a, b, TERT expression levels as determined by transcriptome sequencing (a) and telomerase activity (b) as determined by telomeric repeat amplification assay in neuroblastoma cell lines bearing TERT rearrangements (GI-ME-N and CLB-GA), MYCN amplification (SK-N-BE(2)C and IMR-5/75), and cell lines without these alterations (LAN-6 and SK-N-FI). c, Distribution of telomere length ratios between the tumours and matched normals (computed from whole-genome sequencing) in primary neuroblastoma subgroups defined by TERT, MYCN, and ATRX alterations and risk group (HR, high-risk without the aforementioned alterations; LR, low-risk). d, Telomere FISH analyses of two TERT-rearranged (NBL41, NBL37) and two ATRX-mutated (NBL08, NBL04) primary tumours. e, A revised model for neuroblastoma pathogenesis based on recurrent genomic alterations, the presence or absence of telomere maintenance pathways, and clinical courses of the disease (modified after ref. 24). In this model, high-risk tumours are distinguished from low-risk tumours by active mechanisms of telomere lengthening. The most aggressive neuroblastomas are defined by telomerase activation as a result of either TERT rearrangement (TERT) or MYCN amplification (MNA). In addition, near-diploid (2n) or near-tetraploid (4n) karyotypes are preferentially observed in high-risk tumours, while near-triploid karyotypes are mostly found in low-risk tumours24. Overall survival of patient subgroups at 5 years: 0.51 ± 0.08 (MNA/TERT) versus 0.79 ± 0.08 (high-risk tumours) versus 0.98 ± 0.02 (low-risk tumours).