Associations Between Genetic Variations On Chromosome6q25，CDC27gene And Risk Of Breast Cancer In Chinese Han Population

Objective:1. To explore the association between the genetic polymorphism (rs2046210) in6q25region and the risk of breast cancer in Chinese Han population and then to validate theassociation through meta-analysis.2. To evaluate the association of rs2046210with breast cancer stratified by differentethnicity, estrogen receptor and menopausal status.3. To explore the association between six tag SNPs on CDC27gene and the risk of breastcancer in Chinese Han population and evaluate the effect of different haplotype on the riskof breast cancer by haplotype analysis.Methods: A hospital-based case-control study was conducted initially, the cases wereprimary breast cancer and the controls that frequently age-matched to the cases wererandomly selected from a health check-up program during the same period. The genotypeof rs2046210was carried out using the Taqman SNP Genotyping Assay and the haplotypescomposing the six SNPs were estimated using PHASE2.0.2. The association between eachpolymorphism or haplotype and breast cancer risk was evaluated by SPSS12.0. Wesearched Pubmed, EMBASE, ISI Web of Science databases and CNKI for literaturesconcern with rs2046210and breast cancer published in any language up to June2012. Thenwe extracted the data according to the inclusive and excluded criteria and conducted themeta-analyses using statistical software STATA10.0.Results:1. The general information: in Part I, a total of461incident cases and537controls wereenrolled, and in Part III,432cases and527controls were enrolled. Genotypes in controlswere consistent with the Hardy-Weinberg equilibrium. The age of cases and controls in twoparts has no significant difference (P>0.05). 2. Association analysis: A multivariate logistic regression model demonstrated that thepolymorphism rs2046210G>A variation presented a significantly elevated risk of breastcancer with an OR value of1.32(95%CI=1.10-1.59，P=0.003) after adjusting for age andmenopausal status. Meanwhile，rs11570443T>C and rs12601027C>T variation on CDC27gene also increase the breast cancer risk with ORs of1.734（95%CI=1.135-2.649，P=0.011）and1.275（95%CI=1.062-1.530，P=0.009）.The haplotype analysis of six SNPsshowed that haplotypes T-C-T-C-G-C was significantly associated with increased risk ofbreast cancer with OR of2.08(95%CI=1.25-3.45, P=0.005).3.23potentially relevant publications were identified through searching the data bases,10publications were finally enrolled. Plus the current study, a total of36studies consisting of53,379cases and55,493controls were included in this meta-analysis based on our searchstrategy and eligibility criteria.4. In overall meta-analysis, A allele conferred a pooled OR of1.14(95%CI=1.10-1.18, P<0.001) compared to G allele. After stratifying by ethnicity, the rs2046210G>A variationpresented a significantly increased risk of breast cancer in Asian and European populations,with pooled ORs of1.27（95%CI=1.23-1.31, P <0.001）and1.09（95%CI=1.07-1.12, P<0.001）, however, there was no obvious association between the SNP and breast cancerrisk in the African population in any genetic model. When we subsequently stratified thedata by ER and menopausal status, the pooled ORs of A VS. G were1.23(95%CI=1.14–1.32, P <0.001) in the ER negative population and1.12(95%CI=1.04–1.20, P=0.002) in the ER positive population. After comparing to cases with ER positive breastcancer, the OR (95%CI) for ER negative breast cancer was1.11(95%CI=1.06–1.15, P=8.27×10-7） for allelic model. Conclusion:1. The common polymorphism located in6q25region, rs2046210, is associated with anincreased risk of breast cancer in Chinese Han population.2. rs2046210is associated with an increased risk of breast cancer in Asian and Europeanpopulations but not in Africans and this association is more significant in ER negative thanin ER positive breast cancer.3. The common polymorphisms located in CDC27gene, rs11570443and rs12601027, areassociated with an increased risk of breast cancer in Chinese Han population. Meanwhile,haplotypes C-C-T-C-G-T and C-C-C-C-G-T significantly increased breast cancer risk.4. All the association studies above are based on the statistical analysis and could onlyprovide epidemiology clues for the etiology of breast cancer. The underlying biologicalmechanism of them still needs further investigation.