@article {Chan32, author = {K Y-K Chan and W Liu and J-R Long and S-P Yip and S-Y Chan and X-O Shu and D T-T Chua and A N-Y Cheung and J C-Y Ching and H Cai and G K-H Au and M Chan and W Foo and H Y-S Ngan and Y-T Gao and E S-W Ngan and M-M Garcia-Barcel{\'o} and Wei Zheng and U-S Khoo}, title = {Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women}, volume = {46}, number = {1}, pages = {32--39}, year = {2009}, doi = {10.1136/jmg.2007.057174}, publisher = {BMJ Publishing Group Ltd}, 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{\textrightarrow}C (rs799908:T{\textrightarrow}C), c.-2265C{\textrightarrow}T (rs11655505:C{\textrightarrow}T), c.-2004A{\textrightarrow}G (rs799906:A{\textrightarrow}G) and c.-1896(ACA)1{\textrightarrow}(ACA)2 (rs8176071:(ACA)1{\textrightarrow}(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{\textrightarrow}T, which could affect susceptibility to breast cancer in the Chinese population. Its significance in other populations remains to be investigated.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/46/1/32}, eprint = {https://jmg.bmj.com/content/46/1/32.full.pdf}, journal = {Journal of Medical Genetics} }