<i>MYCN</i> Amplification and <i>ATRX</i> Mutations are Incompatible in Neuroblastoma

Zeineldin, Maged; Federico, Sara M.; Chen, Xiang; Fan, Yiping; Xu, Beisi; Stewart, Elizabeth A.; Zhou, Xin; Jeon, Jiehyun; Griffiths, Lyra; Easton, John; Mulder, Heather L.; Yergeau, Donald; Liu, Yanling; Wu, Jianrong; Ryn, Collin Van; Naranjo, Arlene; Hogarty, Michael D.; Kamiński, Marcin M.; Valentine, Marc; Miller, Shondra; Pappo, Alberto S.; Zhang, Jinghui; Clay, Michael R.; Bahrami, Armita; Lee, Seungjae; Shelat, Anang A.; George, Rani E.; Mardis, Elaine R.; Wilson, Richard K.; Downing, James R.; Dyer, Michael A.

doi:10.1101/379636

Cited by 18 publications

(50 citation statements)

References 57 publications

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“…MYCN-altered samples had significantly more signature 18 (Fig. 4e), consistent with reported MYCN-induced ROS generation in neuroblastoma 57 , as did samples with 1p deletion and 2p gain (P < 3 × 10 −4 for each of these alterations by Wilcoxon rank-sum test; we required a significance level of α = 2.94 × 10 −3 using a Bonferroni adjustment for multiple hypothesis testing of the 17 alterations in Supplementary Fig. 17).…”

Section: Mutational Signatures and Genetic Correlates Of Signature 18supporting

confidence: 80%

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Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations

et al. 2020

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Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome and/or transcriptome data from 702 neuroblastoma samples. Forty percent of samples harbor at least one recurrent driver gene alteration and most aberrations, including MYCN, ATRX, and TERT alterations, differ in frequency by age. MYCN alterations occur at median 2.3 years of age, TERT at 3.8 years, and ATRX at 5.6 years. COSMIC mutational signature 18, previously associated with reactive oxygen species, is the most common cause of driver point mutations in neuroblastoma, including most ALK and Ras-activating variants. Signature 18 appears early and is continuous throughout disease evolution. Signature 18 is enriched in neuroblastomas with MYCN amplification, 17q gain, and increased expression of mitochondrial ribosome and electron transport-associated genes. Recurrent FGFR1 variants in six patients, and ALK N-terminal structural alterations in five samples, identify additional patients potentially amenable to precision therapy.

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Section: Mutational Signatures and Genetic Correlates Of Signature 18supporting

confidence: 80%

“…Significantly mutated SNVs and indels were identified with GRIN and MutSigCV 21,22 . ATRX mutation status was determined by either WGS or custom capture sequencing of the entire gene, including both exons and introns (COG cohort 57 ). Artefactual variants.…”

Section: Discussionmentioning

confidence: 99%

Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations

et al. 2020

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“…Further studies have shown that although TERT alterations and MYCN amplification do co-exist in a small proportion of cases, there is no overlap between the telomerase expressing and ALT positive neuroblastoma [47]. This is in keeping with a recent publication also showing that ATRX mutations and MYCN amplification are synthetically lethal in neuroblastoma [91]. Taken together, the evidence in neuroblastoma to date is that the presence of either ALT or telomerase activation is associated with differing distinct genetic drivers and occurs in mutually exclusive nature [4,5].…”

Section: Tumour Heterogeneity Evolution and Tmm Targeted Therapeuticssupporting

confidence: 80%

“…Finally although it has been shown that activation of a TMM is the key determinant of poor outcome in neuroblastoma, the key drivers of TMM's in neuroblastoma; MYCN amplification and genetic alterations in ATRX are also associated with distinct patterns of wider transcriptional activation which drive malignant transformation [91,95,96]. Furthermore it is known that the cooccurrence of RAS/TP53 pathway alterations with a TMM is associated with a particularly dismal outcome [6] and accordingly, alterations in the RAS and TP53 pathways are enriched at the time of neuroblastoma relapse [97,98].…”

Section: Tumour Heterogeneity Evolution and Tmm Targeted Therapeuticsmentioning

confidence: 99%

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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“…Neuroblastoma (NB) is a malignant tumor originating from sympathetic nerves [1]. Tumors are composed of undifferentiated neuroblasts.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition

Ye¹,

Lü²,

Tang³

et al. 2020

Int. J. Biol. Sci.

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Our previous studies demonstrated that MEG3 was significantly downregulated in neuroblastoma (NB) and its expression was negatively associated with the INSS stage. Overexpression of MEG3 promoted apoptosis and inhibited proliferation in NB cells. In this study, we discovered more potential functions and molecular mechanisms of MEG3 in NB. According to the database, MEG3 positively correlated with the NB survival rate and was negatively associated with malignant clinical features. Moreover, we determined that MEG3 was mainly located in the nucleus by nuclear-cytoplasmic separation and RNA fish assays. Upregulation of MEG3 in stably transfected cell lines was accomplished, and CCK8, colony formation, and EDU assays were performed, which indicated that MEG3 significantly suppressed cell proliferation. Both wound healing and transwell experiments demonstrated that MEG3 decreased cell migration and invasion. CHIRP enrichments showed the anticancer effects of MEG3 were probably linked to autophagy and the mTOR signaling pathway. LC3 fluorescence dots and western blots showed that MEG3 attenuated autophagy by inhibiting FOXO1, but not the mTOR signaling pathway. Furthermore, MEG3 inhibited metastasis through epithelial-mesenchymal transition via the mTOR signaling pathway. Consistent with the above results, downregulation of MEG3 facilitated NB malignant phenotypes. Mechanistically, MEG3 and EZH2 regulated each other via a negative feedback loop and promoted NB progression together. In conclusion, our findings suggested that MEG3 was a tumor suppressor in NB and could be a potential target for NB treatment in the future.

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MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

Abstract: SUMMARY

Cited by 18 publications

References 57 publications

Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations

Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations

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

Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition

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