Study On The Relationship Between P21codon31 Polymorphism And Cervical Cancer Susceptibility

BackgroundCervical cancer is the second most common malignancies in both of incidence and mortality rates in worldwide. 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. Compelling evidences from both epidemiological and experimental studies have indicated that infection of oncogenic HPV, predominantly types 16 and 18, are the major risk factors for the development of cervical cancer, and HPV DNA is found in over 95% of cervical cancers. However, HPV infection is frequent among sexually active women, with incidence ranging from 15% to 40%, most HPV infections are transient and only a small proportion of infected women develop malignant cervical lesions. Therefore HPV is considered to be a necessary but not sufficient cause for cervical cancer and other factors contribute to the carcinogenic process. Although age of first intercourse, number of sexualpartners, more parities, cigarette smoking, race and low socioeconomic status consistently have been shown as risk factors for cervical cancer, none has been shown to be as a significant independent risk factor.Recently, other factors causing host genetic susceptibility have been considered to be involved in the development of cervical cancer. HLA and p53 gene polymorphisms in cervical cancer were mostly studied. p21 gene is another one that have a close relationship with neoplasma. p21 gene polymorphism was concerned in cervical cancer recently. The cyclin-dependent kinase inhibitor (CDKi) gene p21 plays a paramount role in the p53-mediated G1 arrest. In response to DNA damage, elevated level of p53 induces increase of p21 expression. As a negative regulator of the cell cycle, increased p21 expression causes Gl arrest and allows for DNA repair or apoptosis. This blockade of DNA synthesis prevents accumulation of mutations that would promote evolution into cancer cells. Therefore, p21 plays a crucial role in the cancer development. Alteration in p21 may adversely affect the regulation of cellular proliferation and increase the susceptibility to cancer. In the general population, two common variants were identified in p21 codon 31, as the result of the third base pair change ( A or C) that involves coding for Arg (AGA) or Ser (AGC) residues at codon 31. Although it was suggested that p21 codon 31 Arginine allele appears to be associated with an increased risk for a variety of human malignancies , such as endometrial cancer, lung cancer, breast cancer, sarcoma, and prostate cancer, very few studies have concerned on the association between p21 codon 31 polymorphisms and cervical cancer. It was reported that the codon 31 Ser/Ser homozygote of p21 gene could be a risk factor for development of cervical adenocarcinoma in Korean women. Another study implied that codon 31 Arg allele may be associated with a tendency to develop cervical cancer in Japanesewomen.To our knowledge, this is the first study on the association between p21 codon 31 polymorphisms and cervical cancer in Chinese women. Our aim is to investigate p21codon31 polymorphisms distribution in Chinese women and its' relationship with cervical cancer susceptibility.Materials and MethodsFrom 2004.1 to 2006.2, a total of 317 patients with uterine cervical carcinoma was histologically confirmed at the Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University and Zhejiang Oncology Hospital. Healthy volunteer women (n=353) were randomly selected as the control groups, who had no evidence of any cervical malignant or precancerous lesions by cytology check-up and so on. All patients and controls were of the Chinese Han nationality . Peripheral blood or cervical tissue was sampled. Phenol-chloroform was used to extract DNA. High risk HPV-DNA was detected by hybrid-capture II assay. Single nucleotide polymorphisms of p21 codon31 were determined by MAMA-PCR.Results1) The Arg allele frequency in patients with squamous cell carcinoma(SCC) was significantly higher than that in controls (37.42% vs 23.23%, x2 = 31.14, p=0.000, OR = 1.98, 95% CI = 1.07- 3.65). The distribution of AGA/AGA, AGA/AGC, and AGC/AGC genotpyes differed significantly between SCC patients and controls ( ( x2 =27.77, p=0.000) ) with AGA/AGA (OR=3.16, 95% CI = 1.91 ~ 5.24) and AGA/AGC (OR=1.98, 95% CI =1.41 ~ 2.77)genotypes more frequently found in squamous cell cancer than controls.2) The Arg allele frequency in patients with HR-HPV positive cervical cancer was significantly higher than that in HR-HPV positive controls (43.09% vs 26.09%, x2 = 7.62, p=0.006, OR = 2.14, 95% CI = 1.18-3.88). The distribution of AGA/AGA, AGA/AGC, and AGC/AGC genotpyes differed significantly between HR-HPV positive cervical cancer patients and HR-HPV positive controls (x2= 6.12, p=0.047) with AGA/AGA (OR=3.45, 95% CI = 1.20 ~ 9.95) genotype more frequently found in SCC than controls.3) There was no significant different in genotype distribution between cervical adenocarcinomas and controls (x2=1.13, p=0.287) .4) There was no significant different in genotype distribution between HR-HPV positive controls and HR-HPV negative controls ( x2 =4.76, p=0.093) .Conclusions1) The Arg allele of p21 codon 31 may be a genetic risk factor of squamous cervical cancer.2) There is no significant correlation between p21 codon 31 single nucleotide polymorphisms and HR-HPV infection. It is indicated that p21codon31 SNPs changes cervical cancer susceptibility by a way other than by changing host susceptibility to HR-HPV infection.