Correlation Study Of Gene Polymorphisms On The3’UTR Of Differentially Expressed Genes And The Prognosis Of Tripie Negative Breast Cancer

Part I Correlation study of gene polymorphisms on the3’UTR of differentially expressed genes and the prognosis of triple negative breast cancerObjective Triple negative breast cancer (TNBC) is a subtype with poor prognosis and high heterogeneity. The aim of this study was to screen single nucleotide polymorphisms (SNPs) associated with the prognosis of triple TNBC patients and to explore the potential mechanism, so as to looking for the clinical helpful molecular markers to guide individualized treatment.Methods Retrospective analysis was conducted on TNBC patients treated in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Patients with sufficient blood samples and complete information on clinical pathology features were enrolled (n=235) and divided into disease free survival group (n=167) and recurrence&metastasis group (n=68).SNPs(MAF≥1%) located on the3’ untranslated region (3’UTR)of differentially expressed genes in breast cancer were selected though databases(Nextbio、ensemble、NCBI、MirSNP). Sequenom’s MassARRAY system was used to detect the SNPs. Finally, the association between genotypes and different diseases status among patients was analyzed through case-control study.Results4SNPs were found to be related to the recurrence&metastasis of triple negative breast cancer. TT genotype of FGFR2rs1047057and TC/TT genotype of THSD4rs1054260were identified as protective factors. TNBC patients carrying such genotype would less likely to have recurrence and metastasis, with adjusted HR of0.42(95%CI0.18-0.98) and0.42(95%CI0.22-0.83) respectively. GA/GG genotype of KRAS rs7973450and ZNF365rs11819488were found to be associated with unfavorable prognosis of higher recurrence and metastasis risk with adjusted HR of2.97(95%CI1.37-6.40) and1.90(95%CI1.02-3.54) respectively. However, rs1054260-TT/TC genotype were surprisingly found to be related with larger tumor size (HR=1.91,95%CI1.09～3.37, P=0.022). By combining four SNPs for prognosis, we observed a strong dose-response trend toward an increasing risk of disease progression with an increasing number of high-risk genotypes. All results were adjusted with age, family history of cancer, tumor size and other important pathology factors.Conclusions The single nucleotide polymorphisms(SNPs) located in the3’UTR of differentially expressed genes in breast cancer may affect the genes’expression by changing the combination between MicroRNA (miRNA)and targeted mRNA, and then be related to the different prognosis of TNBC patients. Part Ⅱ Genetic variants of genes in circadian rhythm and risk of breast cancerObjective To investigate the relationship between Genetic variants of genes in circadian rhythm and risk of breast cancer.Methods A case-control study which consisted of406patients and412controls was conducted and Clock(rs2070062) and Per2(rs2304672、rs2304669、rs934945) were genotyped by TaqMan Real-Time PCR. Unconditional logistic regression model was used to analyze the association between genetic polymorphisms and breast cancer.Results There was significant difference for the alleles’distribution of rs2304669between case and control after adjusted by age, smoke, alcohol consumption and menopause status (p=0.004). However, rs2304672, rs2070062and rs934945polymorphisms were not found to be related to breast cancer (p=0.939,0.302and0.307respectively).Conclusion rs2304669was associated with breast cancer risk. Genetic variants of genes in circadian rhythm may contribute to the susceptibility of breast cancer.