Association Study Of SNPs Within MicroRNA Binding Sites And Prognosis Of Breast Cancer

ObjectBreast cancer is the most common malignant tumors and causes the leading cancer-related death in women. Prognosis of breast cancer is influenced by interaction of environmental factors, behavioral factors and hereditary factors. Multiple studies have confirmed significant roles of genetic variance within micro RNA binding sites in the development of cancer. The genetic variance had effects on the expression of target genes. If the genes involves in cells migration and invasion, the genetic variance would impact clinical outcome of patients. Our study screened out genowide SNP within micro RNA binding sites and detected different survival in the genetic variance of breast cancer patients. In order to provide a clue to predict clinical outcome of breast cancer patients precisely, we explore the association of SNP within micro RNA binding sites and prognosis of breast cancer patients.Methods1. Screening of genowide micro-RNA binding sequences seed region SNP. According to genowide association study strategy, 192 SNPs were identified from the “Patrocles” database and all over 22 euchromosome. All the selected SNPs met the following standards: the SNPs located in the micro RNA seed region; datas on Chinese or at least Asian were available; minimum genotype frequency was more than 0.05. 2. Patients resource. Subjects enrolled in our study were diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital since January 1, 2006. Finally, a total of 2647 new cases were included in this study. The study was divided into two stages. In Stage?, 1297 cases were selected and 1350 cases in stage ?. 3. Experimental methods. In Stage?, we used custom Illumina Golden Gate Vera Code assaying on the Illumina Bead Xpress platform to detect genotype distribution among 192 SNPs. In stage ?, Taqman genotyping technique was applied to detect SNP genotype distribution selected from Stage?. 4. Follow-up. 2647 breast cancer patients were followed up to observe their survival by phone calls, emails or letters annually. We performed follow-up to October, 2015. The breast cancer-specific survival time, overall survival time and disease-free survival time of were calculated. 5. Statistical analysis. Using Kaplan Meier and multivariate Cox regression dissect the association between the genotypes of the SNPs and breast cancer patients' survival. Multivariate logistic regression model was used to analyze the association between the genotypes and clinical characters of patients. Bilateral test was used and P<0.05 was statistically significant.Results 1. In Stage ?, prognosis of patients were found differently among different genotypes in 8 SNPs(P<0.05). In Stage?, We finally confirmed GREM1 rs10318 associated with the prognosis of breast cancer patients(P<0.05). 2. Patients with T genotype had shorter breast cancer special suvival time(HR=1.911; 95%CI: 1.204-3.031, P=0.006) and shorter overall survival time(HR=1.862; 95%CI: 1.208-2.871, P=0.005) than CC genotype in rs10318. Rs10318 was located in GREM1 which probably was regulated by mi RNA-633 by sequence CTATTAA. 3. Stratified analysis of epidemiological data, compared to CC genotype, patients who carried TT genotype had shorter survival time, specially in the patients who had ever breastfeeding, menopause, family history of cancer, non-smoking, history of benign breast disease, more than 1 live births, more than twice pregnancies, or blood groups A?B; as well as clinical data, including, tumor size?2.5cm, lymph node biopsy(-) or infiltrating ductal carcinoma. 4. We found significant difference of the distribution of rs10318 genotype in ER state. Compared to CC genotype, patients carried TT genotype were eager to be ER(-)(OR= 0.634; 95%CI: 0.472-0.852, P=0.007).Conclusion 1. GREM1 rs10318 was associated with the prognosis of breast cancer, moreover the prognosis of patients with TT genotype were poorer, compared to the CC genotype. Ever Since, we found a new SNP was associated with the prognosis of breast cancer. 2. rs10318 was related to ER state: patients with TT genotype(compared to CC genotype) were eager to be ER(-).