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Telomerase activation by genomic rearrangements in high-risk neuroblastoma

Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system1. Roughly half of these tumors regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavorable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive2-4. We have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n=39; low-risk, n=17) and discovered recurrent genomic rearrangements affecting a chromosomal region (5p15.22) proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumor type1,2,5. In an extended case series (n=217), TERT rearrangements defined a subgroup of high-risk tumors with particularly poor outcome. Despite the large diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumors, TERT expression was also elevated in MYCN-amplified tumors, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.22 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodeling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cells bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodeling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the center of transformation in a large fraction of these tumors.

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Dataset ID Description Technology Samples
EGAD00001001687 Illumina HiSeq 2000 56
Publications Citations
Telomerase activation by genomic rearrangements in high-risk neuroblastoma.
Nature 526: 2015 700-704
Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome.
Nat Commun 12: 2021 1269
Neuroblastoma Risk Assessment and Treatment Stratification with Hybrid Capture-Based Panel Sequencing.
J Pers Med 11: 2021 691
Identification and Characterization of a Glucometabolic Prognostic Gene Signature in Neuroblastoma based on N6-methyladenosine Eraser ALKBH5.
J Cancer 13: 2022 2105-2125
RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition.
Sci Adv 8: 2022 eabn1382
Reliable assessment of telomere maintenance mechanisms in neuroblastoma.
Cell Biosci 12: 2022 160
Inherited rare variants in homologous recombination and neurodevelopmental genes are associated with increased risk of neuroblastoma.
EBioMedicine 87: 2023 104395
SMAD9-MYCN positive feedback loop represents a unique dependency for MYCN-amplified neuroblastoma.
J Exp Clin Cancer Res 41: 2022 352
Genomic ALK alterations in primary and relapsed neuroblastoma.
Br J Cancer 128: 2023 1559-1571
Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome.
Nat Genet 55: 2023 619-630