【作者】 朱慧；

【导师】 韩素萍；

【作者基本信息】 南京医科大学 ， 妇产科学， 2008， 硕士

【摘要】 宫颈癌是常见的妇科恶性肿瘤,发病率占女性恶性肿瘤中的第2位。全世界每年的新发病例约50万,其中亚洲占一半约23.5万。在我国每年新发宫颈癌病例约有13万,死于宫颈癌的病例大概有2～3万,且近年宫颈癌的发病率和死亡率有增长的趋势,发病也趋于年轻化。大量的流行病学调查提示,宫颈癌的病因比较复杂,其发生是遗传和坏境因素共同作用的结果。JWA是周建伟等首先从培养的原代人气管和支气管上皮细胞中分离克隆的受维甲酸（ATRA）诱导与细胞分化相关的新的细胞骨架相关蛋白,JWA基因位于3p14,由3个外显子和2个内含子组成,其中cDNA包含2114个核苷酸,编码188个氨基酸,其启动子序列中含有多种反应元件,如TRE、SRE、RARE等。前期的研究结果表示JWA和多种化学物质（如:ATRA等）介导的白血病细胞分化和凋亡有关,JWA对环境刺激（如:氧化应激、热休克等）应答活跃,JWA积极参与苯并茨B[a]P和H₂O₂诱导的细胞DNA损伤和修复过程的调节,JWA极有可能作为一个有效的早期氧化应激反应基因,并可能与反应性氧化物（reactive oxygen species ROS）造成的细胞内DNA损伤和修复有关。越来越多的研究证明,和生物进程有关的基因的单核苷酸多态性SNP和癌症紧密相关。作为有效的遗传生物标记,一些SNPs被认为和疾病改变的易感性有关,包括癌症。SNP通常位于致病基因的附近或偶尔其本身和疾病有关,因此常用来搜寻和分离致病基因。已有研究发现,JWA基因的两个SNPs位点（-76G＞C和723T＞G）和白血病、膀胱癌、消化道肿瘤发生危险型的相关性具有统计学意义,其中-76G＞C增加了上述肿瘤发病的危险性,并-76C等位基因对环境刺激应答过程中可以减少或者关闭JWA启动子的作用,导致JWA基因表达下调或者缺失。JWA基因可能在DNA损伤相关癌症的发生中起作用,并且其变异基因型可能促使个体对环境诱导的癌症的易感性产生差异。【研究目的】通过宏观流行病学和分子流行病学相结合的方法,探讨JWA基因多态性与江苏人群宫颈癌易感性之间的关系。【研究方法】采用基于医院的分子流行病学病例-对照研究方法,选取227例经组织病理学诊断为宫颈癌患者和333例年龄（±5岁）、性别相匹配的非肿瘤患者作为对照研究;对象均来自江苏省人民医院、江苏省肿瘤医院以及南通市肿瘤医院的江苏地区病例和健康体检人群,采用聚合酶链反应限制性片段长度多态性（PCR-RFLP）方法对JWA启动子区-76G＞C,第二外显子45C＞A和第三外显子723T＞G多态性进行基因分型,比较不同基因型携带者惠子宫颈癌的危险性;通过分层分析探讨初潮年龄、初次生育年龄和产次对患有宫颈癌影响的频率和分布,比较不同基因型携带者患子宫颈癌的危险性。【研究结果】JWA-76GC和454AA基因型均可增加罹患宫颈癌的危险性。携带3～5个危险等位基因者比携带0～2个等位基因者患宫颈癌的危险性更大（OR=1.70,95%CI=1.20～2.42）。分层分析结果显示,初潮年龄早、生育年龄晚和产次多且携带3～5个危险等位基因者能增加患宫颈癌的危险性。本研究未发现JWA基因723T＞G多态性与宫颈癌之间存在显著相关。【研究结论】JWA基因-76G＞C和454C＞A多态性显著增加江苏地区汉族人群患宫颈癌的危险性。更多还原

【Abstract】 Cervical cancer is the second most common cancer among women worldwide. There were 500 thousands new cervical cancer cases every year and half of this happened in Asian country. In our country there are about 13 thousands new cervical cancer cases and about 2 thousands to 3 thousands cases who died of this cancer every year. In the recent years the incidence and mortality of cervical cancer is continually increasing in China and the new cases are younger than before. JWA gene was initially isolated from ATRA-treated primary human tracheal bronchial epithelial cells by Zhou et al, which was mapped on chromosome 3p14, consisting of 3 exons and 2 introns. The full length of cDNA sequence of the gene contains 2114 nucleotides, which encoding 188 amino acids. Within the identified 3000 base pairs of promoter sequence of the gene, several cis-response elements, such as phorbol ester response element（TRE）,stress response element（SRE）and the retinoic acid response element（rare）were identified. Previous investigation have demonstrated that JWA gene was not only important for chemicals（e.g. ATRA）mediated directional cell differentiation and apoptosis in primary cultured APL cells and leukemia cell lines, but also was actively responsive to environmental stress stimulations（e.g. heat shock, oxidative stress）.JWA positively involved in the DNA damage and repair process induced by H₂O₂ and B[a]P induced oxidative stress, suggesting that JWA may be involved in signaling of DNA damage and repair process.More and more evidence support that SNP in genes involved in biological process have association with cancer. As useful genetic biomarkers, some SNPs were identified to be associated with altered susceptibility to diseases, including cancer. Most SNPs are usually located near a gene found to be associated with a certain disease, occasionally, a SNP may be associated with development of a disease and, therefore, it can be used to search for and isolated the disease-causing gene.Latest investigation has demonstrated that two novel polymorphisms in the JWA gene （-76G>C和723T>G） were associated with risk of bladder cancer, leukemia and digestive system cancers. The -76G>C could increase the risks of the above-mentioned cancers.The -76C allele might decrease or prevent the role of the JWA promoter in regulating the transcription of the JWA gene, resulting in down regulation or deletion of the JWA gene expression, particularly in the presence of oxidative stress. Therefore JWA gene may play a role in DNA damage-associateddevelopment of cancers and that its variants may contribute to individualvariation in susceptibility to environmentally induced cancer.[Objective] To investigate the association between of JWA gene singlenucleotide polymorphisms and the risk of cervical cancer.[Methods] In a hospital-based case-control study of 227 cervical patients and333 cancer-free controls frequency-matched by age, the genotype of the -76G>C,454C>A and 723T>G polymorphisms of JWA gene were detected by thepolymerase chain reaction-restriction fragment length polymorphism（PCR-RFLP） method; the interaction of menarche age, reproductive age for thefirst time （RAFT） and parity were further analyzed.[Results] A significant increased risk of cervical cancer was found to beassociated with the -76GC genotype compared with the -76GG genotype（OR=1.84, 95%CI=1.21～2.78）, and 454AA genotype compared with the454CC genotype （OR=1.84, 95%CI=1.08～3.14）. Moreover, individuals with3～5 risk alleles will further increase the risk of cervical cancer accompaniedwith early menarche age, late RAFT and many parity. There was no associationwas found between JWA 723T>G polymorphism and cervical cancer.[Conclusion] The JWA-76G>C and 454C>A polymorphisms might positivelycontribute to the etiology of cervical cancer.更多还原