Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women

• Published in: Journal of medical genetics Vol. 46; no. 1; pp. 32 - 39
• Main Authors: Chan, K Y-K, Liu, W, Long, J-R, Yip, S-P, Chan, S-Y, Shu, X-O, Chua, D T-T, Cheung, A N-Y, Ching, J C-Y, Cai, H, Au, G K-H, Chan, M, Foo, W, Ngan, H Y-S, Gao, Y-T, Ngan, E S-W, Garcia-Barceló, M-M, Zheng, Wei, Khoo, U-S
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.01.2009; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Asian Continental Ancestry Group - genetics; Binding Sites; Biological and medical sciences; BRCA1 Protein - genetics; Breast cancer; Breast Neoplasms - epidemiology; Breast Neoplasms - genetics; Case-Control Studies; China - epidemiology; Cohort Studies; Electrophoretic Mobility Shift Assay; Female; Fundamental and applied biological sciences. Psychology; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Gynecology. Andrology. Obstetrics; Hong Kong - epidemiology; Humans; Mammary gland diseases; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Polymorphism; Polymorphism, Genetic - genetics; Promoter Regions, Genetic - genetics; Risk Factors; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Tumors; Womens health; Hong Kong; China; Hong Kong China; United States > US; Human; Breast disease; Transcription; Risk; Breast cancer; Malignant tumor; Promoter; Mammary gland diseases; Association; Risk factor; Chinese; Genetics; Woman; Cancer; Tumor suppressor gene; Polymorphism
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2007.057174

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.