Pbf And Mirnas And Related Gene Polymorphisms Associated With Tumor Susceptibility

The etiology of common cancer such as breast cancer and esophageal cancer has been shown to be multifactorial, including genetic, environmental factors. The aberrant expression and disfunction of estrogen-or miRNA-related genes have been implicated in the development of breast cancer or esophageal cancer. In two case-control studies, we have explored the association of the variable number of tandem repeats (VNTRs) polymorphism in the promoter region of PBF, a novel breast cancer gene targeted by estrogen receptor (ER), with the susceptibility of breast cancer and functional significance. We have also analyzed the associations between SNPs of candidate miRNA-related genes and risk of esophageal cancer.Pituitary tumor transforming gene binding factor(PBF; PTTG1IP) is a breast cancer-related oncogene, whose high expression is associated with cell invasion. The estrogen response elements (ERE) in PBF promoter mediate the trascriptional activation of PBF by ER, and PBF promoter contains VNTRs of an18-bp sequence, whose relation with the susceptibility of breast cancer and metastasis genotype has not reported yet. In this study, we tested this hypothesis in a case-control study of688patients with newly diagnosed breast cancer and866healthy controls in ethnic Han Chinese, and found9types of alleles and29types of genotypes. In dominant model,5repeats might reduce the risk of breast cancer (OR=0.71,95%CI=0.53-0.95),6repeats (OR=1.51,95%CI=1.13-2.04), S/L+L/L genotype (S>L, S for short≤5, L for long≥6)(OR=2.00,95%CI=1.34-2.97), and heterozygotes genotype (OR=1.62,95%CI=1.15-2.29) might increase the risk of breast cancer. Stratification analysis revealed that the VNTR polymorphism was associated with cancer risk of breast cancer mainly in ER-positive subjects. In further study of association between VNTR polymorphism and lymph node metastasis, heterozygotes genotype was significantly associated with increased metastasis. Reporter gene assay and gel-shift assay showed that the binding of ERa and the PBF promoter region was promoted by the increased repeats, however, the transcriptional activation of PBF was the lowest when the VNTR region contained5repeats. Our results provide first epidemiological evidence that PBF genetic polymorphism is associated with the susceptibility of breast cancer, further supporting the role of PBF in the development and progression of breast cancer.In the study of esophageal cancer, we assessed the associations between cancer risk and24SNPs in13miRNA-related genes in a case-control study of354newly diagnosed esophageal cancer patients and473controls in ethnic Han Chinese. We found that the SNP rs197412in GEMIN3gene was associated with cancer risk, C allele odds ratio (OR) of0.80(95%CI=0.65-0.97), C/T+T/T genotype OR of0.64(95%CI=0.45-0.91). Compared with the reference group of non-smokers carrying the C/C genotype, ORs (95%CI) of the C/T+T/T genotype for non-smokers, smokers who smoked<25, and≥25pack-years were0.89(95%CI=0.53-1.48),1.63(95%CI=0.89-2.99),3.07(95%CI=1.49-6.34), respectively, suggesting an interaction between this genetic polymorphism and smoking status. These findings provide the evidence that SNPs of miRNA-related genes might affect esophageal cancer risk in the population and the rs197412in GEMIN3encoding region might be a susceptibility factor for esophageal cancer by interacting with tobacco smoking.