Neuroblastoma (University of Cologne, Nature 2015)

Overview

The nbl_ucologne_2015 dataset is from Peifer et al. (Nature, 2015) and comprises whole-genome sequencing of 56 neuroblastomas (39 high-risk, 17 low-risk) with an extended validation cohort of 217 German patients diagnosed 1991–2014, enrolled through GPOH clinical trials. The study identified recurrent structural rearrangements at chromosome 5p15.33 upstream of TERT as a novel mechanism of telomerase activation in high-risk neuroblastoma. WGS data are deposited in the European Genome-phenome Archive (EGA accession EGAS00001001308). The cohort is mirrored in cBioPortal as study nbl_ucologne_2015.

Composition

  • Discovery cohort: 56 NBL with matched normals (high-risk n=39, low-risk n=17); profiled by whole-genome sequencing (Illumina HiSeq 2000, 2×100 nt paired-end, hg19/BWA), RNA-seq, ChIP-seq, HM450 methylation array, and custom Agilent oligonucleotide microarrays.
  • Validation cohort: 161 additional primary neuroblastomas profiled by FISH and hybrid-capture targeted sequencing over the TERT/CLPTM1L region.
  • Extended combined cohort: 217 patients (German, single trial network GPOH).
  • Mean WGS non-synonymous mutation rate: 13.3 per genome (low-risk 5.9 ± 5.5; high-risk 16.6 ± 9.9).
  • Reference genome: hg19.

Assays / panels (linked)

Papers using this cohort

  • PMID:26466568 — Peifer et al. 2015, Nature — “Telomerase activation by genomic rearrangements in high-risk neuroblastoma.”

Notable findings derived from this cohort

  • Recurrent 5p15.33 structural rearrangements upstream of TERT found in 12/39 (31%) high-risk WGS cases and 27/114 (24%) of the extended high-risk cohort; absent in all 17 low-risk WGS cases (P=0.01) PMID:26466568.
  • TERT rearrangements, MYCN amplification, and ATRX mutations were mutually exclusive in high-risk disease (P=0.008), defining three convergent routes to telomere lengthening PMID:26466568.
  • TERT-rearranged patients had overall survival comparable to MYCN-amplified patients and significantly worse event-free survival than other high-risk patients (EFS P=0.038); TERT rearrangement was an independent prognostic factor in multivariable analysis controlling for stage and MYCN PMID:26466568.
  • Mechanism is enhancer hijacking: rearrangements juxtapose TERT to strong super-enhancer clusters (H3K27ac/H3K4me1) without altering TERT copy number; TERT expression was 92-fold higher (median) than in low-risk tumors PMID:26466568.
  • MYCN directly activates TERT transcription; TERT was the top downregulated gene upon MYCN siRNA knockdown in MYCN-amplified IMR5/75 cells PMID:26466568.

Sources

  • Peifer M et al. “Telomerase activation by genomic rearrangements in high-risk neuroblastoma.” Nature. 2015;526(7575):700-704. PMID:26466568. DOI: 10.1038/nature14980.

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