Carcinogenesis Advance Access published online on July 13, 2006
Carcinogenesis, doi:10.1093/carcin/bgl126
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1 Institut für Humangenetik, Charité - Universitätsmedizin Berlin, Campus - Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
* To whom correspondence should be addressed. The human genetic disorder, Nijmegen Breakage Syndrome (NBS), is characterised 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 5bp deletion. This mutation is actually hypomorphic, since a functionally relevant truncated protein, of approximately 70kDa, 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.
Received April 28, 2006
Revised June 12, 2006
Accepted June 17, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein
Lars Krüger 1,
Ilja Demuth 1,
Heidemarie Neitzel 1,
Raymonda Varon 1,
Karl Sperling 1,
Krystyna H. Chrzanowska 2,
Eva Seemanova 3,
and
Martin Digweed 1 *
2 Department of Genetics, Memorial Hospital-Child Health Center, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland
3 Department of Clinical Genetics, Institute of Biology and Medical Genetics, 2nd Medical School of Charles University, V Úvalu 84, 150 06 Prague 5 -Motol, Czech Republic
Martin Digweed, E-mail: martin.digweed{at}charite.de
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