Screening for gene mutations in a 500 kb neuroblastoma tumor suppressor candidate region in chromosome 1p; mutation and stage-specific expression in UBE4B/UFD2

Oncogene. 2003 Apr 17;22(15):2343-51. doi: 10.1038/sj.onc.1206324.

Abstract

Deletion of a part of the short arm of chromosome 1 is one of the most common chromosomal rearrangements observed in neuroblastoma (NBL) tumors and it is associated with a poor prognosis. No NBL tumor suppressor gene has yet been identified in the region. Our shortest region of overlap of deletions, ranging from marker D1S80 to D1S244, was shown to partly overlap a 500 kb region that was homozygously deleted in a NBL cell line. We have screened seven genes known to reside in or very close to this overlap consensus region, UBE4B/UFD2, KIF1B, DFFA, PGD, CORT, PEX14, and ICAT, for coding mutations in NBL tumor DNA. A few deviations from the reference sequences were identified; most interestingly being a splice site mutation that was detected in UBE4B/UFD2 in a stage 3 NBL with a fatal outcome. This mutation was neither present in the patients constitutional DNA nor in any of 192 control chromosomes analysed. Also, the expression of UBE4B/UFD2 was markedly diminished in the high-stage/poor-outcome tumors as compared to the low-stage/favorable-outcome tumors. Overall, the number of amino-acid changes in the genes of the region was low, which shows that mutations in these genes are rare events in NBL development. Given the data presented here, UBE4B/UFD2 stands out as the strongest candidate NBL tumor suppressor gene in the region at this stage.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Chromosomes, Human, Pair 1 / genetics*
  • Cysteine Endopeptidases / metabolism
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics*
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor*
  • Humans
  • Loss of Heterozygosity
  • Multienzyme Complexes / metabolism
  • Mutation*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics*
  • Neoplasm Staging
  • Neuroblastoma / genetics*
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Prognosis
  • Proteasome Endopeptidase Complex
  • RNA Splice Sites / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Treatment Outcome
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligase Complexes
  • Ubiquitin-Protein Ligases

Substances

  • DNA, Neoplasm
  • Multienzyme Complexes
  • Neoplasm Proteins
  • RNA Splice Sites
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Ubiquitin-Protein Ligase Complexes
  • UBE4B protein, human
  • Ubiquitin-Protein Ligases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex