How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

Akter, Jesmin

doi:10.3390/biom11081112

Cited by 9 publications

(5 citation statements)

References 104 publications

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“…In IDH wildtype high-risk samples, most of them carry the mutations of PTEN and/or EGFR , which are the characteristics of primary GBMs. The result is consistent with the telomere replacement extension mechanism discussed in previous studies ( Heaphy et al, 2011 ; Akter and Kamijo, 2021 ; Rachakonda et al, 2021 ; Valenzuela et al, 2021 ). This indicates that our signature is capable of identifying the high-risk samples with either primary or recurrent malignant GBM characteristics.…”

Section: Discussionsupporting

confidence: 93%

A Qualitative Signature to Identify TERT Promoter Mutant High-Risk Tumors in Low-Grade Gliomas

Zheng

Zhang

Huang

et al. 2022

Front. Mol. Biosci.

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Background: Telomerase reverse transcriptase promoter (TERT-p) mutation has been frequently found, but associated with contrary prognosis, in both low-grade gliomas and glioblastomas. For the low-grade gliomas (Grades II-III), TERT-p mutant patients have a better prognosis than the wildtype patients, whereas for the GBMs (Grade IV), TERT-p mutation is related to a poor prognosis. We hypothesize that there exist high-risk patients in LGGs who share GBM-like molecular features, including TERT-p mutation, and need more intensive treatment than other LGGs. A molecular signature is needed to identify these high-risk patients for an accurate and timely treatment.Methods: Using the within-sample relative expression orderings of gene pairs, we identified the gene pairs with significantly stable REOs, respectively, in both the TERT-p mutant LGGs and GBMs but with opposite directions in the two groups. These reversely stable gene pairs were used as the molecular signature to stratify the LGGs into high-risk and low-risk groups.Results: A signature consisting of 21 gene pairs was developed, which can classify LGGs into two groups with significantly different overall survival. The high-risk group has a similar genetic mutation profile and a similar survival profile as GBMs, and these high-risk tumors may progress to a more malignant state.Conclusion: The 21 gene-pair signature based on REOs is capable of identifying high-risk patients in LGGs and guiding the clinical choice for appropriate and timely intervention.

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Section: Discussionsupporting

confidence: 93%

A Qualitative Signature to Identify TERT Promoter Mutant High-Risk Tumors in Low-Grade Gliomas

Zheng

Zhang

Huang

et al. 2022

Front. Mol. Biosci.

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“…Accordingly, the uncontrolled confounding by SCA is unlikely to be responsible of the whole difference in survival observed in our study. With regards to telomere maintenance, E2F3 was demonstrated to upregulate the telomerase activity via the RB pathway, 11,57 then a possible role in the deregulation of the telomere maintenance in NB with not‐amplified M YCN and high E2F3 expression cannot be excluded, and deserves further investigation. Other potential limits include the multiple testing bias in stratified analyses, the small sample size in subgroup analyses, which prevents the adjustment by potential confounders, and the insufficient number of events in some subgroups with a consequent lack of statistical power.…”

Section: Discussionmentioning

confidence: 98%

E2F3 gene expression is a potential negative prognostic marker for localised and MYCN not‐amplified neuroblastoma: Results of in silico analysis of 786 samples

Ognibene

Cangelosi

Sorrentino

et al. 2022

Pediatric Blood & Cancer

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Background: Neuroblastoma (NB) is an enigmatic childhood malignancy characterised by a wide range of clinical behaviour. Many potential oncogenes for NB have recently been identified. Among them, E2 transcription factor 3 (E2F3) expression was associated with a poor survival in 134 stage 4S patients, but evidence for other stage groups remains poorly investigated. Methods:We have analysed the expression of E2F3 gene from a database of 786 NB samples. Overall and event-free survivals (EFS) were assessed by the Kaplan-Meier method, splitting the data on the median and tertile expression values. The Cox model was applied to control for the confounding by stage, age and MYCN amplification. Validation was performed by an in silico analysis of an independent cohort of 283 NB patients. Furthermore, an immunofluorescence analysis on 48 formalin-fixed, paraffin-embedded NB specimens was also performed.Results: E2F3 overexpression was associated with a poor survival (EFS = 84%, 95% CI: 79%-95%, for low expression levels; EFS = 62%, 95% CI: 56%-68% for middle levels; EFS = 30%, 95% CI: 24%-36%, for high levels, p < .001). This association was confirmed in multivariable analysis and was more evident in patients with MYCN notamplified and localised stages. Immunofluorescence results and the validation on an independent cohort of NB primary samples confirmed these findings. Conclusions: E2F3 is a new potential prognostic marker in NB with favourable characteristics at diagnosis. Further studies are needed to elucidate the potential role of E2F3 in NB oncogenesis and progression, in order to identify new targets for therapeutic interventions.

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“…Evidence has shown that high TERT expression is associated with poor prognosis [ 11 , 12 , 26 , 31 ], which was also supported by our study. Telomerase represents a promising therapeutic target in NTs, and telomerase‐interacting compounds have been developed [ 32 ]. Recently, BET bromodomain inhibitor OTX015 and carfilzomib (an approved oncology drug) have shown strong synergistic effects to block TERT overexpression and suppressed tumour progression [ 33 ], encouraging the potential use of targeted therapy in patients with TERT ‐rearranged NTs.…”

Section: Discussionmentioning

confidence: 99%

Translational practice of fluorescence in situ hybridisation to identify neuroblastic tumours with TERT rearrangements

Yu,

Zhang,

Yao

et al. 2023

The Journal of Pathology CR

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Recently, telomerase reverse transcriptase (TERT) gene rearrangements have been identified in neuroblastoma (NB), the typical pathological type of neuroblastic tumours (NTs); however, the prevalence of TERT rearrangements in other types of NT remains unknown. This study aimed to develop a practical method for detecting TERT defects and to evaluate the clinical relevance of TERT rearrangements as a biomarker for NT prognosis. A TERT break‐apart probe for fluorescence in situ hybridisation (FISH) was designed, optimised, and applied to assess the genomic status of TERT in Chinese children with NTs at the Beijing Children's Hospital from 2016 to 2019. Clinical, histological, and genetic characteristics of TERT‐rearranged NTs were further addressed. Genomic TERT rearrangements could be effectively detected by FISH and were mutually exclusive with MYCN amplification. TERT rearrangements were identified in 6.0% (38/633) of NTs overall, but 12.4% (31/250) in high‐risk patients. TERT rearrangements identified a subtype of aggressive NTs with the characteristics of Stage 3/4, high‐risk category, over 18 months old, and presenting all histological subtypes of NB and ganglioneuroblastoma nodular. Moreover, TERT rearrangements were significantly associated with elevated TERT expression levels and decreased survival chances. Multivariable analysis confirmed that it was an independent prognostic marker for NTs. FISH is an easily applicable method for evaluating TERT defects, which define a subgroup of NTs with unfavourable prognosis. TERT rearrangements would contribute to characterising NT molecular signatures in clinical practice.

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How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

Cited by 9 publications

References 104 publications

A Qualitative Signature to Identify TERT Promoter Mutant High-Risk Tumors in Low-Grade Gliomas

A Qualitative Signature to Identify TERT Promoter Mutant High-Risk Tumors in Low-Grade Gliomas

E2F3 gene expression is a potential negative prognostic marker for localised and MYCN not‐amplified neuroblastoma: Results of in silico analysis of 786 samples

Translational practice of fluorescence in situ hybridisation to identify neuroblastic tumours with TERT rearrangements

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