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Title: Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women
Authors: Chan, KYK
Liu, W
Long, JR
Yip, SP 
Chan, SY
Shu, XO
Chua, DTT
Cheung, ANY
Ching, JCY
Cai, H
Chan, M
Foo, W
Ngan, HYS
Gao, YT
Ngan, ESW
Garcia-Barcelo, MM
Zheng, W
Khoo, US
Issue Date: 2009
Publisher: BMJ Publishing Group Ltd
Source: Journal of medical genetics, 2009, v. 46, no. 1, p. 32-39 How to cite?
Journal: Journal of medical genetics 
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: Using 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 polymorphism was studied independently and in combination by functional assays. Although all four variants significantly altered promoter activity, the c.-2265T allele had 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 Hong Kong Chinese women with breast cancer and age-matched controls and replicated in a large population-based study of Shanghai Chinese, together totalling >3000 participants, showed that carriers of the c.-2265T allele had a reduced risk for breast cancer (combined odd ratio (OR) = 0.80, 95% CI 0.69 to 0.93; p = 0.003) which was more evident among women aged ≥45 years at first diagnosis of breast cancer and without a family history of breast cancer (combined OR = 0.75, 95% CI 0.61 to 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 a family history of breast cancer (OR = 0.64, 95% CI 0.46 to 0.89; p = 0.008).
Conclusion: This comprehensive study of BRCA1 promoter polymorphisms found four variants that 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.
DOI: 10.1136/jmg.2007.057174
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