The functional -969C/T promoter polymorphism in BRCA1 decreases breast cancer risk in Chinese women

Abstract

BRCA1 is an important breast cancer susceptibility gene. As promoter polymorphisms can alter the binding site and transcriptional activity of genes and affect susceptibility to disease, we evaluated the association of BRCA1 promoter polymorphisms with breast cancer risk. Polymorphisms in the promoter region of BRCA1 were identified from dbSNP and by direct sequencing of 20 Chinese individuals. Four polymorphisms, -1508 T/C, -969 C/T, -708 A/G and -600 (ACA)1/(ACA)2, were identified and initially evaluated in 390 pairs of cases and controls from Hong Kong. Statistical significant genotype and allelic associations were found for the -969 C/T polymorphism but not for the other three polymorphisms. Haplotype containing -969 T showed lower risk for breast cancer, the association was stronger in older women (OR=0.70; 95% CI: 0.51-0.96). Individuals carrying the -969 CT or TT genotype, had a reduced risk for breast cancer (OR=0.64; 95% CI=0.47-0.88, p=0.005), and the association was more evident among older women (aged over 45 years) who did not have a family history of breast cancer (OR=0.51, 95%CI=0.32 - 0.81). This association was replicated on a large population-based case-control group of Chinese consisting of 1109 cases and 1185 controls recruited from Shanghai, adjusted OR=0.85 for all women and OR=0.79 (95%CI=0.63 - 0.99) for older women without a family history of breast cancer. Test of heterogeneity comparing the reduced odds ratio between these two populations did not demonstrate any significant difference (p=0.110), allowing for test for overall association based on these two populations. The combined OR=0.75, 95%CI=0.61-0.91; p=0.0037 thus confirms the reduced risk in older women without family history of breast cancer. Preliminary analysis of luciferase reporter promoter activity assay showed that the BRCA1 promoter containing the -969T allele demonstrated 1.7-fold increased activity. Our results suggest that BRCA1 promoter polymorphisms contribute to breast cancer susceptibility, particularly in older women without family history of breast cancer.