The Single Nucleotide Polymorphisms Of Fas-670 And Cervical Cancer Susceptibility

BackgroundCervical cancer is one of the major causes of death of women in the worldwide,especially in the developing countries. Etiology of cervical cancer remains a major concern, and the most important finding is the close relationship between high risk human papillomavirus(HPV) and cervical cancer. Most epidemiologic data and laboratorial results show that special HPV types are the central etiologic agent of cervical carcinogenesis. HPV DNA sequence, especially high-risk HPV types(HPV16/HPV18) was found in about 95% of squamous cell cervical carcinoma. About 15-34% sexually active women experienced HPV infection. However, most HPV infections are transient with only type-special persistence contributes significantly to the development of cervical neoplasma. Therefore, HPV infection is a necessary but not sufficient condition for cervical carcinogenesis. Other environmental and host factors also play decisive roles in the persistence of HPV infection and further malignant conversion of cervical epithelium. Though early sexual intercourse, multiple sexual partners, smoking and oral contraceptive are the risk factors of cervical cancer. But there was no independent risk factor for cervical carcinogenesis. With the development of molecular genetics, host genetic susceptibility factors may be important in modulating the risk and contributing to clean HPV. A large number previous studies suggested that host genetic polymorphisms may explain some of the individual differences in HPV-related cancer occurrence. Since the role of host genetic factors in cervical carcinogenesis is still largely unknown. searching for new molecular markers associated with host genetic susceptibility to development of cervical neoplasma is essential.Apoptosis has been well documented for its important role on autoimmunity and tumorgenesis. Of the pathways of apoptosis known today, signals emanated from cell surface death receptors such as Fas confer a major apoptosis effect. Transduction of signals through Fas receptor has been implicated in physiological regulation of apoptosis process as well as pathogenesis of various human disease. Fas protein is expressed on many cells such as lymphocytes, fibroblasts and on a variety of epithelial cells, among their basal layers of squamous epithelium. The interaction of the Fas receptor with its ligand (FasL) plays an essential role in the physiological regulation of apoptosis but also in the transmission of non-apoptotic signal. Fas (also known as CD95, APO-1) is a death receptor belonging to the tumor necrosis factor (TNF) receptor superfamily. Human Fas is located at 24.1 region in number 10 chromosome, the length of its cDNA is 2534bp. Fas encodes transmembrane glicoprotein with 319 amino acid residual and 36KD of molecular weight. Apart from mutation, expression of this gene could be changed by the genetic element located in the promoter region such as polymorphisms, which could influence transcriptional activity of this gene. The gene encoding Fas receptor contains the single nucleotide polymorphisms (SNP) at -670 position. The transcriptional expression of Fas gene is regulated by a number of the genetic element located in the 5 upstream region of the gene. The promoter region of Fas gene consists of basal promoter, enhancer and silencer region. The single nucleotide polymorphisms at -670 in the enhance region situates at a binding element of gamma interferon activation signal (GAS) . Two polymorphisms (A/G) at FAS -670 were identified. G allele with TTCNNNGAA in GAS results in a significant increase in Fas gene expression. A allele with TTCNNNAAA results in a significant decrease in Fas gene expression. Recent studies have demonstrated that the A/G SNP at-670 of Fas gene promoter is closely associated with the pathogenesis of autoimmune disease and cancer. Downregulation of Fas result resistance to death signal induced by immune cells and rend cancers as sites of immune privilege. To date, few reports has been published describing association between Fas promoter polymorphism and cervical carcinogenesis.The aim of this study is to determine the distribution of -670 A/G Fas gene promoter polymorphism in cervical cancer patients and healthy control group in order to evaluate the potential association between Fas-670 polymorphisms and cervical cancer susceptibility in Chinese Han women.MethodsSNP at -670 of Fas gene promoter (A/G) together with human papillomavirus types were examined in total of 194 cervical cancer cases and 138 healthy controls. The patients with cervical cancer was histologically confirmed .Healthy volunteer women were randomly selected. All patients and controls were of the Chinese Han nationality. Peripheral blood samples were obtained from patients with cervical cancer (n=194,160 squamous cell carcinomas and 34 adenocarcinomas) and healthy controls(n=138) . Genomic DNA was extracted from blood samples, and the mismatch amplification mutation assay - PCR (MAMA-PCR) was used to detect the biallelic polymorphisms at Fas-670 position. Cervical smear samples were obtained from patients with cervical cancer and healthy controls. High risk human papillomavirus was examined by the hybrid capture II test. HPV infection status and Fas -670 polymorphisms were compared between cervical cancer group and control group.Results1. In healthy Han women in China, The 'A' allele frequency and 'G' allele frequency were 50.72% and 49.28%, The distribution of AA, AG , AG allelotype were 23.19%, 55.07% and 21.74%.2. The'A' allele frequency in patients with cervical squamous cell carcinoma was significantly higher than that in controls(60.94% vs 50.72%, x~2=6.27, p=0.012, OR= 1.52,95%CI=1.09-2.10); The distribution of AA, AG, and AG allelotypes was significantly different between cervical squamous cell carcinoma patients and controls (x~2=7.10, p=0.029, AA: OR=2.30, 95%CI=1.16-4.57; AG: OR=1.27, 95%CI=0.68-2.36).3. The'A' allele frequency in HR-HPV positive cervical squamous cell carcinomas was significant higher than that in HR-HPV positive controls (60.47% vs 46.34%, x~2=5.71, p=0.017, OR=1.81, 95%CI=1.11-2.94) .The distribution of AA, AG, and GG allelotypes differed signigicantly between HR-HPV positive cervical squamous cell carcinomas and HR-HPV positive controls (x~2=6.55, p=0.038) with AA allelotype more frequently found in cervical squamous cell carcinomas (OR=3.20, 95%CI=1.26-8.11).4. There was no significant difference in the 'A' allele frequency ( x~2 =0.01, p=0.912) and the allelotype distribution ( x~2 =0.29,p=0.864 )between cervical adenocarcinoma group and control group.5. There was no significant difference in allelotype distribution between HR-HPV positive control group and HR-HPV negtive control group ( x~2=4.02, p=0.134).Conclusions1) The A allele of Fas-670 may be a genetic risk factor of cervical squamous cell carcinoma.2) There is no significant correlation between Fas-670 single nucleotide polymorphisms and HR-HPV infection.It is indicated that Fas-670 SNPs changes cervical cancer susceptibility by a way other than by changing host susceptibility to HR-HPV infection.