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Carcinogenesis Advance Access originally published online on October 28, 2008
Carcinogenesis 2009 30(1):43-49; doi:10.1093/carcin/bgn233
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility

Shian-ling Ding*, Jyh-Cherng Yu1, Shou-Tung Chen2, Giu-Cheng Hsu3, Shou-Jen Kuo2, Yu Hsin Lin4, Pei-Ei Wu4,5 and Chen-Yang Shen4,5,6,7,**

Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei 11485, Taiwan
1 Department of Surgery, Tri-Service General Hospital, Taipei 11472, Taiwan
2 Department of Surgery, Changhua Christian Hospital, Changhua 50006, Taiwan
3 Department of Radiology, Tri-Service General Hospital, Taipei 11472, Taiwan
4 Institute of Biomedical Sciences
5 Section of Medical Genetics, Taiwan Biobank
6 Life Science Library, Academia Sinica, Taipei 11529, Taiwan
7 Graduate Institute of Environmental Science, China Medical University, Taichong 40402, Taiwan

* To whom correspondence should be addressed. Tel: +886 2 26321181 ext. 257; Fax: +886 2 2364 9857; Email: slding{at}knjc.edu.tw

** Correspondence may also be addressed to Chen-Yang Shen. Tel: +886 2 2789 9036; Fax: +886 2 2782 3047; Email: 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. Bloom (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 1539 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.

Abbreviations: BLM, Bloom; DSB, double-strand break; HR, homologous recombination; LD, linkage disequilibrium; SNP, single-nucleotide polymorphism

Received July 1, 2008; revised September 9, 2008; accepted September 30, 2008.


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