Mutational dynamics between primary and relapse neuroblastomas

Nat Genet. 2015 Aug;47(8):872-7. doi: 10.1038/ng.3349. Epub 2015 Jun 29.

Abstract

Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Cell Line, Tumor
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • DNA Helicases / genetics
  • Exome / genetics
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic*
  • Gene Frequency
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mutation*
  • Neoplasm Recurrence, Local / genetics*
  • Nerve Tissue Proteins / genetics
  • Neuroblastoma / genetics*
  • Neuroblastoma / pathology
  • Oligonucleotide Array Sequence Analysis
  • Phosphoproteins / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Sequence Analysis, DNA / methods
  • Signal Transduction / genetics
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • DOCK8 protein, human
  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • PTPN14 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor
  • DNA Helicases
  • CHD5 protein, human

Associated data

  • GEO/GSE65307