Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility.
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.
Ding
Shian-Ling
SL
Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan. slding@knjc.edu.tw
Yu
Jyh-Cherng
JC
Chen
Shou-Tung
ST
Hsu
Giu-Cheng
GC
Kuo
Shou-Jen
SJ
Lin
Yu Hsin
YH
Wu
Pei-Ei
PE
Shen
Chen-Yang
CY
D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D051135:Rad51 Recombinase / Q000235:genetics*; D053484:RecQ Helicases / Q000235:genetics*; D011995:Recombination, Genetic
C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C097151:Bloom syndrome protein; D053484:RecQ Helicases