Carcinogenesis Advance Access published online on October 28, 2008
Carcinogenesis, doi:10.1093/carcin/bgn233
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Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility
1 Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan
2 Departments of Surgery, Tri-Service General Hospital, Taipei, Taiwan
3 Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
4 Departments of Radiology, Tri-Service General Hospital, Taipei, Taiwan
5 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
6 Life Science Library, Academia Sinica, Taipei, Taiwan
7 Graduate Institute of Environmental Science, China Medical University, Taichong, Taiwan
Correspondence: Shian-ling Ding, Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, 11485, Taiwan; phone: +(886)-2-26321181, ext 257; Fax:+(886)-2-2364-9857; E-mail: slding{at}knjc.edu.tw, and Chen-Yang Shen, Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan; phone: +(886)-2-2789-9036; Fax:+(886)-2-2782-3047; E-mail: bmcys{at}ibms.sinica.edu.tw.
The role of the familial breast cancer susceptibility genes, BRCA1 and BRCA2, in the homologous recombination (HR) pathway for DNA double-strand break (DSB) repair suggests that the mechanisms involved in HR and DNA DSB repair are of etiological importance during breast tumorigenesis. BLM helicase directly interacts with RAD51 recombinase, which is involved in regulating HR, and it is thus of particular interest to examine whether this interaction is associated with breast cancer susceptibility. This single nucleotide polymorphism (SNP)-based case-control study was performed to examine this hypothesis using specimens from 933 patients with breast cancer and 1,539 healthy controls. The results showed that one SNP (rs2380165) in BLM and two (rs2412546 and rs4417527) in RAD51 were associated with breast cancer risk. Furthermore, haplotype and diplotype analyses based on combinations of five SNPs in RAD51 revealed a strong association between RAD51 polymorphisms and breast cancer risk (p < 0.05). Support for the interaction between BLM and RAD51 in determining breast cancer risk came from the finding that the association between cancer risk and at-risk genotypes/haplotype pairs of RAD51 was stronger and more significant in women harboring homozygous variant alleles of BLM (p for interaction <0.05). Interestingly, not only the intronic SNP located within the region encoding the helicase domain of BLM, but also those within the RAD51-interaction domain-encoding region showed an interaction with RAD51 polymorphisms in determining breast cancer susceptibility. Our results suggest a contribution of BLM and RAD51 to breast cancer development and provide support for the tumorigenic significance of the functional interaction between these two HR proteins.
Key Words: BLM • RAD51 • Breast cancer • Single nucleotide polymorphism
Received July 1, 2008; revised September 9, 2008; accepted September 30, 2008.
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