This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ebi, H. Articles by Takahashi, T. Search for Related Content PubMed PubMed Citation Articles by Ebi, H. Articles by Takahashi, T.

Novel NBS1 Heterozygous Germ Line Mutation Causing MRE11-Binding Domain Loss Predisposes to Common Types of Cancer

¹ Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine; ² Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences; and Divisions of ³ Epidemiology and Prevention and ⁴ Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan

Requests for reprints: Takashi Takahashi, Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan. Phone: 81-52-744-2454; Fax: 81-52-744-2457; E-mail: tak{at}med.nagoya-u.ac.jp.

DNA damage response (DDR) pathways maintain genomic stability. A 657del5 mutation of NBS1, a key DDR component, causing the rare cancer-predisposing Nijmegen breakage syndrome has been reported nearly exclusively in Slavic populations. In this study, we describe the first identification in a Japanese population of an unprecedented type of heterozygous NBS1 mutant, termed IVS11+2insT, lacking the MRE11- and ATM-binding site at the COOH terminus. Profoundly defective in crucial binding to MRE11, MDC1, BRCA1, and wild-type NBS1, the mutant caused impaired ATM phosphorylation in response to low-dose irradiation in a heterozygous state. Importantly, whereas IVS11+2insT was found in only 2 (0.09%) of 2,348 control subjects, it was identified in 2% (2 of 96) of heterozygotes with gastric cancer, 0.8% (3 of 376) of those with colorectal cancer, and 0.4% (2 of 532) of those with lung cancer, which were comparable to frequencies reported for other DDR-related genes known to confer cancer susceptibility. The presence of the heterozygous IVS11+2insT mutation seemed to be associated with an increased risk for gastrointestinal cancers, with an odds ratio of 12.6 and 95% confidence interval (95% CI) of 2.05 to 132.1 (P = 0.0001). The odds ratios separately calculated for gastric and colorectal cancers were 25.0 (95% CI, 1.78–346.0) and 9.43 (95% CI, 1.08–113.1), respectively. These findings suggest that IVS11+2insT is associated with an increased risk for the development of certain types of common cancers, warranting future investigation including detailed phenotypic characterization of age of onset and penetrance in heterozygotes, as well as screening in other ethnic groups. [Cancer Res 2007;67(23):11158–65]

This article has been cited by other articles:

				J. Huang, M. A. Grotzer, T. Watanabe, E. Hewer, T. Pietsch, S. Rutkowski, and H. Ohgaki Mutations in the Nijmegen Breakage Syndrome Gene in Medulloblastomas Clin. Cancer Res., July 1, 2008; 14(13): 4053 - 4058. [Abstract] [Full Text] [PDF]