Telomere biology including TERT rearrangements in neuroblastoma: a useful indicator for surgical treatments

Kawashima, Masumi; Kojima, Masato; Ueda, Yuka; Kurihara, Sho; Hiyama, Eiso

doi:10.1016/j.jpedsurg.2016.09.042

Cited by 22 publications

(25 citation statements)

References 27 publications

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“…Telomere maintenance is essential for establishment of high risk NB (65). High telomerase expression indicates increased invasiveness and poor prognosis (66), comparable to MYCN amplified tumors (67). Rearrangements at the TERT gene locus (5p15.33) are frequent in NB resulting in overexpression of the TERT gene and subsequent increased telomerase expression (67,68).…”

Section: Telomere Maintenancementioning

confidence: 99%

“…High telomerase expression indicates increased invasiveness and poor prognosis (66), comparable to MYCN amplified tumors (67). Rearrangements at the TERT gene locus (5p15.33) are frequent in NB resulting in overexpression of the TERT gene and subsequent increased telomerase expression (67,68). In contrast to other cancers, mutations in the TERT promoter region are rare in NB primary tumors and cell lines (69) and TERT activation is most likely achieved by amplification or juxtapositions of TERT to strong enhancer elements (70,71).…”

Section: Telomere Maintenancementioning

confidence: 99%

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Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

et al. 2020

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Despite intensive multimodal therapy, the survival rate for high risk neuroblastoma (HR-NB) remains <50%. Most cases initially respond to treatment but almost half will subsequently relapse with aggressive treatment resistant disease. Novel treatments exploiting the molecular pathology of NB and/or overcoming resistance to current genotoxic therapies are needed before survival rates can significantly improve. DNA damage response (DDR) defects are frequently observed in HR-NB including allelic deletion and loss of function mutations in key DDR genes, oncogene induced replication stress and cell cycle checkpoint dysfunction. Exploiting defects in the DDR has been a successful treatment strategy in some adult cancers. Here we review the genetic features of HR-NB which lead to DDR defects and the emerging molecular targeting agents to exploit them.

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Section: Telomere Maintenancementioning

confidence: 99%

Section: Telomere Maintenancementioning

confidence: 99%

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

et al. 2020

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“…In addition, alignment based approaches offer single base pair resolution and genome-wide coverage in the case of WGS. Recent studies using alignment based detection of SVs from WGS profiles from primary neuroblastomas revealed structural rearrangements as key oncogenic drivers mediating focal enhancer amplification or enhancer hijacking, influencing telomere maintenance through activation of telomerase reverse transcriptase gene (TERT) 24,27,28 or by deregulating the MYC oncogene 29 . Despite the demonstrated importance of somatic CNVs and other SVs in neuroblastoma, studies systematically integrating CNV analysis and alignment based approaches are lacking; hence the global landscape and mechanisms of pathogenicity of many of these events remain poorly understood.…”

mentioning

confidence: 99%

Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

López

Conkrite

Doepner

et al. 2019

Preprint

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Neuroblastoma, like many childhood cancers, exhibits a relative paucity of somatic single nucleotide variants (SNVs). Here, we assess the contribution of structural variation (SV) in neuroblastoma using a combination of whole genome sequencing (WGS; n=135) and single nucleotide polymorphism (SNP) genotyping (n=914) of matched tumor-normal pairs. Our study design provided means for orthogonal validation of SVs as well as validation across genomic platforms. SV frequency, type, and localization varied significantly among high-risk tumors, with MYCN non-amplified tumors harboring an increased SV burden overall (P=1.12x10 -5 ). Genes disrupted by SV breakpoints were enriched in neuronal lineages and autism spectrum disorder. The postsynaptic adapter protein-coding gene SHANK2, located on chromosome 11q13, was disrupted by SVs in 14% and 10% of MYCN non-amplified highrisk tumors based on WGS and SNP array cohorts, respectively. Forced expression of SHANK2 in neuroblastoma cell models resulted in significant growth inhibition (P=2.62x10 -2 to 3.4x10 -5 ) and accelerated neuronal differentiation following treatment with all-trans retinoic acid (P=3.08x10 -13 to 2.38x10 -30 ). These data further define the complex landscape of structural variation in neuroblastoma and suggest that events leading to deregulation of neurodevelopmental processes, such as inactivation of SHANK2, are key mediators of tumorigenesis.Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly affects children under 5 years of age, with a median age at diagnosis of 17 months 1 . Approximately 50% of cases present with disseminated disease at the time of diagnosis, and despite intense multi-modal therapy, the survival rate for this high-risk subset remains less than 50% 1 . Recent whole genome and exome sequencing studies of neuroblastoma have revealed relatively few recurrent protein-coding somatic mutations including single nucleotide variations (SNVs) and small (<50b) insertion/deletions (indels) 2-5 .Large-scale structural variations (SVs) such as deletions, insertions, inversions, tandem duplications and translocations can arise from mutational processes that alter chromosome structure and evade innate mechanisms of maintaining genomic stability. These diverse SVs are commonly acquired somatically and act as driver mutations 6 .A plethora of approaches have been applied to detect SVs across large cancer datasets 6-9 .First, methods that identify copy number variations (CNVs) can be applied to intensity log R ratios from genotyping and comparative genomic hybridization (CGH) arrays as well as read-depth measures from next generation sequencing. Different segmentation algorithms have been applied to either platform in order to obtain copy number gain and loss calls, which range from a few hundred base-pair size to whole chromosomal alterations. These methods are dosage sensitive, allowing numerical quantification of amplifications and homozygous deletions. Analysis of CNVs in neuroblastoma primary tumor and matched...

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“…This relationship highlights the major role of telomere/telomerase biology in NBL. These three mechanisms identify therefore distinct groups of NBL patients at very high risk with poor outcome [139]. That low-risk tumors lack such alterations support the notion that these kinds of tumors are more prone to spontaneously regress.…”

Section: Arid1a and Arid1bmentioning

confidence: 65%

“…In an extended case series (n = 217), the authors showed that hTERT rearrangements are associated with a poor patient outcome and occur in mutually exclusive fashion with MYCN amplification and ATRX mutations (see below). They do not affect directly the hTERT gene or its promoter but they are all associated with an increase in hTERT transcription and telomerase activity as well as genes present in its vicinity (SLC6A18 and SLC6A19) [139]. ChIP sequencing of hTERT-rearranged tumors indicated next to the breakpoints the presence of histone modifications known to mark active promoters (H3K4me3 and H3K27ac) and transcription elongation (H3K36me3), whereas in cells lacking hTERT alterations the repressive mark H3K27me3 was identified.…”

Section: Htert Rearrangementsmentioning

confidence: 99%

Telomeres and Telomerase in Neuroblastoma

Hajj¹,

Garsuault²,

Bouyer³

et al. 2017

Neuroblastoma - Current State and Recent Updates

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Telomeres are nucleoprotein structures located at the ends of linear chromosomes. In most human adult normal somatic cells, telomeres shorten after each cellular division. This shortening ultimately leads to senescence and/or apoptosis. By contrast, in most cancer cells, telomerase activation compensates this loss and confers to these cells their infinite cell proliferation potential. Neuroblastoma (NBL) is a malignant tumor of the peripheral sympathetic nervous system and the most frequent extracranial solid tumor of childhood. NBLs are remarkably heterogeneous both at the levels of biology, genetic and clinical courses. Indeed, some of NBLs can regress spontaneously or after a mild treatment, while others are in the high-risk category with poor prognosis. The molecular bases underlying this heterogeneity are poorly understood. MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-derived Homolog) amplification, recognized as strongly associated with unfavorable patient outcome, is found in only 40% of the high-risk disease, indicating the involvement of other mechanisms. Recent observations suggest that telomerase expression and telomere dysfunctions may be one critical step in NBL development. This review provides recent insights on telomeres/telomerase regulation in NBL. Because of their involvement in the tumor cell biology, telomere and telomerase are currently at the core of new drug development.

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Telomere biology including TERT rearrangements in neuroblastoma: a useful indicator for surgical treatments

Cited by 22 publications

References 27 publications

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

Telomeres and Telomerase in Neuroblastoma

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