PUBLICATION

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

Authors
Idilli, A.I., Pagani, F., Kerschbamer, E., Berardinelli, F., Bernabé, M., Cayuela, M.L., Piazza, S., Poliani, P.L., Cusanelli, E., Mione, M.C.
ID
ZDB-PUB-200426-20
Date
2020
Source
Cancers   12(4): (Journal)
Registered Authors
Idilli, Aurora, Mione, Marina
Keywords
ALT, C-circles, heterochromatin, pediatric brain tumors, pre-replicative complex, telomere maintenance mechanisms, zebrafish
MeSH Terms
none
PubMed
32331249 Full text @ Cancers
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.
Genes / Markers
Marker Marker Type Name
mcm2GENEminichromosome maintenance complex component 2
orc4GENEorigin recognition complex, subunit 4
orc6GENEorigin recognition complex, subunit 6
rpa3GENEreplication protein A3
rps11GENEribosomal protein S11
tercGENEtelomerase RNA component
tertGENEtelomerase reverse transcriptase
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Figures
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
hzm5Et; io006Tgstandard conditionsDays 14-20
hzm5Et; io006Tgstandard conditionsDays 14-20
hzm5Et; io006Tgstandard conditionsDays 30-44
hzm5Et; io006Tgstandard conditionsDays 30-44
hzm5Et; io006Tgstandard conditionsDays 30-44
hzm5Et; io006Tgstandard conditionsDays 30-44
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hzm5EtTransgenic Insertion
    io006TgTransgenic Insertion
      utn7TgTransgenic Insertion
        utn8TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          Human Disease Fish Conditions Evidence
          brain cancerhzm5Et; utn7Tg; utn8Tgchemical treatment by injection: double-stranded DNATAS
          brain cancerhzm5Et; io006Tgstandard conditionsTAS
          high grade gliomahzm5Et; io006Tgstandard conditionsTAS
          1 - 3 of 3
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          Sequence Targeting Reagents
          No data available
          Fish
          Fish
          hzm5Et
          hzm5Et; io006Tg
          hzm5Et; utn7Tg; utn8Tg
          1 - 3 of 3
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          Antibodies
          No data available
          Orthology
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          GAL4TA4EFGGAL4TA4
          mCherryEFGmCherry
          1 - 3 of 3
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          Mapping
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          Citation
          Idilli, A.I., Pagani, F., Kerschbamer, E., Berardinelli, F., Bernabé, M., Cayuela, M.L., Piazza, S., Poliani, P.L., Cusanelli, E., Mione, M.C. (2020) Changes in the Expression of Pre-Replicative Complex Genes in hTERT and ALT Pediatric Brain Tumors. Cancers. 12(4).