A Molecular Epidemiology Study On The Association Of Functional Polymorphisms Related To Hpv E6/e7 Protein And The Susceptibility Of Cervical Cancer

Cervical cancer is the second most common cancer among women worldwide, with most of the cases occurring in developing countries. China is also the area of high incidence of cervical cancer. How to identify high-risk groups of cervical cancer, to further reduce the incidence of cervical cancer, is a serious problem before us.The exact mechanisms of cervical cancer development remains unclear, although multiple factors have been proposed to play a role in cervical carcinogenesis, such as parity and HPV. Exposures to the exogenous risk factors may attribute to cervical cancer, and the host susceptibility may also play an important role in cervical cancer development. Human Papillomavirus (HPV) infection is a necessary but insufficient etiological factor in the development of cervical cancer. Among the different components of the HPV genome, the most commonly expressed viral proteins closely associated with cervical cancer development are the E6 and E7 oncoproteins. High-risk HPV E6 and E7 oncoproteins can inactivate critical tumor suppressor proteins, which makes the virus override cell cycle checkpoints and cause cellular transformation. MicroRNAs (miRNAs) are small noncoding RNAs that may regulate thousands of mRNA targets. MiRNAs are transcribed in the nucleus and after processing they associate with the RNA-induced silencing complex and act as negative regulators of gene expression by binding to complementary sequences in the 3'UTR of mRNA targets and either repressing translation or promoting mRNA degradation. Changes in the expression of miRNAs have been shown to be associated with a variety of human cancers. Recent researches show that HPV E6/E7 oncoproteins interacting genes and miRNAs, play a critical role in cervical carcinogenesis with an interactive manner. To test the hypothesis that potentially functional polymorphisms in HPV E6/E7 protein interacted genes and miRNAs may contribute to cervical cancer risk, we performed genotyping analysis on non-synonymous SNPs in TP53, BRCA1,BARD1 and pre-miR-218 with a case-control study in Chinese women.Partâ… Polymorphisms in HPV E6/E7 protein interacted genes and risk of cervical cancer in Chinese women: a case-control analysisPurpose: Accumulating studies indicate that HPV E6/E7 oncoproteins interacting genes, TP53, BRCA1 and BARD1, play a critical role in cervical carcinogenesis. We hypothesized that potentially functional polymorphisms in TP53, BRCA1 and BRAD1 may individually and/or jointly contribute to cervical cancer risk.Experimental Design: We ge notyped 4 single nucleotide polymorphisms (SNPs) with amino acid changes, TP53 Pro72Arg (rs1042522), BRCA1 Pro871Leu (rs799917), BARD1 Pro24Ser (rs1048108) and Arg378Ser (rs2229571), in a case-control study of 404 cervical cancer cases and 404 cancer-free controls in Chinese women.Results: Logistic regression analysis showed that the BRCA1 variant rs799917 TT genotype was associated with a significantly decreased risk of cervical cancer in a recessive genetic model (adjusted OR = 0.62, 95% CI = 0.40-0.95), compared with the genotypes CT/CC. However, no significant associations with cervical cancer were observed for other 3 SNPs (adjusted OR = 1.01, 95% CI = 0.68-1.50 for rs1048108 TT vs CT/CC; adjusted OR = 1.04, 95% CI = 0.67-1.64 for rs2229571 CC vs GG/GC; adjusted OR = 0.84, 95% CI = 0.59-1.20 for rs1042522 CC vs GG/GC).Conclusion: These findings indicate that BRCA1 rs799917 polymorphism may contribute to the risk of cervical cancer in this Chinese population, and further validation in other populations are warranted.Partâ…¡A case-control study on functional polymorphisms in pre-miR-218 and TP53 and the susceptibility of cervical cancerPurpose: MicroRNAs (miRNAs) are small noncoding RNAs. Changes in the expression of miRNAs have been shown to be associated with a variety of human cancers.Recent researches show HPV-16 E6 oncogene promotes ubiquitination of the tumor suppressor protein p53,then indirectly downregulates miR-218, which indicates that miR-218 may play a critical role in cervical carcinogenesis. We hypothesized that potentially functional polymorphisms in pre-miR-218 and TP53 may individually and/or jointly contribute to cervical cancer risk.Experimental Design: We genotyped 2 single nucleotide polymorphisms (SNPs), pre-miR-218 rs11134527 and TP53 rs1042522, in a case-control study of 633 cervical cancer cases and 633 cancer-free controls in Chinese women.Results: Logistic regression analysis showed that the pre-miR-218 variant rs11134527 GG genotype was associated with a significantly decreased risk of cervical cancer (adjusted OR = 0.70, 95% CI = 0.50-0.99), compared with the AA genotype. However, no significant associations with cervical cancer were observed for TP53 rs1042522 (adjusted OR = 1.56, 95% CI = 0.84-1.60 ).Conclusion: These findings indicate that pre-miR-218 rs11134527 polymorphism may contribute to the risk of cervical cancer in this Chinese population, but need further validation in other populations.