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Article

A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value

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UMR CNRS 7021, Laboratory Bioimaging and Pathologies, Tumoral Signaling and Therapeutic Targets, Faculty of Pharmacy, 67401 Illkirch, France
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Pediatric Onco-Hematology Unit, University Hospital of Strasbourg, 67098 Strasbourg, France
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ICube-UMR7357, CSTB, Centre de Recherche en Biomédecine de Strasbourg, 67084 Strasbourg, France
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Multiomics Data Science Research Group, Quantitative Biology Unit, Department of Oncology and Bioinformatics Platform, Luxembourg Institute of Health, L-1445 Luxembourg, Luxembourg
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Pathology Department, University Hospital of Strasbourg, 67098 Strasbourg, France
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Centre de Ressources Biologiques, University Hospital of Strasbourg, 67098 Strasbourg, France
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Paul Strauss Comprehensive Cancer Center, Radiobioly Laboratory, ICANS (Institut de Cancérologie Strasbourg Europe), University of Strasbourg, Unicancer, 67200 Strasbourg, France
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Oncobiology Platform, Laboratory of Biochemistry, University Hospital of Strasbourg, 67098 Strasbourg, France
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Team Genomics & Oncogenesis of Pediatric Brain Tumors, Inserm U981, Gustave Roussy Institute, 94805 Villejuif, France
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DNA Repair and Chemoresistance, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg
*
Authors to whom correspondence should be addressed.
Academic Editor: Felice Giangaspero
Cancers 2021, 13(9), 2252; https://doi.org/10.3390/cancers13092252
Received: 1 March 2021 / Revised: 27 April 2021 / Accepted: 30 April 2021 / Published: 7 May 2021
(This article belongs to the Special Issue Pediatric Brain Tumors)
Pediatric high-grade gliomas are incurable brain tumors for which there is a critical need for new therapeutic strategies as well as treatment-predictive biomarkers. This study examined the expression of DNA repair and cell cycle genes in pediatric high-grade gliomas with distinct driving mutations. The aim is to propose a novel classification of these tumors based on sub-groups exposing therapeutic vulnerabilities. Several DNA repair factors were identified that might become new diagnostic markers.
Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding of the DNA damage response pathways that operate in pHGGs and the vulnerabilities that these pathways might expose, we sought to identify and characterize a specific DNA repair and cell-cycle gene expression signature of pHGGs. Methods: Transcriptomic analyses were performed to identify a DNA repair and cell-cycle gene expression signature able to discriminate pHGGs (n = 6) from low-grade gliomas (n = 10). This signature was compared to related signatures already established. We used the pHGG signature to explore already transcriptomic datasets of DIPGs and sus-tentorial pHGGs. Finally, we examined the expression of key proteins of the pHGG signature in 21 pHGG diagnostic samples and nine paired relapses. Functional inhibition of one DNA repair factor was carried out in four patients who derived H3.3 K27M mutant cell lines. Results: We identified a 28-gene expression signature of DNA repair and cell cycle that clustered pHGGs cohorts, in particular sus-tentorial locations, in two groups. Differential protein expression levels of PARP1 and XRCC1 were associated to TP53 mutations and TOP2A amplification and linked significantly to the more radioresistant pHGGs displaying the worst outcome. Using patient-derived cell lines, we showed that the PARP-1/XRCC1 expression balance might be correlated with resistance to PARP1 inhibition. Conclusion: We provide evidence that PARP1 overexpression, associated to XRCC1 expression, TP53 mutations, and TOP2A amplification, is a new theranostic and potential therapeutic target. View Full-Text
Keywords: pediatric high-grade gliomas; DNA damage repair; prognostic clustering; PARP1; XRCC1 pediatric high-grade gliomas; DNA damage repair; prognostic clustering; PARP1; XRCC1
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MDPI and ACS Style

Entz-Werlé, N.; Poidevin, L.; Nazarov, P.V.; Poch, O.; Lhermitte, B.; Chenard, M.P.; Burckel, H.; Guérin, E.; Fuchs, Q.; Castel, D.; Noel, G.; Choulier, L.; Dontenwill, M.; Van Dyck, E. A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value. Cancers 2021, 13, 2252. https://doi.org/10.3390/cancers13092252

AMA Style

Entz-Werlé N, Poidevin L, Nazarov PV, Poch O, Lhermitte B, Chenard MP, Burckel H, Guérin E, Fuchs Q, Castel D, Noel G, Choulier L, Dontenwill M, Van Dyck E. A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value. Cancers. 2021; 13(9):2252. https://doi.org/10.3390/cancers13092252

Chicago/Turabian Style

Entz-Werlé, Natacha, Laetitia Poidevin, Petr V. Nazarov, Olivier Poch, Benoit Lhermitte, Marie P. Chenard, Hélène Burckel, Eric Guérin, Quentin Fuchs, David Castel, Georges Noel, Laurence Choulier, Monique Dontenwill, and Eric Van Dyck. 2021. "A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value" Cancers 13, no. 9: 2252. https://doi.org/10.3390/cancers13092252

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