宫颈鳞状细胞癌发病和生存因素分析及其与食管鳞状细胞癌遗传易感性对比研究
发布时间：2018-08-24 15:43
【摘要】：1 研究背景 宫颈癌位居中国妇科恶性肿瘤的第二位,严重影响女性生育和生命健康。其主要组织学类型为宫颈鳞状细胞癌(鳞癌)(cervical squamous cell carcinoma,CSCC),发病率占75%~80%。宫颈癌的预后与临床分期密切相关,早发现和早治疗是改善患者预后的有效途径。流行病学调查显示与宫颈癌发病相关的因素主要包括:人乳头瘤病毒(human pappilloma virus,HPV)感染、性行为及分娩次数等。对高危人群的筛查是提升宫颈癌早期诊断率的重要手段。相关研究发现有宫颈癌家族史人群的一级亲属中患宫颈上皮内瘤变(Cervical intraepithelial neoplasia,CIN)Ⅲ级及浸润性宫颈癌的机率明显高于无宫颈癌家族史人群。随着对宫颈癌分子生物学研究的进展,发现遗传因素可能是宫颈癌发病因素的重要组成部分。宫颈鳞癌和食管鳞癌(esophageal squamous cell carcinoma,ESCC)是中国最为常见的两种恶性肿瘤,而且,二者在流行特征,发病危险因素,特别是组织学发生模式等方面具有明显的相似性。流行病学调查显示河南、山西和新疆石河子等食管癌高发区同时存在宫颈癌高发的现象。HPV感染已被证明与宫颈癌发生和发展密切相关;非常有趣的是,近年越来越多的研究提示,HPV感染能明显提高食管癌发病风险。宫颈与食管鳞癌的组织学发生均为多阶段进行性发展过程,即,正常鳞状上皮经基底细胞过度增生→不典型增生→原位癌→早期浸润癌。此外,食管癌变组织学发生名词多借鉴于宫颈癌组织学发生的命名原则。特别需要指出的是,近年肿瘤遗传分子生物学研究提示食管癌和其他肿瘤存在相似的基因单核苷酸多态易感位点(single nucleiotide polymorphism,SNP)。本研究组前期利用全基因组关联分析(Genome-wide association study,GWAS)所发现的中国人群食管鳞癌易感位点,被后来的研究证明与人体许多其他肿瘤也相关,包括胃癌、食管腺癌、肺癌、胆囊癌,甚至脑神经胶质瘤有关;近年有关肺鳞癌和胃癌GWAS研究又发现了一些重要易感位点。鉴于此,本研究旨在探讨中国汉族人群宫颈鳞癌患者临床表型特征及其与生存关系,并结合近年有关食管鳞癌、肺癌和胃癌GWAS发现的主要易感位点,利用Sequenom Mass Array分子量阵列技术甄别宫颈癌相关易感位点,进一步明确这些易感位点与宫颈癌临床表型的关系,加深对宫颈癌发病分子机理的了解。2资料与方法2.1宫颈鳞癌发病因素和生存影响因素分析2.1.1研究对象病例组来自郑州大学第三附属医院,河南省肿瘤医院和郑州市妇幼保健院2000年1月1日-2014年4月30日收治的宫颈鳞癌患者。宫颈鳞癌的患者入选标准:均经组织病理学证实为宫颈鳞状细胞癌。809例宫颈鳞癌患者平均年龄50±11岁(年龄范围:25~83岁);795例对照组均来自于郑州大学第三附属医院健康体检人群,平均年龄48±11岁(年龄范围:24~88岁)。2.1.2问卷调查流行病学调查采用问卷调查方式,内容包括:年龄、户籍类型、结婚年龄、吸烟史、孕产史、月经初潮年龄、绝经年龄、家族史等信息。2.1.3随访采用电话、家访等方法对患者进行随访,并结合当地村医对患者生存情况进行调查,将调查随访资料集中整理后输入EXCEL表格,以便于数据分析应用。2.1.4统计学分析所有信息录入EXCEL软件,SPSS17.0统计软件处理,组间比较采用卡方检验,Logistic回归分析,采用Kaplan-Meier绘制生存曲线,Log-Rank检验进行组间比较分析各因素与生存关系,COX-regression回归计算风险比例及95%可信区间,检验水准取α=0.05。2.2宫颈鳞状细胞癌易感位点研究2.2.1研究对象病例组来自郑州大学第三附属医院,河南省肿瘤医院和郑州市妇幼保健院2011年10月23日-2012年5月5日收治的宫颈鳞癌患者。宫颈鳞癌患者入选标准同前。376例宫颈鳞癌患者平均年龄53±11岁(年龄范围:25~83岁);731例对照组均来自于郑州大学第一附属医院健康体检人群,平均年龄51±11岁(年龄范围:18~80岁);女性对照组389例,平均年龄51±10岁(年龄范围:18~77岁);男性对照组342例,平均年龄51±11岁(年龄范围:19~80岁)。2.2.2血样收集和DNA提取采集每位病例组宫颈鳞癌患者和对照组健康人晨起空腹外周静脉血5ml,分装成5管,每管1ml,-80℃储存。采用Flexi Gene DNA提取试剂盒(Qiagen),并按照说明书中操作步骤提取血样品中的全基因组DNA,将用于验证的DNA浓度进行标准化,使浓度保持在15ng-20ng/ul,OD值范围为1.8-2.0。2.2.3基因型检测本研究检测的易感位点来自食管鳞癌、肺癌和胃癌GWAS研究所发现的18个SNPs,包括4个食管鳞癌、12个肺癌和2个胃癌SNP位点。根据这些SNP位点进行引物的设计,采用Sequenom Mass Array分子阵列技术,检测这些位点在病例组和对照组的变化。2.2.4统计学分析计算最小等位基因频率(minor allele frequency,MAF)以及哈迪-温伯格(Hardy-Weinberg,HWE)平衡律,利用Plink 1.06软件对经过质控后数据进行分析,并采用Cochran-Armitage trend检验计算P值、95%可信区间(95%confidence interval,95%CI)以及优势比(odds ratio,OR)。比较验证每个SNP等位基因频率在病例组和对照组之间差异采用卡方检验,检验标准α=0.05。3 结果 3.1宫颈鳞癌发病风险3.1.1宫颈鳞癌患者发病年龄≤35岁、36~45岁、46~55岁、56~65岁和≥66岁所占比例分别为7.17%(58/809)、30.41%(246/809)、33.87%(274/809)、20.52%(166/809)和8.03%(65/809),提示宫颈鳞癌患者高发年龄为36~55岁。3.1.2宫颈鳞癌患者农村居民所占比例明显高于城市居民(510/809,63%VS.299/809,37%),提示社会经济地位低下是宫颈鳞癌发病的风险因素。3.1.3宫颈鳞癌患者月经初潮年龄14岁所占比例明显低于对照组(195/804,24%VS.437/795,55%),提示初潮年龄晚明显影响宫颈癌发病风险(OR=0.262,95%CI 0.212-0.325,P=0.000)。3.1.4宫颈鳞癌患者结婚年龄22岁所占比例明显高于对照组(315/767,41%VS.109/795,14%),提示早婚是宫颈癌发病风险又一重要影响因素(OR=4.386,95%CI 3.422~5.621,P=0.000)。3.1.5宫颈癌患者月经初潮年龄与结婚年龄时间间隔8年所占比例明显高于对照组(368/767,48%VS.141/795,19%),提示结婚年龄与初潮年龄时间间隔短可以增加宫颈癌的发病风险(OR=3.999,95%CI 3.185~5.021,P=0.000)。3.1.6宫颈鳞癌患者妊娠次数≥3次所占比例明显高于对照组(621/805,77%VS.349/795,44%),提示妊娠次数多是宫颈癌发生的风险因素(OR=4.313,95%CI 3.475~5.353,P=0.000)。3.1.7宫颈鳞癌患者分娩次数≥2次所占比例明显高于对照组(643/805,75%VS.210/795,26%),提示多产与宫颈癌的发病风险相关(OR=11.057,95%CI8.754~13.966,P=0.000)。3.1.8宫颈癌不同发病风险影响因素Logistic回归分析发现:月经初潮年龄、早婚、多孕和多产是影响宫颈癌发生的独立风险因素。3.2宫颈鳞癌临床生存影响因素3.2.1单因素分析表明,分娩次数、FIGO分期和治疗方式与宫颈鳞癌患者预后密切相关(P0.05);COX回归分析发现:FIGO分期不同是影响患者预后的独立风险因素(P0.05)。3.2.2宫颈鳞癌Ⅰb~Ⅱa期患者生存影响单因素和COX回归分析提示:淋巴结转移阳性是影响患者预后的风险因素(P0.05)。3.3宫颈鳞状细胞癌遗传易感性3.3.1宫颈鳞癌患者和女性对照组18个SNP位点对比分析发现rs36600 SNP位点明显提高宫颈癌发病风险(OR=0.68,95%CI 0.53~0.88,P=3.40×10-3),该位点定位在肌管素相关蛋白3(myotubularin related protein 3 MTMR3)基因上。为了鉴别对于女性特有疾病遗传易感性的研究是否可以把男性作为对照组,再次将宫颈鳞癌患者与男性对照组进行比较分析,结果两者无明显差异(OR=0.78,95%CI 0.60~1.03,P=0.08)。进一步将宫颈鳞癌患者与男女混合对照组进行分析验证,发现该SNP位点与宫颈鳞癌的发生仍然存在相关性(OR=0.73,95%CI 0.58~0.92,P=6.68×10-3)。3.3.2宫颈癌患者rs36600 SNP位点与生存预后相关性分析发现:携带不同基因表型患者的生存预后无明显差异(X2=0.000,P=0.985)。4 结论 4.1月经初潮年龄小是宫颈癌发生风险的保护性因素,而早婚、孕产次数多可能是宫颈癌发生的风险因素。4.2宫颈癌患者临床分期差异是影响生存预后的独立风险因素;淋巴结转移阳性影响Ⅰb~Ⅱa期宫颈鳞癌患者预后。4.3首次证实了与中国汉族人宫颈鳞癌发病明显相关的重要SNP位点,即位于22q12.2染色体上的MTMR3基因上的rs36600 SNP位点。
[Abstract]:1. Background Cervical squamous cell carcinoma (CSCC) is the second most common gynecological malignancy in China, which seriously affects women's fertility and life. Epidemiological studies have shown that the risk factors for cervical cancer include human papillomavirus (HPV) infection, sexual behavior and the number of deliveries. Screening high-risk groups is an important means to improve the early diagnosis rate of cervical cancer. The incidence of cervical intraepithelial neoplasia (CIN) grade III and invasive cervical cancer in the first-degree relatives was significantly higher than that in the first-degree relatives without family history of cervical cancer. Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in China. The epidemiological characteristics, risk factors and histological patterns of ESCC are similar. Epidemiological investigation shows that cervical cancer coexists in high incidence areas of esophageal cancer such as Henan, Shanxi and Shihezi in Xinjiang. HPV infection has been shown to be closely related to the occurrence and development of cervical cancer; interestingly, in recent years, more and more studies suggest that HPV infection can significantly increase the risk of esophageal cancer. In addition, the nomenclature of histogenesis of esophageal carcinogenesis is mainly based on the nomenclature of cervical carcinogenesis. In particular, recent studies on genetic and molecular biology of cancer suggest that there are similar single nucleotide polymorphism susceptibility loci in esophageal cancer and other tumors. The susceptibility sites of esophageal squamous cell carcinoma (ESCC) in Chinese population, which were identified by genome-wide association study (GWAS), were also associated with many other human tumors, including gastric cancer, esophageal adenocarcinoma, lung cancer, gallbladder cancer, and even brain glioma. In recent years, some important susceptibility sites have been found in GWAS studies of lung squamous cell carcinoma and gastric cancer. In view of this, this study aimed to investigate the clinical phenotype and survival relationship of cervical squamous cell carcinoma in Chinese Han population, and to utilize the molecular weight of Sequenom Mass Array in combination with the major susceptibility sites found by GWAS in esophageal squamous cell carcinoma, lung cancer and gastric cancer in recent years. Material and Methods 2.1 Pathogenesis and Survival Factors of Cervical Squamous Cell Carcinoma 2.1.1 The case group was from the Third Affiliated Hospital of Zhengzhou University, Henan Province. Patients with cervical squamous cell carcinoma were admitted to the provincial Cancer Hospital and Zhengzhou Maternal and Child Health Hospital from January 1, 2000 to April 30, 2014. 2.1.2 Questionnaire was used to investigate the epidemiology of the health examination population in the three affiliated hospitals. The contents included age, household registration type, marriage age, smoking history, pregnancy and childbirth history, menarche age, menopausal age, family history and other information. 2.1.3 Follow-up visits were conducted by telephone and home visits. Patients were followed up, and the survival situation of the patients was investigated by local village doctors. The follow-up data were collected and entered into EXCEL form for data analysis and application. 2.1.4 All the information was entered into EXCEL software for statistical analysis. SPSS17.0 software was used for statistical analysis. Chi-square test, logistic regression analysis and Kaplan-M were used for inter-group comparison. The survival curve was drawn by eier, and the survival relationship was analyzed by Log-Rank test. The risk ratio and 95% confidence interval were calculated by COX-regression regression. The test level was 0.05.2.2. The susceptibility site of cervical squamous cell carcinoma was 2.2.1. The case group was from the Third Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital and Zheng Zheng. From October 23, 2011 to May 5, 2012, a total of 376 patients with cervical squamous cell carcinoma were enrolled in this study. The average age of the patients was 53 18-80 years old; female control group 389 cases, average age 51 (- 77 years old); male control group 342 cases, average age 51 (- 11 years old) (age range: 19-80 years old). 2.2.2 blood sample collection and DNA extraction collection of each case group of cervical squamous cell carcinoma patients and control group healthy people in the morning fasting peripheral venous blood 5ml, packed into five tubes, each tube 1ml, - 80 (- 80%) storage Using Flexi Gene DNA Extraction Kit (Qiagen), genome-wide DNA was extracted from the blood samples according to the instructions. The DNA concentration for verification was standardized to keep the concentration at 15ng-20ng/ul. The OD value ranged from 1.8 to 2.0.2.3 genotype. The susceptibility loci detected in this study were from esophageal squamous cell carcinoma, lung cancer and gastric cancer G. 18 SNPs, including 4 esophageal squamous cell carcinoma, 12 lung cancer and 2 gastric cancer, were identified by WAS. Primers were designed according to these SNPs and the changes of these SNPs in the case group and control group were detected by Sequenom Mass Array molecular array technique. Y, MAF, and Hardy-Weinberg (HWE) equilibrium laws were used to analyze the data after quality control using Plink 1.06 software. Cochran-Armitage tree test was used to calculate P value, 95% confidence interval (95% CI) and odds ratio (OR). The frequencies of each SNP allele were compared between the case group and the pair. Chi-square test was used to test the difference between the control group and the control group. Results The risk of cervical squamous cell carcinoma was 3.1.1 Results The proportion of patients with cervical squamous cell carcinoma was 7.17% (58/809), 30.41% (246/809), 33.87% (274/809), 20.52% (166/809) and 8.03% (65/809), respectively. The proportion of rural residents with a high incidence of cervical squamous cell carcinoma was significantly higher than that of urban residents (510/809,63% VS.299/809,37%), suggesting that low socioeconomic status was a risk factor for cervical squamous cell carcinoma. It was suggested that the late menarche age significantly affected the risk of cervical cancer (OR = 0.262, 95% CI 0.212-0.325, P = 0.000). 3.1.4 The proportion of married patients aged 22 years was significantly higher than that of the control group (315/767, 41% VS.109/795, 14%). Early marriage was another important risk factor of cervical cancer (OR = 4.386, 95% CI 3.422-5.621, P = 0.000). The 8-year interval between menarche age and marriage age in cervical cancer patients was significantly higher than that in the control group (368/767,48% VS.141/795,19%), suggesting that the short interval between marriage age and menarche age could increase the risk of cervical cancer (OR = 3.999,95% CI 3.185-5.021,P = 0.000). 3.1.6 patients with cervical squamous cell carcinoma had more than 3 pregnancies. It was significantly higher than that of the control group (621/805,77% VS.349/795,44%), suggesting that the number of pregnancies was a risk factor for cervical cancer (OR = 4.313,95% CI 3.475-5.353,P = 0.000). 3.1.7 The proportion of patients with cervical squamous cell carcinoma having more than two deliveries was significantly higher than that of the control group (643/805,75% VS.210/795,26%), suggesting that prolificacy was associated with cervical cancer (OR = 11.057,P = 0.000). 95% CI8.754-13.966, P = 0.000).3.1.8 The logistic regression analysis showed that the age of menarche, early marriage, polygamy and fertility were independent risk factors for cervical cancer. COX regression analysis showed that FIGO staging was an independent risk factor for prognosis (P 0.05). 3.2.2 Univariate and COX regression analysis showed that positive lymph node metastasis was a risk factor for prognosis (P 0.05). 3.3 Cervical squamous cell carcinoma legacy. A comparative analysis of 18 SNP loci in cervical squamous cell carcinoma patients and female control group showed that rs36600 SNP loci significantly increased the risk of cervical cancer (OR = 0.68, 95% CI 0.53-0.88, P = 3.40 *10-3), which was located in myotubin-related protein 3 (MTMR3) gene. Genetic susceptibility study whether the male as a control group, again cervical squamous cell carcinoma patients and male control group were compared and analyzed, the results showed no significant difference between the two (OR = 0.78, 95% CI 0.60-1.03, P = 0.08). Further cervical squamous cell carcinoma patients and mixed control group were analyzed and verified, found that the SNP locus and cervical squamous cell carcinoma. There was still a correlation between the survival and prognosis of cervical cancer patients (OR = 0.73, 95% CI 0.58-0.92, P = 6.68 *10-3). 3.3.2 The correlation analysis showed that there was no significant difference between the survival and prognosis of patients with different genotypes (X2 = 0.000, P = 0.985). Conclusion The early menarche age in April is a protective factor for the risk of cervical cancer. 4.2 Difference in clinical stage of cervical cancer patients is an independent risk factor for survival and prognosis; positive lymph node metastasis affects the prognosis of patients with stage I b~II a cervical squamous cell carcinoma. 4.3 confirmed for the first time that an important SNP locus, located at 22q, was significantly associated with the incidence of cervical squamous cell carcinoma in Chinese Han population. The rs36600 SNP locus of the MTMR3 gene on the 12.2 chromosome.
【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R737.33;R735.1
本文编号：2201277
[Abstract]:1. Background Cervical squamous cell carcinoma (CSCC) is the second most common gynecological malignancy in China, which seriously affects women's fertility and life. Epidemiological studies have shown that the risk factors for cervical cancer include human papillomavirus (HPV) infection, sexual behavior and the number of deliveries. Screening high-risk groups is an important means to improve the early diagnosis rate of cervical cancer. The incidence of cervical intraepithelial neoplasia (CIN) grade III and invasive cervical cancer in the first-degree relatives was significantly higher than that in the first-degree relatives without family history of cervical cancer. Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in China. The epidemiological characteristics, risk factors and histological patterns of ESCC are similar. Epidemiological investigation shows that cervical cancer coexists in high incidence areas of esophageal cancer such as Henan, Shanxi and Shihezi in Xinjiang. HPV infection has been shown to be closely related to the occurrence and development of cervical cancer; interestingly, in recent years, more and more studies suggest that HPV infection can significantly increase the risk of esophageal cancer. In addition, the nomenclature of histogenesis of esophageal carcinogenesis is mainly based on the nomenclature of cervical carcinogenesis. In particular, recent studies on genetic and molecular biology of cancer suggest that there are similar single nucleotide polymorphism susceptibility loci in esophageal cancer and other tumors. The susceptibility sites of esophageal squamous cell carcinoma (ESCC) in Chinese population, which were identified by genome-wide association study (GWAS), were also associated with many other human tumors, including gastric cancer, esophageal adenocarcinoma, lung cancer, gallbladder cancer, and even brain glioma. In recent years, some important susceptibility sites have been found in GWAS studies of lung squamous cell carcinoma and gastric cancer. In view of this, this study aimed to investigate the clinical phenotype and survival relationship of cervical squamous cell carcinoma in Chinese Han population, and to utilize the molecular weight of Sequenom Mass Array in combination with the major susceptibility sites found by GWAS in esophageal squamous cell carcinoma, lung cancer and gastric cancer in recent years. Material and Methods 2.1 Pathogenesis and Survival Factors of Cervical Squamous Cell Carcinoma 2.1.1 The case group was from the Third Affiliated Hospital of Zhengzhou University, Henan Province. Patients with cervical squamous cell carcinoma were admitted to the provincial Cancer Hospital and Zhengzhou Maternal and Child Health Hospital from January 1, 2000 to April 30, 2014. 2.1.2 Questionnaire was used to investigate the epidemiology of the health examination population in the three affiliated hospitals. The contents included age, household registration type, marriage age, smoking history, pregnancy and childbirth history, menarche age, menopausal age, family history and other information. 2.1.3 Follow-up visits were conducted by telephone and home visits. Patients were followed up, and the survival situation of the patients was investigated by local village doctors. The follow-up data were collected and entered into EXCEL form for data analysis and application. 2.1.4 All the information was entered into EXCEL software for statistical analysis. SPSS17.0 software was used for statistical analysis. Chi-square test, logistic regression analysis and Kaplan-M were used for inter-group comparison. The survival curve was drawn by eier, and the survival relationship was analyzed by Log-Rank test. The risk ratio and 95% confidence interval were calculated by COX-regression regression. The test level was 0.05.2.2. The susceptibility site of cervical squamous cell carcinoma was 2.2.1. The case group was from the Third Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital and Zheng Zheng. From October 23, 2011 to May 5, 2012, a total of 376 patients with cervical squamous cell carcinoma were enrolled in this study. The average age of the patients was 53 18-80 years old; female control group 389 cases, average age 51 (- 77 years old); male control group 342 cases, average age 51 (- 11 years old) (age range: 19-80 years old). 2.2.2 blood sample collection and DNA extraction collection of each case group of cervical squamous cell carcinoma patients and control group healthy people in the morning fasting peripheral venous blood 5ml, packed into five tubes, each tube 1ml, - 80 (- 80%) storage Using Flexi Gene DNA Extraction Kit (Qiagen), genome-wide DNA was extracted from the blood samples according to the instructions. The DNA concentration for verification was standardized to keep the concentration at 15ng-20ng/ul. The OD value ranged from 1.8 to 2.0.2.3 genotype. The susceptibility loci detected in this study were from esophageal squamous cell carcinoma, lung cancer and gastric cancer G. 18 SNPs, including 4 esophageal squamous cell carcinoma, 12 lung cancer and 2 gastric cancer, were identified by WAS. Primers were designed according to these SNPs and the changes of these SNPs in the case group and control group were detected by Sequenom Mass Array molecular array technique. Y, MAF, and Hardy-Weinberg (HWE) equilibrium laws were used to analyze the data after quality control using Plink 1.06 software. Cochran-Armitage tree test was used to calculate P value, 95% confidence interval (95% CI) and odds ratio (OR). The frequencies of each SNP allele were compared between the case group and the pair. Chi-square test was used to test the difference between the control group and the control group. Results The risk of cervical squamous cell carcinoma was 3.1.1 Results The proportion of patients with cervical squamous cell carcinoma was 7.17% (58/809), 30.41% (246/809), 33.87% (274/809), 20.52% (166/809) and 8.03% (65/809), respectively. The proportion of rural residents with a high incidence of cervical squamous cell carcinoma was significantly higher than that of urban residents (510/809,63% VS.299/809,37%), suggesting that low socioeconomic status was a risk factor for cervical squamous cell carcinoma. It was suggested that the late menarche age significantly affected the risk of cervical cancer (OR = 0.262, 95% CI 0.212-0.325, P = 0.000). 3.1.4 The proportion of married patients aged 22 years was significantly higher than that of the control group (315/767, 41% VS.109/795, 14%). Early marriage was another important risk factor of cervical cancer (OR = 4.386, 95% CI 3.422-5.621, P = 0.000). The 8-year interval between menarche age and marriage age in cervical cancer patients was significantly higher than that in the control group (368/767,48% VS.141/795,19%), suggesting that the short interval between marriage age and menarche age could increase the risk of cervical cancer (OR = 3.999,95% CI 3.185-5.021,P = 0.000). 3.1.6 patients with cervical squamous cell carcinoma had more than 3 pregnancies. It was significantly higher than that of the control group (621/805,77% VS.349/795,44%), suggesting that the number of pregnancies was a risk factor for cervical cancer (OR = 4.313,95% CI 3.475-5.353,P = 0.000). 3.1.7 The proportion of patients with cervical squamous cell carcinoma having more than two deliveries was significantly higher than that of the control group (643/805,75% VS.210/795,26%), suggesting that prolificacy was associated with cervical cancer (OR = 11.057,P = 0.000). 95% CI8.754-13.966, P = 0.000).3.1.8 The logistic regression analysis showed that the age of menarche, early marriage, polygamy and fertility were independent risk factors for cervical cancer. COX regression analysis showed that FIGO staging was an independent risk factor for prognosis (P 0.05). 3.2.2 Univariate and COX regression analysis showed that positive lymph node metastasis was a risk factor for prognosis (P 0.05). 3.3 Cervical squamous cell carcinoma legacy. A comparative analysis of 18 SNP loci in cervical squamous cell carcinoma patients and female control group showed that rs36600 SNP loci significantly increased the risk of cervical cancer (OR = 0.68, 95% CI 0.53-0.88, P = 3.40 *10-3), which was located in myotubin-related protein 3 (MTMR3) gene. Genetic susceptibility study whether the male as a control group, again cervical squamous cell carcinoma patients and male control group were compared and analyzed, the results showed no significant difference between the two (OR = 0.78, 95% CI 0.60-1.03, P = 0.08). Further cervical squamous cell carcinoma patients and mixed control group were analyzed and verified, found that the SNP locus and cervical squamous cell carcinoma. There was still a correlation between the survival and prognosis of cervical cancer patients (OR = 0.73, 95% CI 0.58-0.92, P = 6.68 *10-3). 3.3.2 The correlation analysis showed that there was no significant difference between the survival and prognosis of patients with different genotypes (X2 = 0.000, P = 0.985). Conclusion The early menarche age in April is a protective factor for the risk of cervical cancer. 4.2 Difference in clinical stage of cervical cancer patients is an independent risk factor for survival and prognosis; positive lymph node metastasis affects the prognosis of patients with stage I b~II a cervical squamous cell carcinoma. 4.3 confirmed for the first time that an important SNP locus, located at 22q, was significantly associated with the incidence of cervical squamous cell carcinoma in Chinese Han population. The rs36600 SNP locus of the MTMR3 gene on the 12.2 chromosome.
【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R737.33;R735.1
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