Carcinogenesis Advance Access originally published online on February 12, 2006
Carcinogenesis 2006 27(8):1593-1599; doi:10.1093/carcin/bgi360
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RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability
1 Department of Clinical Genetics, University of Oulu/Oulu University Hospital Oulu, Finland
2 Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB Helsinki University Central Hospital Finland
3 Department of Genetics, Norwegian Radium Hospital Oslo, Norway
4 Department of Oncology, Lund University Hospital Lund, Sweden
5 Department of Pathology, University Hospital of Iceland Reykjavik, Iceland
6 Department of Molecular Biology, Memorial Sloan-Kettering Cancer Center New York, NY, USA
*To whom correspondence should be addressed at: Department of Clinical Genetics, Oulu University Hospital, P.O. Box 24, FIN-90029 OYS, Finland. Tel: +358 8 3153228; Fax: +358 8 3153243; Email: robert.winqvist{at}oulu.fi
The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case–control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5–12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
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