Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein

Carcinogenesis. 2007 Jan;28(1):107-11. doi: 10.1093/carcin/bgl126. Epub 2006 Jul 13.


The human genetic disorder, Nijmegen breakage syndrome (NBS), is characterized by radiosensitivity, immunodeficiency and an increased risk for cancer, particularly B-cell non-Hodgkin lymphoma. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double-strand breaks and in cell cycle checkpoints. The majority of patients are homozygous for a founder mutation, a 5 bp deletion. This mutation is actually hypomorphic, since a functionally relevant truncated protein, of approximately 70 kDa, is produced by alternative translation. Null mutation of the homologous gene in mice is lethal; however, null-mutant murine cells can be rescued by a human NBS1 cDNA carrying the founder mutation. Clearly, the truncated p70-nibrin is able to sustain vital cellular functions of the full-length protein. We have used semi-quantitative immunoprecipitation to examine a panel of 26 lymphoblastoid B-cell lines from NBS patients for their level of p70-nibrin expression and correlate this with details of clinical phenotype provided by the two contributing centres. We find considerable variation in the amount of p70-nibrin in cell lines from different patients. Examination of clinical history indicated a clear and statistically significant correlation between p70-nibrin expression levels and lymphoma incidence. The variation in p70-nibrin levels between patients probably reflects the susceptibility of the alternative translation process to other genetic and non-genetic factors. Patients whose cells are able to maintain particularly high levels of the truncated p70-nibrin protein are at a lower risk for lymphoma than those patients with low levels of p70-nibrin in their cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Child
  • Female
  • Humans
  • Immunoprecipitation
  • Incidence
  • Lymphoma, B-Cell / etiology*
  • Lymphoma, B-Cell / pathology
  • Male
  • Nijmegen Breakage Syndrome / genetics
  • Nijmegen Breakage Syndrome / metabolism*
  • Nijmegen Breakage Syndrome / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Tumor Cells, Cultured


  • Cell Cycle Proteins
  • NBN protein, human
  • Nuclear Proteins