title: Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women.
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.
  
  
  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 >or=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 >or=45 years without a family history of breast cancer (OR = 0.64, 95% CI 0.46 to 0.89; p = 0.008).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
authors.forename: K Y-K
authors.initials: KY
authors.lastname: Chan
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: J-R
authors.initials: JR
authors.lastname: Long
authors.forename: S-P
authors.initials: SP
authors.lastname: Yip
authors.forename: S-Y
authors.initials: SY
authors.lastname: Chan
authors.forename: X-O
authors.initials: XO
authors.lastname: Shu
authors.forename: D T-T
authors.initials: DT
authors.lastname: Chua
authors.forename: A N-Y
authors.initials: AN
authors.lastname: Cheung
authors.forename: J C-Y
authors.initials: JC
authors.lastname: Ching
authors.forename: H
authors.initials: H
authors.lastname: Cai
authors.forename: G K-H
authors.initials: GK
authors.lastname: Au
authors.forename: M
authors.initials: M
authors.lastname: Chan
authors.forename: W
authors.initials: W
authors.lastname: Foo
authors.forename: H Y-S
authors.initials: HY
authors.lastname: Ngan
authors.forename: Y-T
authors.initials: YT
authors.lastname: Gao
authors.forename: E S-W
authors.initials: ES
authors.lastname: Ngan
authors.forename: M-M
authors.initials: MM
authors.lastname: Garcia-Barceló
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: U-S
authors.initials: US
authors.lastname: Khoo
mesh_terms: D044466:Asian People / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D015331:Cohort Studies; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006723:Hong Kong / Q000453:epidemiology; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014157:Transcription Factors
references.citation: J Biol Chem. 1999 Mar 26;274(13):8837-43
references.pmid: 10085126
references.citation: Breast Cancer Res Treat. 2005 May;91(2):179-86
references.pmid: 15868446
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8638-43
references.pmid: 11438703
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 Aug;13(8):1290-5
references.pmid: 15298948
references.citation: Clin Chem. 2003 Oct;49(10):1656-9
references.pmid: 14500591
references.citation: Hum Mol Genet. 1997 Feb;6(2):285-9
references.pmid: 9063749
references.citation: Carcinogenesis. 2000 Sep;21(9):1761-5
references.pmid: 10964110
references.citation: Int J Cancer. 1998 Jul 3;77(1):1-6
references.pmid: 9639385
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Nucleic Acids Res. 1998 Jan 1;26(1):362-7
references.pmid: 9399875
references.citation: Cancer Res. 2004 Oct 15;64(20):7622-8
references.pmid: 15492291
references.citation: Hum Mol Genet. 1995 Dec;4(12):2259-64
references.pmid: 8634696
references.citation: Cancer Res. 2003 Sep 15;63(18):5727-30
references.pmid: 14522892
references.citation: N Engl J Med. 1997 May 15;336(20):1409-15
references.pmid: 9145677
references.citation: Nat Rev Cancer. 2007 Dec;7(12):937-48
references.pmid: 18034184
references.citation: Hum Mol Genet. 2005 Jan 15;14(2):191-204
references.pmid: 15548547
references.citation: Oncogene. 1999 Aug 12;18(32):4643-6
references.pmid: 10467410
references.citation: Breast Cancer Res. 2005;7(2):R171-5
references.pmid: 15743496
references.citation: J Biol Chem. 1997 Aug 22;272(34):20994-7
references.pmid: 9261099
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Jun;15(6):1148-52
references.pmid: 16775174
references.citation: Int J Cancer. 2000 Jul 15;87(2):295-300
references.pmid: 10861490
references.citation: Breast Cancer Res Treat. 2007 Nov;106(1):121-6
references.pmid: 17431766
references.citation: J Natl Cancer Inst. 2001 Aug 15;93(16):1215-23
references.pmid: 11504767
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Nucleic Acids Res. 2000 Sep 1;28(17):3233-9
references.pmid: 10954590
references.citation: Nat Genet. 1995 Apr;9(4):444-50
references.pmid: 7795653
references.citation: Cancer Res. 2005 Aug 15;65(16):7516-22
references.pmid: 16103107
references.citation: Cancer Res. 2002 Jul 15;62(14):4151-6
references.pmid: 12124354
references.citation: Science. 2003 Oct 24;302(5645):643-6
references.pmid: 14576434
references.citation: Am J Hum Genet. 1998 Mar;62(3):676-89
references.pmid: 9497246