【作者】 吴冬梅；

【导师】 蔡琳； 林安；

【作者基本信息】 福建医科大学 ， 病原生物学， 2010， 博士

【摘要】 [目的]研究高危型HPV基因型与宫颈癌及宫颈癌前期病变的关联；探讨性传播病原体感染及其DNA负荷量对宫颈癌发生的作用；探讨宫颈癌发病的危险因素,以及性传播病原体感染、行为因素在HPV致癌中的交互作用。[方法]1、采用病例-对照研究设计,对每位研究对象(308例宫颈癌病例、336例对照)行宫颈癌危险因素调查,取宫颈细胞标本及采集6ml血样。提取宫颈细胞DNA,行HPV DNA、HCMV、HSV-Ⅱ、CT、UU和NG的检测。血清标本用于TP及HIV检测。研究本地区HR-HPV与宫颈癌的关系,性传播病原体感染及其DNA负荷量对宫颈癌发生的作用以及性传播病原体感染、行为因素与HPV致癌的交互作用。2、对2338位妇女行宫颈三阶梯诊疗程序筛查及HPV DNA检测,以组织病理学检查为金标准,分析HR-HPV基因型与宫颈病变的关系。对因CINⅡ／Ⅲ行LEEP治疗且宫颈切缘阴性的236位患者随访2年。所有患者在LEEP术前,术后6个月,1年和2年取宫颈细胞行HPV DNA检测。探讨HPV基因型与CIN治疗后残留／复发的关系。[结果]1、HR-HPV基因型与宫颈癌发生危险性分析：HR-HPV-16(OR=51.55；95%CI=28.73-61.86)、HR-HPV-18(OR=52.81;95%CI=22.84-61.27)、HR-HPV-31(OR=12.41；95%CI=10.59-16.68)、HR-HPV-53(OR=2.92;95%CI=1.03-8.28)、HR-HPV-59(OR=13.58；95%CI=10.76-21.07)、HR-HPV多重感染(OR=1.11；95%CI=0.81-3.13)。HR-HPV-33、HR-HPV-39、HR-HPV-45仅在宫颈癌病例中检出。2、性传播病原体感染与宫颈癌发生的危险性分析：HCMV(OR=7.106；95%CI=3.479-14.512)；HSV-Ⅱ(OR=32.489；95%CI=7.514-40.478)；CT(OR=12.315;95%CI=5.824-26.039)；UU(OR=4.564；95%CI=3.177-6.556)；NG(OR=1.662；95%CI=0.427-6.467)；TP(OR=21.104；95%CI=7.324-60.816)。HCMV、UU的DNA负荷量在宫颈癌组及对照组,差异有统计学意义(P<0.001)；HSV-Ⅱ、CT、NG的DNA负荷量在宫颈癌组及对照组,差异无统计学意义(P＞0.05)。3、宫颈癌的危险因素：结核病史(OR=4.388；95%CI=1.846-10.426)、性传播疾病史(OR=20.501;95%CI=7.097-59.226)、怀孕次数多、初次性关系年龄小(16-20岁)、性伴侣数≥3、HR-HPV、HSV-Ⅱ、TP感染。4、HPV基因型与宫颈癌及癌前期病变的危险性分析：与CINⅠ有关：HPV-66、-68、-CP8304；与CINⅡ／Ⅲ有关：HPV-52。5、HR-HPV基因型与CIN治疗后残留／复发的关系：治疗前HPV亚型为HR-HPV-16(P=0.007)、HR-HPV-18(P=0.000)、HR-HPV-33(P=0.001)、HR-HPV-45(P=0.019)和HR-HPV多重感染(P=0.005),术后残留／复发率高。[结论]1、本地区宫颈癌高危HPV基因型是：HPV-16、-18、-31、-33、-39、-45、-53、-59。感染HPV-18、HPV-16发生宫颈癌的风险最高。2. HCMV、HSV-Ⅱ、CT、UU、TP感染与宫颈癌发生有关,HCMV、HSV-Ⅱ、CT、UU、TP感染与HPV感染对宫颈癌发生有联合作用,HCMV、TP感染与HPV感染对宫颈癌发生未见交互作用,感染病原体种类数与HPV致癌有联合作用。3、结核病史、性传播疾病史、怀孕次数多、初次性关系年龄小(16-20岁)、性伴侣数≥3、HR-HPV、HSV-Ⅱ、TP感染是福建地区宫颈癌的主要危险因素。性传播疾病、孕次、性伴侣数在宫颈癌的发生中有联合作用。4、高危型HPV多重感染无明显增加宫颈癌及癌前病变的风险。5、感染HPV-66,-68和-CP8304与发生CINⅠ有关,感染HPV-52与发生CINⅡ／Ⅲ有关。CINⅡ／Ⅲ治疗前感染亚型为HPV-16、-18、-33、-45以及HR-HPV多重感染,与治疗后残留／复发的发生有关。更多还原

【Abstract】 [Objective]To study the association of HR-HPV genotype with cervical cancer and precancerous lesions, the relation of infections of sexually transmitted pathogenic microbes with cervical cancer, risk factors of cervical cancer in Fujian and the synergistic action of pathogen microbes and behavial factor in etiology of cervicle cancer.[methods]1. A case-control design was applied in this study. A total of 308 patients of cervical cancer diagnosed with histology were enrolled and 336 control subjects consisted of patients of hysterectomy with benign lesions. Each participant was scheduled for a face-to-face interview with the structured questionnaire. Cervical cells were obtained and 6 ml blood was collected from all women. Cervical cells DNA was extracted, and HPV DNA、HCMV、HSV-Ⅱ、CT、UU and NG were detected. TP and HIV were done with blood sample.2. A total of 2338 women were screened for cervical lesions. The correlation of HR-HPV genotypes with the histological results was evaluated. Two hundred and thirty six women with CIN2/3 treated by LEEP conization with negative margins confirmed by pathology examination of the surgical specimen were included. The cervical cells for HPV genotype testing were collected before and 6,12,24 months after treatment respectively. HPV genotype and multiple HPV infection were evaluated as possible predictors of residual/recurrent disease.[Results]1. The OR of each HR-HPV type for cervical cancer showed that HR-HPV-16 (OR=51.55; 95%CI=28.73-61.86), HR-HPV-18 (OR=52.81; 95%CI=22.84-61.27), HR-HPV-31 (OR= 12.41; 95%CI=10.59-16.68), HR-HPV-53 (OR=2.92; 95%CI= 1.03-8.28), HR-HPV-59 (OR= 13.58; 95%CI=10.76-21.07) and multiple HR-HPV infection (OR=1.11; 95%CI=0.81-3.13). HR-HPV-33, HR-HPV-39, HR-HPV-45 were detected in cervicle cancer only.2. The crude OR for infections of sexually transmitted pathogenic microbes associated with cervical cancer showed that HCMV (OR=7.106; 95%CI=3.479-14.512), HSV-Ⅱ(OR=32.489; 95%CI=7.514-40.478), CT (OR=12.315; 95%CI= 5.824-26.039), UU (OR=4.564; 95%CI=3.177-6.556), NG (OR=1.662; 95%CI= 0.427-6.467), TP (OR=21.104; 95%CI=7.324-60.816). There was statistically significant difference between cancer group and control group with respect to the pathogen loading dose of HCMV and UU (P＜0.001). There was no statistically significant difference between cancer group and control group with respect to the pathogen loading dose of HSV-Ⅱ, CT and NG (P>0.05)3. The major risk factors of cervicle cancer included:tuberculosis (OR=4.388; 95%CI=1.846-10.426), sexually transmitted diseases (OR=20.501; 95%CI=7.097-59.226), gravidity, age 16 to 20 of sexual life for the first time, number’of sex partner, HR-HPV,HSV-Ⅱand TP.4. Analysis by OR revealed that HPV-66,-68, and -CP8304 were associated with CIN 1; HPV-52 was CIN 2/3-associated types.5. Preoperative infection with either HPV-16 (P=0.007), HPV-18 (P=0.000), HPV-33 (P=0.001) or HPV-45 (P=0.019) was associated with higher rates of residual /recurrent lesions after conization with negative margins. Preoperative infection with multiple HPV types was associated with the highest rate of residual/recurrent lesions compared with infection with single HPV type and HPV negative cases (P=0.005)[Conclusion]1. HPV-16,-18,-31,-33,-39,-45,-53, and -59 have more dominant oncogenic risk over others in Fujian. HPV-18 and -16 have the highest oncopotency.2. Infection of HCMV, HSV-Ⅱ, CT, UU, TP was closely related to the genesis of cervical cancer. Significant combined effects between HPV and infection of HCMV、HSV-Ⅱ、CT、UU、TP was found. Their combination could strengthen the process of the disease and lead to the pathogenesis of cervical cancer.3. Tuberculosis, sexually transmitted diseases, smoking, gravidity, age 16 to 20 of sexual life for the first time, number of sex partner, HR-HPV, HSV-Ⅱ, TP and so on, were the main risk factors of cervical cancer. 4. The presence of multiple HR-HPV had no increased risk of having cervical carcinoma or precancerous lesion.5. HPV-66,-68, and -CP83:04 were associated with CIN1; HPV-52 was CIN2/3-associated types in Fujian. The presence of HPV-16,-18,-33 and -45, as well as multiple HPV types pre-LEEP are associated with higher rates of residual/recurrent disease after LEEP.更多还原