Journal of the National Cancer Institute Advance Access originally published online on December 11, 2007
JNCI Journal of the National Cancer Institute 2007 99(24):1875-1880; doi:10.1093/jnci/djm251
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Cancer Risk of Heterozygotes With the NBN Founder Mutation
Affiliations of authors: Department of Clinical Genetics, Institute of Biology and Medical Genetics (ES) and Department of Pediatric Neurology (PS), 2nd Medical School, Charles University, Prague, Czech Republic; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (PJ); Institute of Human Genetics, Charité—Universitätsmedizin Berlin, Humboldt-University, Berlin, Germany (RV, MD, KS); Disease Insight Research Foundation, Ardsley, NY (MS)
Correspondence to: Eva Seemanová, DrSc, Department of Clinical Genetics, Charles University Hospital, 2nd Medical School of Charles University, V úvalu 84, 150 06 Praha 5 Motol, Czech Republic (e-mail: eva.seemanova{at}lfmotol.cuni.cz).
Background: The autosomal recessive chromosomal instability disorder Nijmegen breakage syndrome (NBS) is associated with increased risk of lymphoid malignancies and other cancers. Cells from NBS patients contain many double-stranded DNA breaks. More than 90% of NBS patients are homozygous for a founder mutation, 657del5, in the NBN gene. We investigated the 657del5 carrier status of cancer patients among blood relatives (i.e., first-, through fourth-degree relatives) of NBS patients in the Czech Republic and Slovakia to test the hypothesis that NBN heterozygotes have an increased cancer risk.
Methods: Medical information was compiled from 344 blood relatives of NBS patients in 24 different NBS families from January 1, 1998, through December 31, 2003. The 657del5 carrier status of subjects was unknown at the time of their recruitment but was later determined from blood samples collected at the time of the interview. Medical records and death certificates were used to confirm a diagnosis of cancer. For the relatives with cancer who are not obligate heterozygotes (such as parents and two grandparents in consanguineous families), the observed and expected number of mutation carriers were compared by use of the index-test method, which estimated the risk of cancer associated with carrying the mutation. All P values were two-sided.
Results: Thirteen of the 344 blood relatives had confirmed cases of any type of cancer;11 of these 13 cancer patients carried the NBN 657del5 mutation, compared with 6.0 expected (P = .005). Among the 56 grandparents with complete data from 14 NBS families, 10 of the 28 carriers of 657del5, but only one of the 28 noncarriers, developed cancer (odds ratio = 10.7, 95% CI = 1.4 to 81.5; P<.004).
Conclusions: The NBN 657del5 mutation appears to be associated with an elevated risk of cancer in heterozygotes.
| CONTEXT AND CAVEATS Prior knowledge Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder that is associated with increased risk of lymphoid malignancies and other cancers. More than 90% of NBS patients are homozygous for a founder mutation in the NBN gene, 657del5. The frequency of the 657del5 mutation varies from a low of 0.2% to a high of at least 1% in various Slavic populations. Study design Family study among blood relatives (i.e., first- through fourth-degree relatives) of NBS patients to test the hypothesis that NBN heterozygotes have an increased risk of any cancer. Contribution The NBN 657del5 founder mutation appears to be associated with an increased risk of cancer in heterozygotes. Implications There may be more than a million 657del5 carriers worldwide and the development of several hundred new cancers may be associated with this NBN mutation. Limitations Cancer sites reported on death certificates may be inaccurate. The confidence intervals for the estimated odds ratios of the association between the mutation and the risk of cancer are wide.
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Manuscript received June 8, 2007; revised October 9, 2007; accepted November 2, 2007.
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