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

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.

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Multiomics approach showing genome-wide copy number alterations and differential gene expression in different types of North-Indian pediatric brain tumors

Gene ◽

10.1016/j.gene.2015.09.078 ◽

2016 ◽

Vol 576 (2) ◽

pp. 734-742 ◽

Cited By ~ 3

Author(s):

Neetu Singh ◽

Dinesh Kumar Sahu ◽

Archana Mishra ◽

Preeti Agarwal ◽

Madhu Mati Goel ◽

...

Keyword(s):

Gene Expression ◽

Brain Tumors ◽

Copy Number ◽

Indian Pediatric ◽

Pediatric Brain Tumors ◽

Copy Number Alterations ◽

Genome Wide ◽

Different Types ◽

Differential Gene ◽

Pediatric Brain

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ALT: A Multi-Faceted Phenomenon

Genes ◽

10.3390/genes11020133 ◽

2020 ◽

Vol 11 (2) ◽

pp. 133 ◽

Cited By ~ 4

Author(s):

Aurore Sommer ◽

Nicola J. Royle

Keyword(s):

Molecular Markers ◽

Cancer Cells ◽

Targeted Therapies ◽

Sequence Variation ◽

Telomere Maintenance ◽

Hallmarks Of Cancer ◽

Telomere Elongation ◽

Maintenance Mechanism ◽

Alternative Lengthening ◽

Made In

One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.

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Selective cancer-germline gene expression in pediatric brain tumors

Journal of Neuro-Oncology ◽

10.1007/s11060-008-9577-6 ◽

2008 ◽

Vol 88 (3) ◽

pp. 273-280 ◽

Cited By ~ 20

Author(s):

Joannes F. M. Jacobs ◽

Oliver M. Grauer ◽

Francis Brasseur ◽

Peter M. Hoogerbrugge ◽

Pieter Wesseling ◽

...

Keyword(s):

Gene Expression ◽

Brain Tumors ◽

Pediatric Brain Tumors ◽

Germline Gene ◽

Pediatric Brain ◽

Cancer Germline

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Mechanisms of telomere maintenance in pediatric brain tumors: Promising targets for therapy – A narrative review

Glioma ◽

10.4103/glioma.glioma_20_20 ◽

2020 ◽

Vol 3 (3) ◽

pp. 105

Author(s):

Felice Giangaspero ◽

Simone Minasi ◽

Francesca Gianno ◽

Hiba Alzoubi ◽

Manila Antonelli ◽

...

Keyword(s):

Brain Tumors ◽

Pediatric Brain Tumors ◽

Narrative Review ◽

Telomere Maintenance ◽

Pediatric Brain

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Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors

10.1101/718551 ◽

2019 ◽

Cited By ~ 2

Author(s):

Aurora Irene Idilli ◽

Emilio Cusanelli ◽

Francesca Pagani ◽

Emanuela Kerschbamer ◽

Francesco Berardinelli ◽

...

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Cancer Progression ◽

Replicative Senescence ◽

Telomere Maintenance ◽

Telomeric Dna ◽

Expression Of Genes ◽

Alternative Lengthening ◽

Brain Tumor Cells ◽

Telomeric Heterochromatin

ABSTRACTThe activation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape replicative senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear.Here, we report a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks at chromosome ends. Surprisingly, expression of telomerase reverts ALT features. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed increase of telomeric heterochromatin and maintenance of telomere length compared to ALT tumors, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of telomeric DNA replication and chromatin status in brain cancers.

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Expression of Bmi-1 in Pediatric Brain Tumors as a New Independent Prognostic Marker of Patient Survival

BioMed Research International ◽

10.1155/2013/192548 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 7

Author(s):

Shirin Farivar ◽

Reza Zati Keikha ◽

Reza Shiari ◽

Farzaneh Jadali

Keyword(s):

Gene Expression ◽

Brain Tumors ◽

Prognostic Marker ◽

Patient Survival ◽

Insertion Site ◽

Pediatric Brain Tumors ◽

High Expression ◽

Low Grade ◽

Normal Brain ◽

Pediatric Brain

Objectives. The B-cell-specific moloney leukemia virus insertion site 1 (the Bmi-1) gene is an important member in the family of polycomb group (PcG) genes that plays an oncogenic role in several types of cancer, but it’s expression as a prognostic marker in pediatric brain tumors has not been indicated.Materials and Methods. The Bmi-1 gene expression, clinic pathological and prognostic significance in a series of pediatric brain tumors were examined by real-time PCR method in 56 pediatric brain tumors.Results. The Bmi-1 gene expression in various types of pediatric brain tumors compared to that in normal brain tissue was 4.85-fold. The relative expression varied from 8.64-fold in ependymomas to 2.89-fold in other types. Expression level in high-grade tumors compared to that in low-grade tumors was 2.5 times. In univariate survival analysis of the pediatric brain tumors, a significant association of high expression of the Bmi-1 with patient survival was demonstrated. In multivariate analysis, the Bmi-1 high expression provided significant independent prognostic factors.Conclusion. Increased expression of the Bmi-1 in pediatric brain tumors may be important in the acquisition of an aggressive phenotype. In addition, it can be used as a strong and independent molecular marker of prognosis in pediatric brain tumors.

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