Abstract

Background: The BRCA1 gene is an important breast cancer susceptibility gene. Promoter polymorphisms can alter the binding affinity of transcription factors, changing transcriptional activity and may affect susceptibility to disease.

Methods and Results: By direct sequencing of the BRCA1 promoter region, we identified four polymorphisms c.-2804T>C (rs799908:T>C), c.-2265C>T (rs11655505:C>T), c.-2004A>G (rs799906:A>G) and c.-1896(ACA)₁/(ACA)₂ (rs8176071:(ACA)₁/(ACA)₂) present in Hong Kong Chinese. Each was studied independently and in combination by functional assays. While all four variants significantly altered promoter activity, the c.-2265T allele most clearly provided stronger binding than the C allele and the most common mutant haplotype which contains the c.-2265T allele increased promoter activity by 70%. Risk association first tested in breast cancer cases and age-matched controls of Hong Kong Chinese women and replicated in a large population-based study of Shanghai Chinese, altogether totaling over 3,000 subjects, demonstrated the c.-2265T allele carriers had a reduced risk for breast cancer (combined ORs=0.80, 95%CI=0.69-0.93; p=0.003) which was more evident among women aged ≥45 years at first diagnosis of breast cancer and without family history of breast cancer (combined ORs=0.75, 95%CI=0.61-0.91; p=0.004). The most common haplotype containing the c.-2265T allele also showed significant risk association for women aged ≥45 years without family history of breast cancer (ORs=0.64, 95%CI=0.46-0.89; p=0.008).

Conclusion: Our comprehensive study of BRCA1 promoter polymorphisms demonstrated four variants which altered promoter activity, and with the most significant contribution from c.-2265C>T, which could affect susceptibility to breast cancer in the Chinese population. Its significance in other populations remains to be investigated.