title: Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein.
abstract: 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.
authors.affiliation: Institut für Humangenetik, Charité-Universitätsmedizin Berlin Campus-Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Krüger
authors.forename: Ilja
authors.initials: I
authors.lastname: Demuth
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.forename: Krystyna H
authors.initials: KH
authors.lastname: Chrzanowska
authors.forename: Eva
authors.initials: E
authors.lastname: Seemanova
authors.forename: Martin
authors.initials: M
authors.lastname: Digweed
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002648:Child; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D015994:Incidence; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000473:pathology; D008297:Male; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins