A DNA repair and cell cycle gene expression signature in pediatric high‐grade gliomas: Prognostic and therapeutic value

Natacha Entz‐werlé, Laetitia Poidevin, Petr V. Nazarov, Olivier Poch, Benoit Lhermitte, Marie Pierre Chenard, Hélène Burckel, Eric Guérin, Quentin Fuchs, David Castel, Georges Noel, Laurence Choulier, Monique Dontenwill, Eric Van Dyck

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

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 glio-blastomas. 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 char-acterize a specific DNA repair and cell‐cycle gene expression signature of pHGGs. Methods: Tran-scriptomic 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 over-expression, associated to XRCC1 expression, TP53 mutations, and TOP2A amplification, is a new theranostic and potential therapeutic target.

Original languageEnglish
Article number2252
JournalCancers
Volume13
Issue number9
DOIs
Publication statusPublished - 7 May 2021

Keywords

  • DNA damage repair
  • PARP1
  • Pediatric high‐grade gliomas
  • Prognostic clustering
  • XRCC1

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