5472.CAN-18-2076) (PMID:30674534)

Abstract

Inevitable tumor recurrence and a poor median survival are frustrating reminders of the inefficacy of our current standard of care for patients with newly diagnosed glioblastoma (GBM), which includes surgery followed by radiation therapy (RT) and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Because resistance to genotoxic damage is achieved mainly through execution of the DNA damage response (DDR) and DNA repair pathways, knowledge of the changes in DNA repair and cell cycle gene expression that occur during tumor development might help identify new targets and improve treatment. Here we performed a gene expression analysis targeting components of the DNA repair and cell cycle machineries in cohorts of paired tumor samples (i.e., biopsies from the same patient obtained at the time of primary tumor operation and at recurrence) from patients treated with RT or RT plus TMZ. We identified and validated a 27-gene signature that resulted in the classification of GBM specimens into three groups, two of which displayed inverse expression profiles. Each group contained primary and recurrent samples, and the tumor at relapse frequently displayed a gene expression profile different from that of the matched primary biopsy. Within the groups that exhibited opposing gene expression profiles, the expression pattern of the gene signature at relapse was linked to progression-free survival. We provide experimental evidence that our signature exposes group-specific vulnerabilities against genotoxicants and inhibitors of the cell cycle and DDR, with the prospect of personalized therapeutic strategies.

• Item Type: Articles
• Additional Information: This work was supported by Télévie-FNRS (grant 7.6532.16 to M. Gobin and E. Van Dyck), the Luxembourg National Research Fund (FNR grant C17/BM/11664971/DEMICS to P.V. Nazarov), and the Anni Hofmann Stiftung (R. Warta).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Chalmers, Professor Anthony
• Authors: Gobin, M., Nazarov, P. V., Warta, R., Timmer, M., Reifenberger, G., Felsberg, J., Vallar, L., Chalmers, A. J., Herold-Mende, C. C., Goldbrunner, R., Niclou, S. P., and Van Dyck, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 0008-5472
• ISSN (Online): 1538-7445
• Published Online: 23 January 2019