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Functional polymorphisms in the promoter of BRCA1 influences transcription and are associated with decreased risk for breast cancer in Chinese women
  1. Kelvin Yuen Kwong Chan (kelvinc{at}pathology.hku.hk)
  1. The University of Hong Kong, Hong Kong
    1. Wei Liu (liuwei{at}pathology.hku.hk)
    1. The University of Hong Kong, Hong Kong
      1. Ji-Rong Long (jirong.long{at}vanderbilt.edu)
      1. Vanderbilt University, United States
        1. Shea-Ping Yip (htspyip{at}inet.polyu.edu.hk)
        1. The Hong Kong Polytechnic University, Hong Kong
          1. Sum-Yin Chan (ann_chan81{at}hotmail.com)
          1. The University of Hong Kong, Hong Kong
            1. Xiao-Ou Shu (xiao-ou.shu{at}vanderbilt.edu)
            1. Vanderbilt University, United States
              1. Daniel Tsin-Tien Chua (dttchua{at}hkucc.hku.hk)
              1. The University of Hong Kong, Hong Kong
                1. Annie Nga-Yin Cheung (anycheun{at}pathology.hku.hk)
                1. The University of Hong Kong, Hong Kong
                  1. Johannes Chi-Yun Ching (johannes{at}pathology.hku.hk)
                  1. The University of Hong Kong, Hong Kong
                    1. Hui Cai (hui.cai{at}vanderbilt.edu)
                    1. Vanderbilt University, United States
                      1. Gordon Kwok-Hung Au (gkhau{at}ha.org.hk)
                      1. The University of Hong Kong, Hong Kong
                        1. Miranda Chan (cemc{at}tungwah.org.hk)
                        1. Kwong Wah Hospital, Hong Kong
                          1. William Foo (wfoofoow{at}netvigator.com)
                          1. Queen Elizabeth Hospital, Hong Kong
                            1. Hextan Yuen-Sheung Ngan (hysngan{at}hkucc.hku.hk)
                            1. The University of Hong Kong, Hong Kong
                              1. Yu-Tang Gao (ytgao{at}vip.sina.com)
                              1. Shanghai Cancer Institute, China
                                1. Elly Sau-Wai Ngan (engan{at}hkucc.hku.hk)
                                1. The University of Hong Kong, Hong Kong
                                  1. Maria-Merce Garcia-Barcelo (mmgarcia{at}hkucc.hku.hk)
                                  1. The University of Hong Kong, Hong Kong
                                    1. Wei Zheng (wei.zheng{at}vanderbilt.edu)
                                    1. Vanderbilt University, United States
                                      1. Ui-Soon Khoo (uskhoo{at}pathology.hku.hk)
                                      1. The University of Hong Kong, Hong Kong

                                        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.

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