| Breast cancer(breast cancer) is a common invasive malignancy harming woman’s health, and ranks second among the world-widely cancer death for women. Its incidence is raising year by year, especially in some of the developed provinces, its incidence ranks first, a serious threat to woman’s health.The incidenece and development of breast cancer is a complex event involving multi-process and multi-genes, and its pathogenesis still remains a mystery. In normal mammary epithelial breast cancer, malignant transformation process, is not only related to the various environmental factors, but also closed to the genetic factors. Exposed to the same carcinogenic factors, only a small number of people will get breast cancer, suggesting that the incidence and development of breast cancer are closely related to an individual’s genetic background Currently, looking for breast cancer susceptibility genes, and screening for single nucleotide polymorphisms(single nucleotide polymorphism, SNP) sites of breast cancer susceptibility gene, have become a hot topic of breast cancer research foundation. For example, incidence of breast cancer will be greatly enhanced if the four rare high penetrance genes, BRCA1, BRCA2, TP53 and PTEN are subject to mutation. However, mutations in these genes can explain only about 10% of the genetic factors, and suggest that there are other onsets associated with breast cancer susceptibility genes. In recent years, the development of genome-wide association analysis(GWAS) has provided the possibility for the study of the loci with low penetrance and high mutaion, and identified about 52 common low penetrance genes, such as FGFR2, MAP3K1, TOX3, ESR1, etc.ESR1, found by Jensen in 1971, an estrogen-dependent transcription factor, also a member of the nuclear receptor super- family, through binding to estrogen and breast cancer metastasis to the nucleus, signaling pathways involved in the regulation of gene transcription, thus contributing to the proliferation of breast cancer cells. Many anticancer drugs in clinic use and control this node to interfere or block a combination of both, for treatment of breast cancer. ER expression is also a significant predictor to decide whether to choose the hormone therapy clinically. In addition, ESR1 has also been co- regulated by BRCA1 and BRCA2, hence an important predisposing gene in the pathogenesis of breast cancer. SNP loci of this gene may play an important role in the development of breast cancer, but many of the results reported are not consistent. And because of breast cancer with a high degree of genetic heterogeneity, different regions and different ethnic groups may have different genetic susceptibility genes and different single nucleotide relationship between the gene locus and the incidence of breast cancer among different populations, including Asians, Europeans and Africans, but there are some contradictions among the results of these studies.There are no reports about the correlation between ESR1 gene polymorphisms and risk of breast cancer in Anhui Han women, nor about the single nucleotide polymorphisms 6 q25.1 rs2046210 and Meta-analysis of breast cancer risk. Therefore, we hope to have a systematic analysis through this study. This study consists of two parts: the first part in Anhui Han women, through case-control study, Sequencing genotyping technology is used to explore the relationship between the risk of breast cancer and polymorphism of SNP of ESR1 gene(rs2046210 and rs3798759). In the second part, meta-analysis is used to give a comprehensive evaluation about the correlation between 6 q25.1 rs2046210 single nucleotide polymorphisms and the risk of breast cancer, to find the molecular markers susceptible for population screening, and thus provides the basis for clinical diagnosis and individual select treatment programs.PartⅠ Initial research on relationship between rs3798759 and rs2046210 gene polymorphisms and risk of breast cancerObjective: To explore the correlation between the main sites of rs3798759 ESR1 gene and gene rs2046210 single nucleotide polymorphisms and risks of breast cancer prevalence in Anhui Han.Methods: Two screened by GWAS ESR1 gene is located on the main site rs3798759 SNP and rs2046210. A case- control design, enrolling a total of 183 cases in Anhui Han women with breast cancer and 146 cases of age-matched healthy Han women, explore the relationship between this site and breast cancer of Hnhui women. Application of Sequencing genotyping technology probes the polymorphism genotyping, gene T allele frequency of breast cancer patients and healthy comparison group rs3798759 locus allele T / G, and rs2046210 locus G / C and genotype, while using the chi-square test and non-conditional logistic regression analysis of rs3798759 and rs2046210 and association analysis of breast cancer. Calculate the odds ratio(odds ratio, OR) and 95% confidence intervals(confidence interval, CI) to evaluate the single nucleotide polymorphisms and the risk of breast cancer by relevance.Results:1. By the Hardy-Weinberg equilibrium genetic testing, found that rs2046210 alleles T, C and genotype CC, TT, TC hereditary distributed in groups no significant difference between groups with a representative. Rs2046210 alleles T, C allele in breast cancer group was 43.32%, 56.68%, in the distribution of normal healthy group was 40.39% frequency, 59.61%. There was no significant difference(P> 0.05) of the two groups. As a reference to the allele C, the OR(95% CI) of T allele in the healthy group and breast cancer groups is 1.12(0.74-1.71). Both groups compared with each other P> 0.05, not statistically significant. Genotype polymorphism loci CC, TT, TC is in the frequency of breast cancer were 44.69%, 41.68% and 13.63%, 42.32% healthy group, 36.86% and 20.82%, comparing the distribution of the frequency of the two groups was significant difference(P <0.05). And the frequency of rs2046210-TC genotype distribution in breast cancer was significantly lower than the normal healthy group. Risk Specifically, this site carrying TC genotype of people suffering from breast cancer compared with TT and CC genotypes carrying low, OR values(95% CI) 0.68( 0.42-1.53).2. By Hardy-Weinberg equilibrium genetic testing, found that rs3798759 alleles T, G and genotype TT, GG, GT hereditary no significant difference in the distribution of the population, with a population representative. Rs3798579 alleles T, G allele in breast cancer group was 46.59%, 53.41%, in the distribution of the frequency of normal healthy group was 40.61%, 59.39%. There was no significant difference(P> 0.05) the two groups. As a reference to the allele T allele G OR values(95% CI) in the healthy group and the group of breast cancer was 1.08( 0.69-1.72). There was no significant difference(P> 0.05) the two groups. TT genotype polymorphic loci-GG, GT allele in breast cancer were 45.50%, 12.26% and 42.24%, 40.95% respectively, healthy group, 20.48% and 38.57%, the distribution of the two groups frequency significant difference(P <0.05). And rs3798759-GG genotype frequencies in the breast cancer group were significantly lower than the normal healthy group. Risk Specifically, this site carrying GG genotype of people suffering from breast cancer compared with TT and GT genotypes carrying low, OR values(95% CI) was 0.81( 0.47-1.63).Conclusion:1 by the Hardy-Weinberg equilibrium genetic testing, the sample, we selected, has a good description of the group representative.2. Rs2046210 and rs3798759 in the ESR1 us allele frequency distribution was no significant difference in breast cancer patients and healthy groups.3. Rs2046210 sites in breast cancer patients and healthy control groups for each genotype frequencies were significantly different. And rs2046210-TC genotype may reduce the incidence of breast cancer.4. Rs3798759 in breast cancer patients and healthy control groups for each genotype frequencies were also significant differences. And rs3798759-GG genotype may reduce the incidence of breast cancer.Part Ⅱ Meta analysis of the association between single nucleotide polymorphisms 6q25.1 rs2046210 and breast cancer Objective: breast cancer is the most common cancer in women, its etiology is not fully clear. Many researchers of single nucleotide polymorphisms 6 q25.1 rs2046210 are interested in their relationship, and studied, but the results appeared contradiction, some research results show that single nucleotide polymorphisms 6 q25.1 rs2046210 and breast cancer have close relationship, others have no such relationship. In order to make clear understanding of the relationship between rs2046210 segments of single nucleotide polymorphism and breast cancer, and search for the clinical significance of molecular markers and therapeutic targets, we investigate the relationship between the single nucleotide polymorphism of 6 q25.1 rs2046210 and breast cancer through meta analysis.Methods: In Pubmed, EMBASE and science in English web search the relationship between rs2046210 at 6 q25.1 single nucleotide polymorphism fragments and breast cancer, searching keywords in English as "6q25.1", "rs2046210", "SNP", "single nucleotide polymorphism", "variant" and "breast cancer". In the CNKI database, use "6q25.1", "rs2046210" and "breast cancer" inscription search. Retrieve the deadline for April 2013. All meet the requirements of the retrieved documents were confirmed, review and review types of literature outside the scope of research. Included in the meta-analysis research literature is in line with the following criteria:(1) to evaluate rs2046210 at 6 q25. 1 and the correlation of disease,(2) the study is designed to control study,(3) there is enough data to evaluate the OR and 95% CI. Same researchers on the study of many of the same data and overlapping data, we use the latest and most participants in the research. All the data extraction by two researchers according to the standard of selected literature independent extract, extract data from each document include: the name of the first author, published in the year, published by the national, ethnic division, the source of the control group, the number of samples, cases and controls the total number of types of genes and research group and the control group. Ethnicity for Europe, Asia and Africa, the content of this research to the different ethnic groups, the data extracted from different ethnic groups as far as possible. All data using STATA11.0 software package for processing. In the control group and experimental group risk alleles and, on the basis of gene frequencies rs2046210 at 6 q25. 1 and breast cancer risk is evaluated using the correlation of the OR values and 95% confidence interval. Subgroup analysis of the main base including ethnicity, sample size(< 0-3000300 to 8000, > 3000300) and the control group. Merge the OR inspection using Z, P < 0.05 difference is statistically significant, with the model of random effects meta-analysis data processing [22], when P > 0.10 the Q test show that there are homogeneity in the study; Otherwise, use the heterogeneity between the fixed effects model analysis. With intuitive funnel figure check for publication bias, using linear regression test small study effects. In addition, the sensitivity analysis of the hardy- arsene wenger(HWE) to include and exclude research study.Results: this study use the retrieved 113 references, as shown in figure S1. According to the inclusion and exclusion criteria, excluding the 99 articles, a total of 14 articles were included in the Meta analysis. 14 articles were all included in the Meta analysis study including 123085 cases of breast cancer patients, 123085 cases of controls, eight of them adopt the European people, nine adopt the Asian people, three research USES is the African people. The results found in all the crowd the segments of single nucleotide polymorphisms and the risk of breast cancer significantly correlation(A- alleles vs the G allele: OR = 1.20, 95% CI = 1.15 1.25, heterogeneity level(P < 0.0001; AA/GA vs. GG: OR = 1.22, 95% CI = 1.16 1.28, heterogeneous level of P < 0.0001; AA vs. GA/GG: OR = 1.18, 95% CI = 1.13 1.24, heterogeneous level of P < 0.064). Heterogeneity between levels in some studies, however, have significant differences, therefore, we according to the ethnicity several subgroups. We people in Europe and Asia, the crowd found 6 q25. 1 rs2046210 has an important correlation and breast cancer risk, including the European population statistical value of A- alleles vs the G allele: OR = 1.10, 95% CI = 1.07 1.14, P = 0.002; heterogeneity level AA/GA vs. GG: OR = 1.13, 95% CI = 1.09 1.17, heterogeneity level P = 0.039; AA vs. GA/GG: OR = 1.11, 95% CI = 1.08 1.14, heterogeneity level P = 0.335; Asian population statistical value of A- alleles vs the G allele: OR = 1.29, 95% CI = 1.25 1.34, heterogeneity level P = 0.283; AA/GA vs. GG: OR = 1.36, 95% CI = 1.31 1.42, heterogeneity level P = 0.458; AA vs. GA/GG: OR = 1.36, 95% CI = 1.28 1.44, heterogeneity, P = 0.265 level. In the current study, however, there is no good data to prove rs2046210 and breast cancer risk in African people. According to the number of samples into several subgroups of the text(sample group and details in small sample groups, groups) are studied, from these segments subgroups of important research results: we got the small sample groups, OR = 1.29, 95% CI = 1.19 1.40, P = 0.012; heterogeneity level In the sample group, OR = 1.16, 95% CI = 1.07 1.26, P = 0.53; heterogeneity level Details groups: OR = 1.12, 95% CI = 1.09 1.16, heterogeneity, P = 0.003 level. In the control group on the basis of further analysis, get the following results based on the research of hospital controlled crowd OR = 1.28, 95% CI = 1.12 1.43, heterogeneity level P < 0.0001; Based on the research of community people OR = 1.18, 95% CI = 1.10 1.27, heterogeneity level(P < 0.0001; Based on the research of hospital and community groups OR = 1.12, 95% CI = 1.09 1.15, heterogeneity, P = 0.036 level.Conclusion: 6q25.1 rs2046210 single nucleotide polymorphisms and breast cancer risk are highly correlated, especially in Asia and European populations. |
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