Neuroblastoma (Broad, TARGET 2013)

Overview

A Broad Institute / TARGET Initiative cohort of 240 matched tumor/normal pairs from high-risk, metastatic (stage 4) neuroblastoma patients, profiled by whole-exome sequencing, whole-genome sequencing, and RNA-seq. This dataset provided the first large-scale characterization of the somatic mutational landscape of high-risk neuroblastoma.

Composition

  • 240 matched tumor/normal pairs from high-risk stage 4 NBL patients (>18 months at diagnosis, metastatic).
  • Males 62%, median age 3.4 years, MYCN amplification in 32%.
  • Whole-exome sequencing: 221 cases (~33 Mb targeted, 124X mean coverage).
  • Whole-genome sequencing: 19 cases (10 Illumina at 29.7X, 10 Complete Genomics at 59.9X).
  • RNA-seq: 10 WGS cases (>10 Gbp per case).
  • Reference genome: hg19/GRCh37.

Assays / panels (linked)

Papers using this cohort

  • PMID:23334666 — The landscape of somatic mutations in neuroblastoma (Broad/TARGET, Nature Genetics 2013).

Notable findings derived from this cohort

  • Low median exonic mutation frequency (0.60/Mb), consistent with other pediatric cancers and far below adult solid tumors PMID:23334666.
  • Only 5 recurrently mutated genes: ALK (9.2%), PTPN11 (2.9%), ATRX (9.6% including deletions), MYCN (1.7%), NRAS (0.83%); RAS/MAPK pathway enriched in gene set analysis PMID:23334666.
  • ALK mutation was the only significantly mutated gene associated with decreased overall survival (p=0.0103) PMID:23334666.
  • ATRX alterations mutually exclusive with MYCN amplification and enriched in older children (p=0.0021) PMID:23334666.
  • Germline pathogenic variants enriched in ALK, CHEK2, PINK1, and BARD1, suggesting broader predisposition than previously recognized PMID:23334666.

Sources

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