| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 91 === Cervical cancer is the second most common cancer among women worldwide. Recently, infection with high-risk types of human papillomavirus (HPV) has been established as the central cause of the disease. Although HPV infection appears to be a necessary cause, it is insufficient in itself to confer the development of high-grade squamous intraepithelial lesion (HSIL) and cervical cancer. Other environmental and host factors are obviously involved in the progression of HPV infection to HSIL and cancer. Recent population based twins and family studies have showed the hereditary component of cervical cancer, indicating genetic susceptibility plays an important role. With the completion of human genome project and compiling message of gene polymorphisms, we are able to explore the individual susceptibility to cervical cancer at the genetic level. Based on the current knowledge of genes involved in cervical carcinogenesis and their polymorphisms, the present study tried to identify critical genetic polymorphisms of the step-wise cervical carcinogenesis. Candidate genes involving apoptosis, immune response, tissue remodeling and P53 were studied. Fresh cases of LSIL, HSIL and cervical cancer and each of their controls at the ratio of 1:1 were recruited from the department of Obstetrics and gynecology of Tri-Service General Hospital. The results showed that genetic polymorphisms do associate with cervical carcinogenesis. The A allele and AA genotype at -670 of Fas promoter confer a higher risk for HSIL and cervical cancer (OR=1.3, 95% CI= 1.0-1.6; OR=1.5, 95% CI= 1.1-2.1). The (CA)12 and (CA)14 alleles of the first intron of IFN- are risky for HSIL (OR=2.1, 95% CI= 1.3-3.4; OR=9.1, 95% CI= 2.1-40.0), so are the genotypes (OR=2.3, 95% CI= 1.3-4.1; OR=7.8, 95% CI= 1.7-35.0). On the contrary, (CA)13 and (CA)18 alleles of IFN- are protective for HSIL (OR=0.5, 95% CI=0.4-0.8； OR=0.2, 95% CI=0.1-0.8), as well as the genotypes (OR=0.4, 95% CI=0.2-0.7； OR=0.2, 95% CI=0.1-0.8). The allele and genotype 105 of IL-10.R confer higher risk for HSIL (OR=14.5, 95% CI= 3.4-61.7; OR=14.5, 95% CI= 1.9-112.5), respectively, while the allele and genotype 109 of IL-10.R are protective (OR=0.2, 95% CI= 0.1-0.5; OR=0.1, 95% CI= 0.0-0.5). As to tissue remodeling genes, the (CA)21 alleles and genotypes of MMP9 confer higher risk for cancer (OR=1.8, 95% CI= 1.1-2.8; OR=1.8, 95% CI= 1.1-3.1). Meanwhile, allele C and genotype CC of p53 also have higher risk for cancer (OR=1.5, 95% CI= 1.0-2.0; OR=2.1, 95% CI= 1.1-4.0). When combining the 8 risky alleles with frequency higher than 5%, the risk for cervical cancer increases as the numbers of risk alleles accumulate (Ptest for trend = 0.0029). Most cervical cancer cases are carriers of two to four risk alleles, while the most risky ones carry six. The present study takes advantages of stepwise cervical carcinogenesis with well-defined phenotypes and includes the most dominant environmental factor, HPV. For the first time, we are able to demonstrate the role of genetic polymorphisms during cervical carcinogenesis. Understanding the genes and polymorphisms contributing to cervical cancer may pave a new way of thinking in this virus-induced cancer.
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