Background: The up-regulation of a telomere maintenance mechanism (TMM) is a common feature of cancer cells and a hallmark of cancer. Routine methods for detecting TMMs in tumor samples are still missing, whereas telomerase targeting treatments are becoming available. In paediatric cancers, alternative lengthening of telomeres (ALT) is found in a subset of sarcomas and malignant brain tumors. ALT is a non-canonical mechanism of telomere maintenance developed by cancer cells with no-functional telomerase. Methods: To identify drivers and/or markers of ALT, we performed a differential gene expression analysis between two zebrafish models of juvenile brain tumors, that differ only for the telomere maintenance mechanism adopted by tumor cells: one is ALT while the other is telomerase-dependent. Results: Comparative analysis of gene expression identified five genes of the pre-replicative complex, ORC4, ORC6, MCM2, CDC45 and RPA3 as upregulated in ALT. We searched for a correlation between telomerase levels and expression of the pre-replicative complex genes in a cohort of paediatric brain cancers and identified a counter-correlation between telomerase expression and the genes of the pre-replicative complex. Moreover, the analysis of ALT markers in a group of 20 patients confirmed the association between ALT and increased RPA and decreased H3K9me3 localization at telomeres. Conclusions: Our study suggests that telomere maintenance mechanisms may act as a driver of telomeric DNA replication and chromatin status in brain cancers and identifies markers of ALT that could be exploited for precise prognostic and therapeutic purposes.

Changes in the Expression of Pre-Replicative Complex Genes in hTERT and ALT Pediatric Brain Tumors / Idilli, Aurora Irene; Pagani, Francesca; Kerschbamer, Emanuela; Berardinelli, Francesco; Bernabé, Manuel; Cayuela, María Luisa; Piazza, Silvano; Poliani, Pietro Luigi; Cusanelli, Emilio; Mione, Maria Caterina. - In: CANCERS. - ISSN 2072-6694. - 12:4(2020). [10.3390/cancers12041028]

Changes in the Expression of Pre-Replicative Complex Genes in hTERT and ALT Pediatric Brain Tumors

Idilli, Aurora Irene;Kerschbamer, Emanuela;Bernabé, Manuel;Piazza, Silvano;Poliani, Pietro Luigi;Cusanelli, Emilio;Mione, Maria Caterina
2020

Abstract

Background: The up-regulation of a telomere maintenance mechanism (TMM) is a common feature of cancer cells and a hallmark of cancer. Routine methods for detecting TMMs in tumor samples are still missing, whereas telomerase targeting treatments are becoming available. In paediatric cancers, alternative lengthening of telomeres (ALT) is found in a subset of sarcomas and malignant brain tumors. ALT is a non-canonical mechanism of telomere maintenance developed by cancer cells with no-functional telomerase. Methods: To identify drivers and/or markers of ALT, we performed a differential gene expression analysis between two zebrafish models of juvenile brain tumors, that differ only for the telomere maintenance mechanism adopted by tumor cells: one is ALT while the other is telomerase-dependent. Results: Comparative analysis of gene expression identified five genes of the pre-replicative complex, ORC4, ORC6, MCM2, CDC45 and RPA3 as upregulated in ALT. We searched for a correlation between telomerase levels and expression of the pre-replicative complex genes in a cohort of paediatric brain cancers and identified a counter-correlation between telomerase expression and the genes of the pre-replicative complex. Moreover, the analysis of ALT markers in a group of 20 patients confirmed the association between ALT and increased RPA and decreased H3K9me3 localization at telomeres. Conclusions: Our study suggests that telomere maintenance mechanisms may act as a driver of telomeric DNA replication and chromatin status in brain cancers and identifies markers of ALT that could be exploited for precise prognostic and therapeutic purposes.
4
Idilli, Aurora Irene; Pagani, Francesca; Kerschbamer, Emanuela; Berardinelli, Francesco; Bernabé, Manuel; Cayuela, María Luisa; Piazza, Silvano; Poliani, Pietro Luigi; Cusanelli, Emilio; Mione, Maria Caterina
Changes in the Expression of Pre-Replicative Complex Genes in hTERT and ALT Pediatric Brain Tumors / Idilli, Aurora Irene; Pagani, Francesca; Kerschbamer, Emanuela; Berardinelli, Francesco; Bernabé, Manuel; Cayuela, María Luisa; Piazza, Silvano; Poliani, Pietro Luigi; Cusanelli, Emilio; Mione, Maria Caterina. - In: CANCERS. - ISSN 2072-6694. - 12:4(2020). [10.3390/cancers12041028]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/260591
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 6
social impact