Universität zu Köln

Gobin, Matthieu, Nazarov, Petr V., Warta, Rolf, Timmer, Marco, Reifenberger, Guido, Felsberg, Joerg, Vallar, Laurent ORCID: 0000-0002-4404-1010, Chalmers, Anthony J., Herold-Mende, Christel C., Goldbrunner, Roland, Niclou, Simone P. and Van Dyck, Eric (2019). A DNA Repair and Cell-Cycle Gene Expression Signature in Primary and Recurrent Glioblastoma: Prognostic Value and Clinical Implications. Cancer Res., 79 (6). S. 1226 - 1239. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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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 radiotherapy and chemotherapy with the DNA alkylating agent temozolomide. 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 radiotherapy or radiotherapy plus temozolomide. 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. Significance: These findings suggest that classification of GBM tumors based on a DNA repair and cell-cycle gene expression signature exposes vulnerabilities to standard-of-care therapies and offers the potential for personalized therapeutic strategies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gobin, Matthieu UNSPECIFIED UNSPECIFIED UNSPECIFIED Nazarov, Petr V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Warta, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmer, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Reifenberger, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Felsberg, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Vallar, Laurent UNSPECIFIED orcid.org/0000-0002-4404-1010 UNSPECIFIED Chalmers, Anthony J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herold-Mende, Christel C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goldbrunner, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED Niclou, Simone P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Dyck, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-153712
DOI:	10.1158/0008-5472.CAN-18-2076
Journal or Publication Title:	Cancer Res.
Volume:	79
Number:	6
Page Range:	S. 1226 - 1239
Date:	2019
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NEWLY-DIAGNOSED GLIOBLASTOMA; PHASE-II; TEMOZOLOMIDE; CHEMOTHERAPY; INHIBITION; SURVIVAL; RADIOTHERAPY; RESISTANCE; MULTIFORME; CISPLATIN Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15371