發(fā)布時(shí)間：2018-08-24 15:43

【摘要】：1 研究背景 宮頸癌位居中國婦科惡性腫瘤的第二位,嚴(yán)重影響女性生育和生命健康。其主要組織學(xué)類型為宮頸鱗狀細(xì)胞癌(鱗癌)(cervical squamous cell carcinoma,CSCC),發(fā)病率占75%~80%。宮頸癌的預(yù)后與臨床分期密切相關(guān),早發(fā)現(xiàn)和早治療是改善患者預(yù)后的有效途徑。流行病學(xué)調(diào)查顯示與宮頸癌發(fā)病相關(guān)的因素主要包括:人乳頭瘤病毒(human pappilloma virus,HPV)感染、性行為及分娩次數(shù)等。對高危人群的篩查是提升宮頸癌早期診斷率的重要手段。相關(guān)研究發(fā)現(xiàn)有宮頸癌家族史人群的一級親屬中患宮頸上皮內(nèi)瘤變(Cervical intraepithelial neoplasia,CIN)Ⅲ級及浸潤性宮頸癌的機(jī)率明顯高于無宮頸癌家族史人群。隨著對宮頸癌分子生物學(xué)研究的進(jìn)展,發(fā)現(xiàn)遺傳因素可能是宮頸癌發(fā)病因素的重要組成部分。宮頸鱗癌和食管鱗癌(esophageal squamous cell carcinoma,ESCC)是中國最為常見的兩種惡性腫瘤,而且,二者在流行特征,發(fā)病危險(xiǎn)因素,特別是組織學(xué)發(fā)生模式等方面具有明顯的相似性。流行病學(xué)調(diào)查顯示河南、山西和新疆石河子等食管癌高發(fā)區(qū)同時(shí)存在宮頸癌高發(fā)的現(xiàn)象。HPV感染已被證明與宮頸癌發(fā)生和發(fā)展密切相關(guān);非常有趣的是,近年越來越多的研究提示,HPV感染能明顯提高食管癌發(fā)病風(fēng)險(xiǎn)。宮頸與食管鱗癌的組織學(xué)發(fā)生均為多階段進(jìn)行性發(fā)展過程,即,正常鱗狀上皮經(jīng)基底細(xì)胞過度增生→不典型增生→原位癌→早期浸潤癌。此外,食管癌變組織學(xué)發(fā)生名詞多借鑒于宮頸癌組織學(xué)發(fā)生的命名原則。特別需要指出的是,近年腫瘤遺傳分子生物學(xué)研究提示食管癌和其他腫瘤存在相似的基因單核苷酸多態(tài)易感位點(diǎn)(single nucleiotide polymorphism,SNP)。本研究組前期利用全基因組關(guān)聯(lián)分析(Genome-wide association study,GWAS)所發(fā)現(xiàn)的中國人群食管鱗癌易感位點(diǎn),被后來的研究證明與人體許多其他腫瘤也相關(guān),包括胃癌、食管腺癌、肺癌、膽囊癌,甚至腦神經(jīng)膠質(zhì)瘤有關(guān);近年有關(guān)肺鱗癌和胃癌GWAS研究又發(fā)現(xiàn)了一些重要易感位點(diǎn)。鑒于此,本研究旨在探討中國漢族人群宮頸鱗癌患者臨床表型特征及其與生存關(guān)系,并結(jié)合近年有關(guān)食管鱗癌、肺癌和胃癌GWAS發(fā)現(xiàn)的主要易感位點(diǎn),利用Sequenom Mass Array分子量陣列技術(shù)甄別宮頸癌相關(guān)易感位點(diǎn),進(jìn)一步明確這些易感位點(diǎn)與宮頸癌臨床表型的關(guān)系,加深對宮頸癌發(fā)病分子機(jī)理的了解。2資料與方法2.1宮頸鱗癌發(fā)病因素和生存影響因素分析2.1.1研究對象病例組來自鄭州大學(xué)第三附屬醫(yī)院,河南省腫瘤醫(yī)院和鄭州市婦幼保健院2000年1月1日-2014年4月30日收治的宮頸鱗癌患者。宮頸鱗癌的患者入選標(biāo)準(zhǔn):均經(jīng)組織病理學(xué)證實(shí)為宮頸鱗狀細(xì)胞癌。809例宮頸鱗癌患者平均年齡50±11歲(年齡范圍:25~83歲);795例對照組均來自于鄭州大學(xué)第三附屬醫(yī)院健康體檢人群,平均年齡48±11歲(年齡范圍:24~88歲)。2.1.2問卷調(diào)查流行病學(xué)調(diào)查采用問卷調(diào)查方式,內(nèi)容包括:年齡、戶籍類型、結(jié)婚年齡、吸煙史、孕產(chǎn)史、月經(jīng)初潮年齡、絕經(jīng)年齡、家族史等信息。2.1.3隨訪采用電話、家訪等方法對患者進(jìn)行隨訪,并結(jié)合當(dāng)?shù)卮遽t(yī)對患者生存情況進(jìn)行調(diào)查,將調(diào)查隨訪資料集中整理后輸入EXCEL表格,以便于數(shù)據(jù)分析應(yīng)用。2.1.4統(tǒng)計(jì)學(xué)分析所有信息錄入EXCEL軟件,SPSS17.0統(tǒng)計(jì)軟件處理,組間比較采用卡方檢驗(yàn),Logistic回歸分析,采用Kaplan-Meier繪制生存曲線,Log-Rank檢驗(yàn)進(jìn)行組間比較分析各因素與生存關(guān)系,COX-regression回歸計(jì)算風(fēng)險(xiǎn)比例及95%可信區(qū)間,檢驗(yàn)水準(zhǔn)取α=0.05。2.2宮頸鱗狀細(xì)胞癌易感位點(diǎn)研究2.2.1研究對象病例組來自鄭州大學(xué)第三附屬醫(yī)院,河南省腫瘤醫(yī)院和鄭州市婦幼保健院2011年10月23日-2012年5月5日收治的宮頸鱗癌患者。宮頸鱗癌患者入選標(biāo)準(zhǔn)同前。376例宮頸鱗癌患者平均年齡53±11歲(年齡范圍:25~83歲);731例對照組均來自于鄭州大學(xué)第一附屬醫(yī)院健康體檢人群,平均年齡51±11歲(年齡范圍:18~80歲);女性對照組389例,平均年齡51±10歲(年齡范圍:18~77歲);男性對照組342例,平均年齡51±11歲(年齡范圍:19~80歲)。2.2.2血樣收集和DNA提取采集每位病例組宮頸鱗癌患者和對照組健康人晨起空腹外周靜脈血5ml,分裝成5管,每管1ml,-80℃儲存。采用Flexi Gene DNA提取試劑盒(Qiagen),并按照說明書中操作步驟提取血樣品中的全基因組DNA,將用于驗(yàn)證的DNA濃度進(jìn)行標(biāo)準(zhǔn)化,使?jié)舛缺３衷?5ng-20ng/ul,OD值范圍為1.8-2.0。2.2.3基因型檢測本研究檢測的易感位點(diǎn)來自食管鱗癌、肺癌和胃癌GWAS研究所發(fā)現(xiàn)的18個(gè)SNPs,包括4個(gè)食管鱗癌、12個(gè)肺癌和2個(gè)胃癌SNP位點(diǎn)。根據(jù)這些SNP位點(diǎn)進(jìn)行引物的設(shè)計(jì),采用Sequenom Mass Array分子陣列技術(shù),檢測這些位點(diǎn)在病例組和對照組的變化。2.2.4統(tǒng)計(jì)學(xué)分析計(jì)算最小等位基因頻率(minor allele frequency,MAF)以及哈迪-溫伯格(Hardy-Weinberg,HWE)平衡律,利用Plink 1.06軟件對經(jīng)過質(zhì)控后數(shù)據(jù)進(jìn)行分析,并采用Cochran-Armitage trend檢驗(yàn)計(jì)算P值、95%可信區(qū)間(95%confidence interval,95%CI)以及優(yōu)勢比(odds ratio,OR)。比較驗(yàn)證每個(gè)SNP等位基因頻率在病例組和對照組之間差異采用卡方檢驗(yàn),檢驗(yàn)標(biāo)準(zhǔn)α=0.05。3 結(jié)果 3.1宮頸鱗癌發(fā)病風(fēng)險(xiǎn)3.1.1宮頸鱗癌患者發(fā)病年齡≤35歲、36~45歲、46~55歲、56~65歲和≥66歲所占比例分別為7.17%(58/809)、30.41%(246/809)、33.87%(274/809)、20.52%(166/809)和8.03%(65/809),提示宮頸鱗癌患者高發(fā)年齡為36~55歲。3.1.2宮頸鱗癌患者農(nóng)村居民所占比例明顯高于城市居民(510/809,63%VS.299/809,37%),提示社會經(jīng)濟(jì)地位低下是宮頸鱗癌發(fā)病的風(fēng)險(xiǎn)因素。3.1.3宮頸鱗癌患者月經(jīng)初潮年齡14歲所占比例明顯低于對照組(195/804,24%VS.437/795,55%),提示初潮年齡晚明顯影響宮頸癌發(fā)病風(fēng)險(xiǎn)(OR=0.262,95%CI 0.212-0.325,P=0.000)。3.1.4宮頸鱗癌患者結(jié)婚年齡22歲所占比例明顯高于對照組(315/767,41%VS.109/795,14%),提示早婚是宮頸癌發(fā)病風(fēng)險(xiǎn)又一重要影響因素(OR=4.386,95%CI 3.422~5.621,P=0.000)。3.1.5宮頸癌患者月經(jīng)初潮年齡與結(jié)婚年齡時(shí)間間隔8年所占比例明顯高于對照組(368/767,48%VS.141/795,19%),提示結(jié)婚年齡與初潮年齡時(shí)間間隔短可以增加宮頸癌的發(fā)病風(fēng)險(xiǎn)(OR=3.999,95%CI 3.185~5.021,P=0.000)。3.1.6宮頸鱗癌患者妊娠次數(shù)≥3次所占比例明顯高于對照組(621/805,77%VS.349/795,44%),提示妊娠次數(shù)多是宮頸癌發(fā)生的風(fēng)險(xiǎn)因素(OR=4.313,95%CI 3.475~5.353,P=0.000)。3.1.7宮頸鱗癌患者分娩次數(shù)≥2次所占比例明顯高于對照組(643/805,75%VS.210/795,26%),提示多產(chǎn)與宮頸癌的發(fā)病風(fēng)險(xiǎn)相關(guān)(OR=11.057,95%CI8.754~13.966,P=0.000)。3.1.8宮頸癌不同發(fā)病風(fēng)險(xiǎn)影響因素Logistic回歸分析發(fā)現(xiàn):月經(jīng)初潮年齡、早婚、多孕和多產(chǎn)是影響宮頸癌發(fā)生的獨(dú)立風(fēng)險(xiǎn)因素。3.2宮頸鱗癌臨床生存影響因素3.2.1單因素分析表明,分娩次數(shù)、FIGO分期和治療方式與宮頸鱗癌患者預(yù)后密切相關(guān)(P0.05);COX回歸分析發(fā)現(xiàn):FIGO分期不同是影響患者預(yù)后的獨(dú)立風(fēng)險(xiǎn)因素(P0.05)。3.2.2宮頸鱗癌Ⅰb~Ⅱa期患者生存影響單因素和COX回歸分析提示:淋巴結(jié)轉(zhuǎn)移陽性是影響患者預(yù)后的風(fēng)險(xiǎn)因素(P0.05)。3.3宮頸鱗狀細(xì)胞癌遺傳易感性3.3.1宮頸鱗癌患者和女性對照組18個(gè)SNP位點(diǎn)對比分析發(fā)現(xiàn)rs36600 SNP位點(diǎn)明顯提高宮頸癌發(fā)病風(fēng)險(xiǎn)(OR=0.68,95%CI 0.53~0.88,P=3.40×10-3),該位點(diǎn)定位在肌管素相關(guān)蛋白3(myotubularin related protein 3 MTMR3)基因上。為了鑒別對于女性特有疾病遺傳易感性的研究是否可以把男性作為對照組,再次將宮頸鱗癌患者與男性對照組進(jìn)行比較分析,結(jié)果兩者無明顯差異(OR=0.78,95%CI 0.60~1.03,P=0.08)。進(jìn)一步將宮頸鱗癌患者與男女混合對照組進(jìn)行分析驗(yàn)證,發(fā)現(xiàn)該SNP位點(diǎn)與宮頸鱗癌的發(fā)生仍然存在相關(guān)性(OR=0.73,95%CI 0.58~0.92,P=6.68×10-3)。3.3.2宮頸癌患者rs36600 SNP位點(diǎn)與生存預(yù)后相關(guān)性分析發(fā)現(xiàn):攜帶不同基因表型患者的生存預(yù)后無明顯差異(X2=0.000,P=0.985)。4 結(jié)論 4.1月經(jīng)初潮年齡小是宮頸癌發(fā)生風(fēng)險(xiǎn)的保護(hù)性因素,而早婚、孕產(chǎn)次數(shù)多可能是宮頸癌發(fā)生的風(fēng)險(xiǎn)因素。4.2宮頸癌患者臨床分期差異是影響生存預(yù)后的獨(dú)立風(fēng)險(xiǎn)因素;淋巴結(jié)轉(zhuǎn)移陽性影響Ⅰb~Ⅱa期宮頸鱗癌患者預(yù)后。4.3首次證實(shí)了與中國漢族人宮頸鱗癌發(fā)病明顯相關(guān)的重要SNP位點(diǎn),即位于22q12.2染色體上的MTMR3基因上的rs36600 SNP位點(diǎn)。
[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.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R737.33;R735.1

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