BRCA1 gene promoter polymorphisms associated with breast cancer risk

Abstract

Inherited mutations in the BRCA1 gene predispose to breast and ovarian cancer but account for less than 10% of all breast cancers. Low penetrance alleles of coding exon single nucleotide polymorphisms (SNPs) have previously been shown to influence susceptibility. We hypothesized that BRCA1 promoter SNPs may contribute to breast cancer susceptibility by changing the transcriptional activity and subsequently altering the expression level of the gene. Direct sequencing of the promoter region on ten Chinese individuals identified two previously unreported polymorphisms, -600 (ACA)1/(ACA)2 and -969 C/T. Genotyping was performed on 275 breast cancer cases and 275 age matched case-control Hong Kong Chinese subjects. The -600 (ACA)1/(ACA)2 was genotyped by GeneScan whilst that of -969 C/T was done by denaturing high performance liquid chromatography (DHPLC). Statistical significant difference was found in the overall genotypes between the cancer and control groups for both polymorphisms, p=0.033 for the ACA repeats and p<0.0001 for the -969 C/T SNP. (ACA)2-allele carriers demonstrated 0.67-fold less risk for breast cancer (OR=0.67, 95%CI =0.46-0.96) whilst T allele carriers showed 0.28-fold less risk (OR=0.28, 95%CI=0.18-0.43). Moreover homozygous T-carriers had significant reduced risk compared with homozygous C-carriers: OR=0.25, 95%CI=0.14-0.47. The two polymorphisms studied are highly in linkage disequilibrium in both cancer and control groups (D’=0.90 and 0.87, respectively). Overall analysis of the four haplotypes showed statistically significant difference between the cancer and control groups (p< 0.0001). The T-(ACA)1 and T-(ACA)2 haplotypes taken together gave significant lower breast cancer risk (p<0.0001, OR=0.47, 95%CI=0.35-0.63) when compared to the other two haplotypes. Our results support the contribution of BRCA1 promoter polymorphisms to breast cancer susceptibility. Transfection studies are currently underway to demonstrate these two promoter polymorphisms can influence expression level of the BRCA1 gene.