Polymorphisms Of MicroRNA And ESR1 Genes And Their Association With Triple Negative Breast Cancer Risk And Prognosis

Background:Triple negative breast cancer (TNBC) is considered as a kind of multi-gene genetic diseases which is a clinicopathologic entity with aggressive behaviors, poor prognosis and no specific targeted approach. MicroRNAs (miRNA) as novel modulators of gene expression has played important regulatory roles in malignancy. Furthermore, dysregulation and/or mutation in miRNAs may contribute to TNBC susceptibility because it is associated with the expression of ER, PR and HER2. The sequence variants in ESR1 genes, the gene coding for ER alpha, have the potential to affect the expression of estrogen receptor, so inherited variations in miRNAs and ESR1 genes may be extremely relevant for TNBC. In this study, We examined the hypothesis that genetic variations in miRNA genes and ESR1 genes are associated with TNBC development. We try to find the candidate biomarkers for TNBC susceptibility, and finally hope to apply it to clinical individualized therapy. Materials and Methods:We screened genetic variants in all miRNA genes, which are listed in the public database miRBase and NCBI. A total of twenty-three common single nucleotide polymorphisms in twenty-two miRNAs, which tagged the known common variants in ethnic Han Chinese people with minor allele freqncy greater than 0.05 were genotyped. This case-control study involved 384 patients with breast cancer and 192 healthy female controls. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with breast cancer susceptibility. Furthermore, to focus on the risk of TNBC, we screened genetic variants in four miRNA genes, which are predicted to regulate ER, HER2 and four single nucleotide polymorphisms in estrogen receptor gene alpha. Differences in genotype or allele frequencies of individual SNPs in cases and controls were tested using Unconditional logistic regression. Survival analyses were used to identify SNPs associated with prognosis of TNBC. In the last part of this study, We retrospectively analyzed the clinical features and long-term survival of 134 patients with metastatic TNBC at Cancer Hospital of CAMS from January 1999 to December 2007. Results:There was no significant association between breast cancer risk and the single nucleotide polymorphisms in miRNA genes (P>0.05). A significant combined effect of rs3798759, a SNP of ESR1, on breast cancer risk was found. Women carrying ESR1 rs3798759-GG genotypes showed decreased breast cancer risk (OR=0.8015, 95%CI=0.4206～1.5272, P=0.0239). This SNP also showed a significant association with poor prognosis of TNBC patients with early clinical stage (phaseⅠandⅡ). The 5-year disease free survival rate of patients with rs3798759-G genotype is significantly lower than those with rs3798759-T genotype(P=0.032) and the 5-year overall survival rate is also lower with a borderline significance(P=0.082). However, there was no significant association between other genotypes of ESR1 genes and TNBC risk. At last, to further evaluate this finding, a retrospective research was be done to characterize the sites of distant recurrence and clinical outcomes in a cohort of patients with metastatic TNBC in Chinese patients. Most patients(72.7%) have a higher predilection for visceral metastasis and early recurrence within the first two years of follow-up. The most common site of first recurrence was lung. And 62(51.7%) patients had more than two sites of metastasis. The median OS (28.5 vs.12.6months, P=0.0001) differed significantly between patients who received first-line chemotherapy and those who did not. The median OS of patients with CR/PR was significantly longer than that of patients with SD/PD(.P=0.0108). Furthermore, first-line chemotherapy and the clinical response were demonstrated to be an independent prognostic factor in the multivariate analysis. The median overall survival time of patients with rs3798759-G genotype is 37.6months significantly lower than those with rs3798759-T genotype(75months)(p=0.019) in metastatic TNBC patients. Conclusions:Taken together, there was no significant association between breast cancer risk and the single nucleotide polymorphisms in miRNA genes in ethnic Han Chinese people. And our findings demonstrate firstly that genetic polymorphism of ESR1 rs3798759 is associated with the decreased TNBC risk among Chinese women. And this SNP also showed a significant association with poor prognosis of TNBC patients, but the findings needs to be validateds in further large studies.