ORIGINAL ARTICLES

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

K Y-K Chan¹, W Liu^1,2, J-R Long³, S-P Yip⁴, S-Y Chan^1,5, X-O Shu³, D T-T Chua⁵, A N-Y Cheung¹, J C-Y Ching¹, H Cai³, G K-H Au⁵, M Chan⁶, W Foo⁷, H Y-S Ngan⁸, Y-T Gao⁹, E S-W Ngan¹⁰, M-M Garcia-Barceló¹⁰, Wei Zheng³, U-S Khoo¹

¹ Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
² Department of Pathology, First Affiliated Hospital of Soochow University, Suzhou
³ Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA
⁴ Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong SAR, China
⁵ Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
⁶ Department of Surgery, Kwong Wah Hospital, Hong Kong SAR, China
⁷ Department of Clinical Oncology, Queen Elisabeth Hospital, Hong Kong SAR, China
⁸ Department of Obstetrics and Gynecology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
⁹ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
¹⁰ Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China

Dr U-S Khoo, Room 324, 3/F, University Pathology Building, Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China; uskhoo{at}pathology.hku.hk

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.-2804TC (rs799908:TC), c.-2265CT (rs11655505:CT), c.-2004AG (rs799906:AG) 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.-2265CT, which could affect susceptibility to breast cancer in the Chinese population. Its significance in other populations remains to be investigated.

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