Telomere Trimming and DNA Damage as Signatures of High Risk Neuroblastoma

Yu, Eun Young; Cheung, Irene Y.; Feng, Yi; Rabie, Mohamed O.; Roboz, Gail J.; Guzmán, Mónica L.; Cheung, Nai‐Kong V.; Lue, Neal F.

doi:10.1016/j.neo.2019.04.002

Cited by 13 publications

(15 citation statements)

References 45 publications

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“…In keeping with this, six common single nucleotide polymorphisms known to be associated with telomere lengthening have been found to be associated with an increased risk of neuroblastoma [49]. In keeping with the hypothesis that additional underlying predisposing factors may contribute to TMMs, a substantial increase in telomeric DNA damage and active telomere trimming has been described consistently across all high-risk neuroblastomas, regardless of telomerase or ALT status [50].…”

Section: Telomeres and Telomere Lengthening In Neuroblastomasupporting

confidence: 52%

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

George

Parmar

Lorenzi

et al. 2020

J Exp Clin Cancer Res

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The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease. Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2′-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted. In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.

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Section: Telomeres and Telomere Lengthening In Neuroblastomasupporting

confidence: 52%

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

George

Parmar

Lorenzi

et al. 2020

J Exp Clin Cancer Res

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“…Three recurrent genetic aberrations in neuroblastoma, MYCN amplification, TERT re-arrangements, and ATRX mutations, promote telomere maintenance mechanisms and are mutually exclusive mutations [40]. TERT is an RBP and is significantly increased in both the MNA and stage 4 tumour groupings (Figure 1).…”

Section: Rbps Involved In Replication Stress and Telomere Maintenancementioning

confidence: 99%

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

Bell

Hagemann

Holien

et al. 2020

IJMS

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Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have reported roles in neuroblastoma development and patient outcome, the role of RBPs in neuroblastoma is relatively unstudied. In order to elucidate novel RBPs involved in MYCN-amplified and other high-risk neuroblastoma subtypes, we performed differential mRNA expression analysis of RBPs in a large primary tumour cohort (n = 498). Additionally, we found via Kaplan–Meier scanning analysis that 685 of the 1483 tested RBPs have prognostic value in neuroblastoma. For the top putative oncogenic candidates, we analysed their expression in neuroblastoma cell lines, as well as summarised their characteristics and existence of chemical inhibitors. Moreover, to help explain their association with neuroblastoma subtypes, we reviewed candidate RBPs’ potential as biomarkers, and their mechanistic roles in neuronal and cancer contexts. We found several highly significant RBPs including RPL22L1, RNASEH2A, PTRH2, MRPL11 and AFF2, which remain uncharacterised in neuroblastoma. Although not all RBPs appear suitable for drug design, or carry prognostic significance, we show that several RBPs have strong rationale for inhibition and mechanistic studies, representing an alternative, but nonetheless promising therapeutic strategy in neuroblastoma treatment.

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“…The presence of c-circles dramatically correlated with enhanced telomeric DNA content and increased survival in malignant glioma samples [76]. Likewise, by characterizing telomere structures in cells and tissues from patients with high-risk neuroblastoma, Yu et al [77] found that neuroblastoma cells harbor high levels of t-circles, which may be due to active "telomere trimming", a pathway that entails recombination excision of telomere repeats. Moreover, the extreme trimming activity in neuroblastoma cells results in rapid telomere deletion and increased t-circles, dramatically promoting extensive proliferation [78].…”

Section: Extrachromosomal Circles Of Telomeric Dnamentioning

confidence: 99%

Current understanding of extrachromosomal circular DNA in cancer pathogenesis and therapeutic resistance

et al. 2020

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Extrachromosomal circular DNA was recently found to be particularly abundant in multiple human cancer cells, although its frequency varies among different tumor types. Elevated levels of extrachromosomal circular DNA have been considered an effective biomarker of cancer pathogenesis. Multiple reports have demonstrated that the amplification of oncogenes and therapeutic resistance genes located on extrachromosomal DNA is a frequent event that drives intratumoral genetic heterogeneity and provides a potential evolutionary advantage. This review highlights the current understanding of the extrachromosomal circular DNA present in the tissues and circulation of patients with advanced cancers and provides a detailed discussion of their substantial roles in tumor regulation. Confirming the presence of cancer-related extrachromosomal circular DNA would provide a putative testing strategy for the precision diagnosis and treatment of human malignancies in clinical practice.

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Telomere Trimming and DNA Damage as Signatures of High Risk Neuroblastoma

Cited by 13 publications

References 45 publications

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

Current understanding of extrachromosomal circular DNA in cancer pathogenesis and therapeutic resistance

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