荧光原位杂交技术检测hTERC基因扩增在新疆部分地区宫颈癌早期筛查中的临床意义研究
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摘要
研究背景：宫颈病变是女性最常见的疾病之一,其中宫颈癌患病率占女性生殖系统恶性肿瘤的半数以上,严重威胁着妇女的健康。全世界每年大约有46万人患病。中国新发病例约计13万,占目前已发现的所有女性肿瘤的6%,是仅次于乳腺癌而引起妇女癌症相关死亡的重要原因。然而,宫颈癌(SCC)是目前唯一一种可以预防的恶性肿瘤。如果在癌前病变或早期即明确诊断,并及时给予积极的预防措施或适宜的治疗方案,可显著改善患者的预后和提高生活质量。而且,早期宫颈癌的治疗效果和五年生存率也位于恶性肿瘤的前列,这一特点使对宫颈癌的筛查及发病机制的研究具有了更加重要的意义。近十年来随着分子细胞遗传学技术飞速发展,荧光原位杂交技术(FISH)应运而生,并逐渐从基础医学研究领域转向临床医学检测领域。一些有关宫颈癌染色体研究显示,染色体的不稳定性常表现为3q的增加和2、3、4、6p,11q的缺失,并且异常基因区多位于3q261-q28。近几年,美国国家健康研究中心(NIH)领导的针对宫颈癌的研究表明,宫颈细胞由非典型性异常增生向宫颈癌转变过程中几乎都伴有3号染色体长臂扩增,其中涉及到的最重要基因可能是人类染色体端粒酶基因(hTERC),它有望成为非典型细胞癌变的基因,该基因的扩增可阻止细胞凋亡,因而可导致肿瘤产生。国外的研究表明：通过FISH技术检测3q26hTERC基因,发现宫颈上皮内瘤样病变Ⅱ级(CINⅡ)中,此基因的拷贝数增加者占63%,宫颈上皮内瘤样病变Ⅲ级(CINⅢ)占76%,四倍体细胞数和hTERC基因扩增随细胞学病变的严重程度而增加,可作为预测宫颈高度病变(HSIL)的独立指标,认为特异的基因组异常改变是宫颈癌前病变发展到浸润癌所必需的条件。运用FISH技术测定宫颈病变脱落细胞中hTERC基因的扩增表达情况,分析其与宫颈病变进展的关系,评估FISH技术在宫颈病变筛查工作中的应用前景将会使宫颈癌防治工作进入一个新的发展阶段。目前国内外已有诸多有关hTERC基因与宫颈癌发生、发展关系的研究报道,但有关民族之间差异性的研究鲜有报道,而新疆南部地区维吾尔族宫颈癌高发这一严峻事实促使我们有责任进行此方面的研究工作,探讨维吾尔族、汉族子宫颈癌的发病机制的差异,为减少新疆维吾尔族宫颈癌发病率,促进临床工作寻求更多的科学依据。近年来,子宫颈癌的病因学研究已经取得了重要进展。目前已经明确人乳头瘤病毒(human papillomavirus HPV)高危亚型及多重感染可以引起子宫颈癌或宫颈上皮内瘤样病变。而且已有研究提示高危型HPV DNA (HR HPV DNA)基因整合导致hTERC基因扩增与宫颈癌的发生密切相关。超过95%的子宫颈癌病例与HPV感染有关,两且不同地区,不同民族的HPV亚型不同,所导致的病情发展及转归也不同。目前HPV致癌机理研究显示,高危型HPV感染后导致端粒酶的激活是宫颈上皮由癌前病变向宫颈癌转化过程中相当关键的步骤。Kanaya等研究显示：高危型HPV感染及p53失活可以激活端粒酶,使宫颈上皮细胞增殖加快,从而引起宫颈上皮内瘤样病变和宫颈癌。目前认为利用FISH技术检测宫颈hTERC基因扩增具有助于诊断早期潜在宫颈癌的价值。本课题研究旨在对新疆各民族宫颈病变妇女宫颈脱落细胞中hTERC基因表达情况与宫颈病变程度的关系进行分析研究,评估FISH检测hTERC基因在宫颈癌筛查中的临床应用前景,并对比分析新疆维吾尔族、汉民族宫颈病变患者在感染HPV高危亚型之后,hTERC基因的扩增特点及差异性,从而在hTERC基因扩增的水平上,探讨维吾尔族与汉族宫颈病变发病机制的特点及差异性,以此寻求更加高效、可靠的宫颈癌前病变及宫颈癌筛查、诊断方法,并为临床工作提供一定的科学理论依据。近10年来,由于人乳头瘤病毒感染的显著上升,国内每年有10%～15%的新发宫颈癌病例,CIN的发病也有增加趋势,子宫颈癌的发病似有反弹的迹象。值得关注的是子宫颈癌年轻化趋势,年轻妇女宫颈癌发病每年以2%～3%的速度增长,据中国医学科学院肿瘤医院统计,35岁以下的妇女宫颈癌占同期所收治宫颈癌总数的比例,从70年代的1.22%增至90年代的9.88%,每年约有3万妇女死于宫颈癌。可见,子宫颈癌是威胁妇女健康和生命的第一杀手。早期诊断宫颈癌及癌前病变是提高宫颈癌治愈率、生存率、降低宫颈癌发病率的关键。目前通用的筛查宫颈病变的方法为：液基细胞涂片法联合高危型人乳头状瘤病毒检测方法。宫颈细胞学检查虽然特异性高,操作简易,成本低,可用于宫颈癌大规模初筛,但是敏感性不高,所以会导致较大程度的假阴性,并且不能进行细胞水平的定量分析。细胞学异常的结果中,观察者之间的一致性不够理想,重复性差。HPV检测虽然灵敏度较高,但假阳性率也高。HPV阳性只表明宫颈感染病毒的状态,并不代表宫颈细胞学病理变化,无法对宫颈癌的病理类型和病程发展做出准确的判断,因此HPV检测不能替代细胞学检查。FISH技术因其具有较高特异性、敏感性和快速、稳定性好、无创等特点,从一定程度上弥补现行宫颈癌和癌前病变筛查方法的局限性,可作为临床宫颈疾病筛查一项重要的辅助检查。研究目的：1)通过检测人类染色体端粒酶RNA基因在新疆各族妇女宫颈病变中的扩增情况,探讨hTERC基因表达与HPV感染的相关性,了解宫颈癌发病的生物学机制,以及hTERC基因检测在宫颈癌筛查中的临床价值,为宫颈癌的早期诊断提供科学依据。2)探讨新疆地区维吾尔族、汉族妇女宫颈病变脱落细胞中人端粒酶RNA (hTERC)基因表达差异、以及与人乳头瘤病毒高危亚型感染的相关性,评价hTERC基因检测在新疆维、汉妇女宫颈癌筛查中的临床价值。3)通过对比分析宫颈病变患者宫颈脱落细胞hTERC基因扩增情况、高危型HPVDNA感染状况及TCT检查结果,拟对FISH检测hTERC基因扩增的方法在宫颈病变早期筛查方案中的应用价值进行评估,以期为寻求最佳的宫颈癌筛查方案提供科学依据。研究方法：1)选择经宫颈液基细胞学检查(TCT)为正常～宫颈浸润癌(SCC)的149例新疆各族妇女宫颈病变患者为研究对象,采用人乳头瘤病毒(HPV)凯普分型检测其高危型HPV (HR-HPV)感染状况,病理学检查明确其病变性质,荧光原位杂交(FISH)技术检测其hTERC基因异常扩增情况。最终以病理学结果为金标准,分析各病变级别组hTERC基因检测扩增结果,并与宫颈液基细胞学和HPV检测结果进行比较。2)采用荧光原位杂交技术,对比研究50例维吾尔族和52例汉族宫颈病变患者的hTERC基因扩增的情况,同时检测两组人群中高危型HPV DNA感染状况,以病理学结果为金标准,将维吾尔族、汉族两组患者hTERC基因扩增多倍体数及检测结果与HPV检测结果进行比较分析。3)将前两部分的156例宫颈病变患者宫颈脱落细胞中hTERC基因扩增情况与高危型HPV DNA检测结果及TCT检查结果进行对比分析,以阴道镜下宫颈活检后宫颈组织病理学诊断为最终诊断金标准,分别计算三种检测方法的敏感度、特异度、阳性预测值、阴性预测值及约登指数等指标,比较3种筛查、诊断宫颈病变方法的准确效率,评价FISH检测hTERC基因扩增在宫颈病变早诊早治临床工作中的应用前景。研究结果：1)①通过对129例宫颈病变患者和20例正常妇女的宫颈脱落细胞hTERC基因检测,显示研究各组中宫颈液基细胞学检查为正常(NILM)、不典型鳞状细胞(ASCUS)、低度鳞状上皮内病变(LSIL)、高度鳞状上皮内病变(HSIL)和宫颈浸润癌(SCC)病例中宫颈脱落细胞hTERC基因异常扩增率分别为5.00%、17.24%、29.73%、80.48%和81.82%,hTERC基因扩增比例在ASCUS组、LSIL组、HSIL组和SCC组各研究组均明显高于正常对照组,差异有统计学意义(P<0.05)；hTERC基因扩增比例在各级病变中ASCUS组、LSIL组明显低于HSIL组(P<0.05),但ASCUS与LSIL组间差异无统计学意义(P>0.05)。②宫颈病变各级病理分组中,CINI、CINⅡ、CINⅢ和SCC各组患者的hTERC基因异常扩增率分别为21.95%、34.48%、85.71%.83.33%,低级别病变组(CINⅠ)细胞中hTERC基因异常扩增率明显低于高级别病变组(CINⅡ-SCC)。2)①50例维吾尔族宫颈病变患者hTERC基因扩增率均数为76.46%,52例汉族宫颈癌hTERC基因扩增率均数为80.91%。随着病变的进展,维吾尔族、汉族宫颈病变患者的hTERC基因扩增数均明显增加,与对照组比较,差异均有统计学意义(P<0.05)；维吾尔族、汉族宫颈病变两组间hTERC基因扩增率比较,差异亦有统计学意义(P<0.05)。②在维吾尔族、汉族两组患者中HPV多重感染与单一感染组内比较差异均有统计学意义(P<0.05)；HPV单一感染的维吾尔族、汉族两组间hTERC基因扩增率比较,差异无统计学意义(P>0.05),但HPV多重感染的维吾尔族、汉族两组间hTERC基因扩增率比较,差异有统计学意义(P<0.05)。维吾尔族、汉族宫颈癌hTERC基因平均扩增倍数,在HPV各感染亚型组间差异无统计学意义(P>0.05),维吾尔族宫颈病变组总的hTERC基因扩增倍数与汉族组比较,差异有统计学意义,可能与维吾尔族宫颈病变患者中多重感染的比率高于汉族宫颈病变有关。维吾尔族、汉族两组hTERC基因扩增比率在高危型HPV DAN感染阳性与阴性组间均有明显差异,但维吾尔族、汉族两组间差异无统计学意义(P>0.05)。3)①156例宫颈病变宫颈脱落细胞标本应用FISH方法检测hTERC基因扩增情况,CINⅠ组宫颈脱落细胞中hTERC基因异常扩增检出率明显低于CINⅢ和SCC组,差异有统计学意义(P<0.05)；CINⅠ组与CINⅡ组,CINⅢ与SCC组之间hTERC基因扩增差异无统计学意义(P>0.05)。随着病变由低级别向高级别发展,hTERC基因阳性扩增检出率明显增加,与病变严重程度呈正相关。②HPV检测最常见的感染亚型为HPV16,HPV58,HPV18,其次为HPV52,HPV31,HPV68,HPV56,HPV39,HPV33,HPV45,HPV51,有83例感染高危型HPV,总阳性率为53.20%,其中HPV16阳性率57.83%,HPV58阳性率18.07%,HPV18阳性率9.64%。③TCT对于低度病变CINⅠ的诊断符合率是34.78%,对于高度病变CINⅡ、CINⅢ的诊断符合率是37.83%,SCC的诊断符合率是58.82%,总检出率是43.82%。④3种方法筛查宫颈病变的效率比较,对于低度病变组(CINⅠ),三种检测方法无论在检测阳性率、敏感度及特异度方面,差异均无统计学意义(P>0.05)。对于高度病变组(CINⅡ-SCC)中,FISH技术检测为hTERC基因异常扩增阳性65例(59.1%),液基细胞学检查为HSIL者仅19例(17.3%),HR-HPV DNA感染阳性66例(60.0%),两两比较,仅液基细胞学检测组检出率明显低于FISH检测组、HPV检测组,结果差异有统计学意义(P<0.05)。三种检测方法的敏感度及特异度分别为：FISH技术检测组82.7%和73.6%,液基细胞学检查组48.4%和66.8%、HR-HPV DNA检测组86.5%和46.5%,两两比较TCT组的敏感度低于HPV组与FISH组,HPV组的特异度低于TCT组与FISH检测组,差异均有统计学意义(P<0.05)。TCT组阴性预测值在三组中最低,HPV组阳性预测值在三组中最低,约登指数FISH检测方法均高于其它两组,TCT组最低,差异均有统计学意义(P<0.05)。结论：1)在液基细胞学检查及宫颈病理组织学检查中,hTERC基因的扩增比率随病变程度的增加而增加,尤其是宫颈低度病变组与高度病变组hTERC基因的表达有明显差异,由此可应用FISH技术检测hTERC基因异常扩增情况区分宫颈高度病变与低度病变。2)hTERC基因的扩增在维吾尔族、汉族两组中随病变程度进展而增加,hTERC基因扩增比例及扩增信号多倍体型在宫颈高度病变及宫颈癌中比例较高,低度病变与高度病变差异有统计学意义(P<0.05),高危型HPV感染hTERC基因扩增比例明显高于HPV阴性组,提示高危型HPV感染与hTERC基因扩增有相关性,可作为预测宫颈癌前病变进展的监测指标。维吾尔族宫颈病变患者中多重HPV高危亚型感染比例较高,导致其hTERC基因扩增明显,可能是维吾尔族宫颈癌发病率高于汉族的原因之一。3)FISH技术检测宫颈细胞hTERC基因扩增具有良好的特异性、敏感性,从一定程度上弥补现行宫颈癌和癌前病变筛查方法的局限性,因此可作为临床宫颈疾病筛查中一项重要的辅助检查。hTERC基因检测可浓缩宫颈癌高风险人群,可提高宫颈细胞学筛查宫颈病变的效率,预测宫颈病变的发展趋势。
Background:Cervical disease is one of the most common diseases of women, the prevalence of cervical cancer which accounts for half of the female reproductive system cancer for more than a serious threat to women's health.each year, about 46 million people around the world sick. There are new cases amounting to approximately 13 million in China, accounting for 6% of all the women has been found the tumor, which is the second only to breast cancer-related deaths of women caused by an important reason. However, cervical cancer (SCC) is the only preventable cancer. If that is the precancerous lesions or early diagnosis and timely preventive measures to give positive or appropriate treatment, which can significantly change the prognosis and quality of life. Moreover, early treatment of cervical cancer and five-year survival rate also in the forefront of cancer, this feature makes for cervical cancer screening and the study of the pathogenesis of a more important significance. Over the past decade with the rapid development of molecular cytogenetic techniques, fluorescence in situ hybridization (FISH) came into being, and gradually transformed from basic medical research into clinical testing areas. Chromosome studies have shown that some of the cancer, chromosomal instability usually presents 3q gain and 2,3,4,6 p, 11q's missing, and the abnormal gene region were located in 3 q26.1-q28. In recent years, the U.S. National Institutes of Health (NIH)-led study shows that for cervical cancer, abnormal cervical cells from atypical hyperplasia to cancer almost always associated with changes in the course of the long arm of chromosome 3 amplification, which involves the most important gene to human chromosome telomerase gene may be hTERC, it is expected to be atypical cell cancer genes, the gene amplification can prevent apoptosis, which can lead to tumor occuring. Overseas research shows that by FISH to detect 3q26 hTERC gene, found cervical intraepithelial neoplasia gradeⅡ(CINⅡ), the increase in the number of copies of this gene accounted for 63%, cervical intraepithelial neoplasia gradeⅢ(CINⅢ) accounted for 76%, tetraploid cells with the cellular number and hTERC genes increase the severity of disease, which can be used to predict a high cervical lesions (HSIL) of the independent indicator of specific genome that is abnormal development of precancerous lesions to invasive cervical cancer by the necessary conditions. Determination of the use of FISH in exfoliated cells of cervical lesions hTERC expression of gene amplification, analysis of its relationship with cervical lesions progress to assess the role of FISH technique in screening of cervical lesions in cervical cancer prevention and control will make the prospect of a new work stage of development. There were lots of research reports about the relationship between the development of hTERC with cervical cancer at home and abroad, but the study of the high incidence of cervical cancer in the southern region of Xinjiang Uygur were rarely reported, the differences between ethnic in this grim fact that we have a responsibility to promote. This research work carried out to explore the differences between Uygur and Han nationalities in the pathogenesis of cervical cancer, in order to reduce the incidence of cervical cancer in Xinjiang Uygur, looking for more clinical work to promote the scientific basis. In recent years, the etiology of cervical cancer research has made important progress, which is now a clear evidence for high-risk papilloma virus (human papillomavirus HPV) subtypes infection and multiple types infection can cause cervical intraepithelial neoplasia or cervical cancer. Moreover, there are research suggests that high-risk HPV DNA (HR HPV DNA) integration causes hTERC gene amplification and is closely related to the incidence of cervical cancer. More than 95% of cervical cancer cases occurring related to HPV infection, there are different HPV subtypes in different regions and different ethnic groups, caused by disease development and prognosis are also different. Carcinogenic mechanism of HPV present study shows that high-risk HPV infection lead to the activation of telomerase by the CIN to SCC cervical epithelial transformation process are critical steps. Kanaya and other studies show:high-risk HPV infection and p53 inactivation can activate telomerase, the accelerated proliferation of cervical epithelial cells, causing CIN and SCC. Now that the use of FISH to detect gene amplification in cervical hTERC potentially helpful value in the diagnosis of early cervical cancer. The research aims to analysis the relationship between the women with cervical lesions of all nationalities in Xinjiang of cervical exfoliated cells and cervical hTERC gene expression, the severity of studies to assess the FISH detection hTERC gene in cervical cancer screening in the clinical application and comparative analysis of Xinjiang Uygur and Han Chinese cervical lesions patients infected with high-risk HPV subtypes, whose hTERC gene amplification characteristics and differences, as well as the level of gene amplification in hTERC, discusses the differences characteristics and pathogenesis of cervical cancer between Uygur and Han, in order to seek more efficient and reliable screening, diagnostic methods in cervical lesions and cervical cancer, so as to provide a clinical basis for scientific theory. The past 10 years, due to human papillomavirus infection in a significant increase,10% -15% per year of new cases in domestic, the incidence of CIN has also increased, incidence of cervical cancer seems to be signs of a rebound. Concerning is getting younger and younger cervical cancer, cervical cancer incidence of young women by 2%-3% annual growth rate, according to the ststistics of Chinese Academy of Medical Sciences Cancer Hospital, which show that cervical cancer for women under 35 years of age accounted for about the same period the proportion of the total number of cervical cancer were treated from 1.22% in 70s to 9.88% in 90s. Each year about 30,000 women were died of cervical cancer, however, cervical cancer is a threat to women's health and of the first line killer. Early diagnosis of cervical cancer and precancerous cervical lesions is to improve the cure rate, survival rate,and also the key to reducing the incidence of cervical cancer. The current general methods for the screening of cervical lesions is liquid-based smears method combined with high risk human papillomavirus detection methods. Although the high specificity of cervical cytology, simple, low cost, large-scale screening for cervical cancer, but sensitivity is not high, it will lead to a greater degree of false negatives, and also can not be carried out quantitative analysis of the cellular level. Abnormal cytology results, the consistency between the observers is not ideal, poor reproducibility. Although HPV detection sensitivity is higher but the false positive rate is high. Positive cervical HPV infection only show that but does not mean that pathological changes in cervical cytology, which can not make accurate judgments about the pathological type and duration to development of cervical cancer, therefore, the HPV test can not replace cytology. FISH, due to its high specificity, sensitivity, fast, stable and non-invasive characteristics, to some extent make up for the existing limitations of screening methods in cervical cancer and precancerous lesions, which can be used as a clinical screening for cervical disease of important adjuvant examinations. Objectives:1) Through the detection of the amplification of human telomerase RNA gene in chromosome of women with cervical lesions of all ethnic groups in Xinjiang, to study the relationship between hTERC gene expression and HPV infection, understanding the biological mechanisms of cervical cancer, and providing a scientific basis for genetic hTERC detection in the clinical value of cervical cancer screening for early diagnosis of cervical cancer.2) Human exfoliated cells of cervical lesions telomerase RNA (hTERC) differences in gene expression of Xinjiang Uygur and Han women, as well as high-risk subtypes of HPV infection, evaluation clinical value of hTERC genetic testing in the Uygur, Han cervical cancer screening.3) Through comparative analysis of cervical exfoliated cells hTERC gene amplification, high-risk HPV DNA infection and TCT test results, to be on the FISH method for detection of hTERC gene amplification in cervical lesions early screening programs, to evaluate the application of the cervical cancer screening programs to find the best available scientific evidence. Methods:1) Select by liquid-based cervical cytology (TCT) is normal-cervical carcinoma (SCC) of the 149 cases of cervical lesions of women of all ethnic groups in Xinjiang as the research object, the use of human papillomavirus (HPV) HybrMax to detect high-risk type HPV (HR-HPV) infection, pathological examination of their lesions, fluorescence in situ hybridization (FISH) technique to detect the abnormal gene amplification of hTERC. Final pathology results to be the gold standard for the level of the research group, results were compared among of hTERC genetic test, liquid-based cervical cytology and HPV test.2) Using fluorescence in situ hybridization, comparative study of hTERC gene amplification in 50 cases of Uygur patients and 52 cases of Han patients with cervical lesions, while high-risk HPV DNA infection were detected, the pathology results as the gold standard, two groups of patients Uygur, Han hTERC genetic test results were compared with HPV test results.3) The first two parts of 156 cases of cervical lesions in cervical exfoliated cells hTERC gene amplification and high-risk HPV DNA test results and the TCT test results were compared, colposcopic cervical biopsy histopathologic diagnosis of cervix as final diagnosis gold standard, the three detection methods were calculated in sensitivity, specificity, positive predictive value, negative predictive value and Youden index,which were compared screening accuracy of cervical lesions of 3 methods, and evaluated prospects for clinical application in FISH detection of hTERC gene amplification. Results:1)①Through hTERC genetic testing cervical exfoliated cells in 129 cases of cervical lesions and 20 normal women, indicating the group of liquid-based cervical cytology is normal (NILM), atypical squamous cells (ASCUS), low grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesion (HSIL) and invasive cervical cancer (SCC) cases of abnormal cervical cytology hTERC gene amplification rate was 5.00%, 17.24%,29.73%, 80.48% and 81.82% respectively, study of hTERC gene amplification ratio of ASCUS group, LSIL group, HSIL group and SCC group was significantly higher than the normal control group, the difference was statistically significant (P<0.05); levels of lesions in the ASCUS group, LSIL group were lower than HSIL group (P<0.05), but the ASCUS and LSIL was no significant difference between groups (P>0.05).②Pathology group at all levels in cervical lesions, genetic abnormalities in patients with CINⅠ, CINⅡ, CINⅢhTERC and SCC were amplified by 21.95%, 34.48%, 85.71%. 83.33%, low grade lesions (CINⅠ) cells group abnormal hTERC gene amplification was significantly lower than the high-level lesion group (CINⅡ～SCC).2)①Number of hTERC gene amplification rate of 50 Uygur patients with cervical lesions is 76.46%, 52 cases of cervical cancer Han number of hTERC gene amplification rate is 80.91%. As the lesions progress, Uygur, Han hTERC patients with cervical lesions significantly increased the number of gene amplification. Compared with the control group, the difference was statistically significant (P<0.05); Uygur, Han cervical lesions hTERC gene amplification rate between the two groups, the difference also statistically significant (P<0.05).②In the Uygur, Han patients in two groups of multiple HPV infection and single infection group differences were statistically significant (P<0.05); HPV single infections Uygur, Han hTERC gene amplification rate between the two groups showed no statistically significant (P>0.05), but multiple HPV infection Uygur, Han hTERC gene amplification rate between the two groups was significantly (P<0.05). Uygur, Han hTERC average gene amplification factor of cervical cancer, the infection of HPV subtypes in the difference between the groups was not significant (P>0.05), total cervical lesions hTERC gene amplification factor difference between the Uygur and Han was statistical significance, may be related to Uygur multiple infections in patients with cervical lesions than the rate of cervical lesions related to the Han. Uygur, Han groups in HR-HPV DAN infection hTERC positive and negative groups were significantly different rate of gene amplification, but the Uygur, Han was no significant difference between the two groups (P>0.05).3)①156 cases of cervical cytology specimens of cervical lesions detected by FISH applications hTERC gene amplification, exfoliated cells detection rate of abnormal hTERC gene amplification in the CINⅠgroup was significantly lower than the CINⅢand SCC group, the difference was statistically significant (P<0.05); between CINⅠgroup and CINⅡgroup, CINⅢand SCC groups, hTERC gene amplification was no significant difference (P>0.05). As the lesions from low grade to high-level development, hTERC gene significantly increased the positive detection rate of amplification, and disease severity were positively correlated.②HPV infection detected the most common subtype were HPV 16, HPV58, and HPV 18, followed by HPV52, HPV31, HPV68, HPV56, HPV39, HPV33, HPV45 and HPV51,83 cases were infected with high-risk HPV, the positive rate was 53.20%, of which HPV 16 positive rate of 57.83%, HPV58-positive rate of 18.07%, HPV18-positive rate of 9.64%. (3) Classification of cervical cytology, LSIL is generally consistent with histopathologic grade in CINI, HSIL corresponding CINII and CINIII. TCT for CINI's diagnostic accuracy was 34.78%, CINII, CINIII the diagnostic accuracy was 37.83%, SCC of the diagnostic accuracy was 58.82%, the total detection rate is 43.82%.④3 ways to compare the efficiency of screening for cervical lesions, for the low-lesion group (CINI), three detection methods in terms of positive rate, sensitivity and specificity, the differences were not statistically significant (P>0.05). For a high degree of lesion group (CINII-SCC), FISH detection of abnormal gene amplification for the hTERC positive in 65 cases (59.1%), liquid-based cytology in HSIL was only 19 cases (17.3%), HR-HPV DNA-positive infections 66 cases (60.0%), pairwise comparison, only liquid-based cytology group's positve detection rate was significantly lower than FISH testing group and HPV testing group (P<0.05), three kinds of detection sensitivity and specificity were: FISH detection of group 82.7% and 73.6%, liquid-based cytology group 48.4% and 66.8%, HR-HPV DNA testing group to 86.5% and 46.5%, pairwise comparison the sensitivity of TCT group is lower than HPV group and the FISH group, specificity of HPV group is lower than TCT group and FISH testing group, the difference was statistically significant (P<0.05). Negative predictive value of the TCT group of the lowest in the three groups, HPV positive predictive value of the lowest group in the three groups, Youden index of FISH detection methods is higher than the other two groups, TCT was the lowest, the differences were statistically significant (P<0.05). Conclusion: l)In liquid-based cervical cytology and histological examination, hTERC gene amplification rate with the increase of the severity, especially in low-grade cervical lesions hTERC and high lesion group were significantly different gene expression, which can be applied FISH to detect abnormal hTERC gene amplification distinguish low-grade cervical lesions with high degree of lesions.2) hTERC gene amplification in the Uygur and Han nationalities in both groups increased with the severity of progress, amplification of hTERC gene and the signal ratio of polyploid types of high grade cervical lesions and cervical cancer in a high proportion, difference between low grade lesions and HSIL was significantly (P<0.05), hTERC gene amplification in high-risk HPV infection group was significantly higher than that of HPV-negative group, suggesting that high-risk HPV was associated with hTERC gene amplification, which can be as a progressive monitoring predictor of cervical precancerous lesions. Uygur patients with multiple HPV cervical lesions infected with a higher proportion of high-risk subtypes, leading to hTERC gene amplification obvious, may be one of the reasons the high incidence of cervical cancer in the Uygur than Han's.3) FISH technology because of its high specificity, sensitivity and speed, good stability, non-invasive and so on, to some extent make up for the current screening of cervical cancer and precancerous lesions of the limitations, it can be used as clinical cervical disease an important auxilury screening examinations. High risk of cervical cancer groups can be concentrated by genetic hTERC testing, which can increase the cervical cytology screening efficiency of cervical lesions, predict the development trend of cervical lesions.
Background:Cervical disease is one of the most common diseases of women, the prevalence of cervical cancer which accounts for half of the female reproductive system cancer for more than a serious threat to women's health.each year, about 46 million people around the world sick. There are new cases amounting to approximately 13 million in China, accounting for 6% of all the women has been found the tumor, which is the second only to breast cancer-related deaths of women caused by an important reason. However, cervical cancer (SCC) is the only preventable cancer. If that is the precancerous lesions or early diagnosis and timely preventive measures to give positive or appropriate treatment, which can significantly change the prognosis and quality of life. Moreover, early treatment of cervical cancer and five-year survival rate also in the forefront of cancer, this feature makes for cervical cancer screening and the study of the pathogenesis of a more important significance. Over the past decade with the rapid development of molecular cytogenetic techniques, fluorescence in situ hybridization (FISH) came into being, and gradually transformed from basic medical research into clinical testing areas. Chromosome studies have shown that some of the cancer, chromosomal instability usually presents 3q gain and 2,3,4,6 p, 11q's missing, and the abnormal gene region were located in 3 q26.1-q28. In recent years, the U.S. National Institutes of Health (NIH)-led study shows that for cervical cancer, abnormal cervical cells from atypical hyperplasia to cancer almost always associated with changes in the course of the long arm of chromosome 3 amplification, which involves the most important gene to human chromosome telomerase gene may be hTERC, it is expected to be atypical cell cancer genes, the gene amplification can prevent apoptosis, which can lead to tumor occuring. Overseas research shows that by FISH to detect 3q26 hTERC gene, found cervical intraepithelial neoplasia gradeⅡ(CINⅡ), the increase in the number of copies of this gene accounted for 63%, cervical intraepithelial neoplasia gradeⅢ(CINⅢ) accounted for 76%, tetraploid cells with the cellular number and hTERC genes increase the severity of disease, which can be used to predict a high cervical lesions (HSIL) of the independent indicator of specific genome that is abnormal development of precancerous lesions to invasive cervical cancer by the necessary conditions. Determination of the use of FISH in exfoliated cells of cervical lesions hTERC expression of gene amplification, analysis of its relationship with cervical lesions progress to assess the role of FISH technique in screening of cervical lesions in cervical cancer prevention and control will make the prospect of a new work stage of development. There were lots of research reports about the relationship between the development of hTERC with cervical cancer at home and abroad, but the study of the high incidence of cervical cancer in the southern region of Xinjiang Uygur were rarely reported, the differences between ethnic in this grim fact that we have a responsibility to promote. This research work carried out to explore the differences between Uygur and Han nationalities in the pathogenesis of cervical cancer, in order to reduce the incidence of cervical cancer in Xinjiang Uygur, looking for more clinical work to promote the scientific basis. In recent years, the etiology of cervical cancer research has made important progress, which is now a clear evidence for high-risk papilloma virus (human papillomavirus HPV) subtypes infection and multiple types infection can cause cervical intraepithelial neoplasia or cervical cancer. Moreover, there are research suggests that high-risk HPV DNA (HR HPV DNA) integration causes hTERC gene amplification and is closely related to the incidence of cervical cancer. More than 95% of cervical cancer cases occurring related to HPV infection, there are different HPV subtypes in different regions and different ethnic groups, caused by disease development and prognosis are also different. Carcinogenic mechanism of HPV present study shows that high-risk HPV infection lead to the activation of telomerase by the CIN to SCC cervical epithelial transformation process are critical steps. Kanaya and other studies show:high-risk HPV infection and p53 inactivation can activate telomerase, the accelerated proliferation of cervical epithelial cells, causing CIN and SCC. Now that the use of FISH to detect gene amplification in cervical hTERC potentially helpful value in the diagnosis of early cervical cancer. The research aims to analysis the relationship between the women with cervical lesions of all nationalities in Xinjiang of cervical exfoliated cells and cervical hTERC gene expression, the severity of studies to assess the FISH detection hTERC gene in cervical cancer screening in the clinical application and comparative analysis of Xinjiang Uygur and Han Chinese cervical lesions patients infected with high-risk HPV subtypes, whose hTERC gene amplification characteristics and differences, as well as the level of gene amplification in hTERC, discusses the differences characteristics and pathogenesis of cervical cancer between Uygur and Han, in order to seek more efficient and reliable screening, diagnostic methods in cervical lesions and cervical cancer, so as to provide a clinical basis for scientific theory. The past 10 years, due to human papillomavirus infection in a significant increase,10% -15% per year of new cases in domestic, the incidence of CIN has also increased, incidence of cervical cancer seems to be signs of a rebound. Concerning is getting younger and younger cervical cancer, cervical cancer incidence of young women by 2%-3% annual growth rate, according to the ststistics of Chinese Academy of Medical Sciences Cancer Hospital, which show that cervical cancer for women under 35 years of age accounted for about the same period the proportion of the total number of cervical cancer were treated from 1.22% in 70s to 9.88% in 90s. Each year about 30,000 women were died of cervical cancer, however, cervical cancer is a threat to women's health and of the first line killer. Early diagnosis of cervical cancer and precancerous cervical lesions is to improve the cure rate, survival rate,and also the key to reducing the incidence of cervical cancer. The current general methods for the screening of cervical lesions is liquid-based smears method combined with high risk human papillomavirus detection methods. Although the high specificity of cervical cytology, simple, low cost, large-scale screening for cervical cancer, but sensitivity is not high, it will lead to a greater degree of false negatives, and also can not be carried out quantitative analysis of the cellular level. Abnormal cytology results, the consistency between the observers is not ideal, poor reproducibility. Although HPV detection sensitivity is higher but the false positive rate is high. Positive cervical HPV infection only show that but does not mean that pathological changes in cervical cytology, which can not make accurate judgments about the pathological type and duration to development of cervical cancer, therefore, the HPV test can not replace cytology. FISH, due to its high specificity, sensitivity, fast, stable and non-invasive characteristics, to some extent make up for the existing limitations of screening methods in cervical cancer and precancerous lesions, which can be used as a clinical screening for cervical disease of important adjuvant examinations. Objectives:1) Through the detection of the amplification of human telomerase RNA gene in chromosome of women with cervical lesions of all ethnic groups in Xinjiang, to study the relationship between hTERC gene expression and HPV infection, understanding the biological mechanisms of cervical cancer, and providing a scientific basis for genetic hTERC detection in the clinical value of cervical cancer screening for early diagnosis of cervical cancer.2) Human exfoliated cells of cervical lesions telomerase RNA (hTERC) differences in gene expression of Xinjiang Uygur and Han women, as well as high-risk subtypes of HPV infection, evaluation clinical value of hTERC genetic testing in the Uygur, Han cervical cancer screening.3) Through comparative analysis of cervical exfoliated cells hTERC gene amplification, high-risk HPV DNA infection and TCT test results, to be on the FISH method for detection of hTERC gene amplification in cervical lesions early screening programs, to evaluate the application of the cervical cancer screening programs to find the best available scientific evidence. Methods:1) Select by liquid-based cervical cytology (TCT) is normal-cervical carcinoma (SCC) of the 149 cases of cervical lesions of women of all ethnic groups in Xinjiang as the research object, the use of human papillomavirus (HPV) HybrMax to detect high-risk type HPV (HR-HPV) infection, pathological examination of their lesions, fluorescence in situ hybridization (FISH) technique to detect the abnormal gene amplification of hTERC. Final pathology results to be the gold standard for the level of the research group, results were compared among of hTERC genetic test, liquid-based cervical cytology and HPV test.2) Using fluorescence in situ hybridization, comparative study of hTERC gene amplification in 50 cases of Uygur patients and 52 cases of Han patients with cervical lesions, while high-risk HPV DNA infection were detected, the pathology results as the gold standard, two groups of patients Uygur, Han hTERC genetic test results were compared with HPV test results.3) The first two parts of 156 cases of cervical lesions in cervical exfoliated cells hTERC gene amplification and high-risk HPV DNA test results and the TCT test results were compared, colposcopic cervical biopsy histopathologic diagnosis of cervix as final diagnosis gold standard, the three detection methods were calculated in sensitivity, specificity, positive predictive value, negative predictive value and Youden index,which were compared screening accuracy of cervical lesions of 3 methods, and evaluated prospects for clinical application in FISH detection of hTERC gene amplification. Results:1)①Through hTERC genetic testing cervical exfoliated cells in 129 cases of cervical lesions and 20 normal women, indicating the group of liquid-based cervical cytology is normal (NILM), atypical squamous cells (ASCUS), low grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesion (HSIL) and invasive cervical cancer (SCC) cases of abnormal cervical cytology hTERC gene amplification rate was 5.00%, 17.24%,29.73%, 80.48% and 81.82% respectively, study of hTERC gene amplification ratio of ASCUS group, LSIL group, HSIL group and SCC group was significantly higher than the normal control group, the difference was statistically significant (P<0.05); levels of lesions in the ASCUS group, LSIL group were lower than HSIL group (P<0.05), but the ASCUS and LSIL was no significant difference between groups (P>0.05).②Pathology group at all levels in cervical lesions, genetic abnormalities in patients with CINⅠ, CINⅡ, CINⅢhTERC and SCC were amplified by 21.95%, 34.48%, 85.71%. 83.33%, low grade lesions (CINⅠ) cells group abnormal hTERC gene amplification was significantly lower than the high-level lesion group (CINⅡ～SCC).2)①Number of hTERC gene amplification rate of 50 Uygur patients with cervical lesions is 76.46%, 52 cases of cervical cancer Han number of hTERC gene amplification rate is 80.91%. As the lesions progress, Uygur, Han hTERC patients with cervical lesions significantly increased the number of gene amplification. Compared with the control group, the difference was statistically significant (P<0.05); Uygur, Han cervical lesions hTERC gene amplification rate between the two groups, the difference also statistically significant (P<0.05).②In the Uygur, Han patients in two groups of multiple HPV infection and single infection group differences were statistically significant (P<0.05); HPV single infections Uygur, Han hTERC gene amplification rate between the two groups showed no statistically significant (P>0.05), but multiple HPV infection Uygur, Han hTERC gene amplification rate between the two groups was significantly (P<0.05). Uygur, Han hTERC average gene amplification factor of cervical cancer, the infection of HPV subtypes in the difference between the groups was not significant (P>0.05), total cervical lesions hTERC gene amplification factor difference between the Uygur and Han was statistical significance, may be related to Uygur multiple infections in patients with cervical lesions than the rate of cervical lesions related to the Han. Uygur, Han groups in HR-HPV DAN infection hTERC positive and negative groups were significantly different rate of gene amplification, but the Uygur, Han was no significant difference between the two groups (P>0.05).3)①156 cases of cervical cytology specimens of cervical lesions detected by FISH applications hTERC gene amplification, exfoliated cells detection rate of abnormal hTERC gene amplification in the CINⅠgroup was significantly lower than the CINⅢand SCC group, the difference was statistically significant (P<0.05); between CINⅠgroup and CINⅡgroup, CINⅢand SCC groups, hTERC gene amplification was no significant difference (P>0.05). As the lesions from low grade to high-level development, hTERC gene significantly increased the positive detection rate of amplification, and disease severity were positively correlated.②HPV infection detected the most common subtype were HPV 16, HPV58, and HPV 18, followed by HPV52, HPV31, HPV68, HPV56, HPV39, HPV33, HPV45 and HPV51,83 cases were infected with high-risk HPV, the positive rate was 53.20%, of which HPV 16 positive rate of 57.83%, HPV58-positive rate of 18.07%, HPV18-positive rate of 9.64%. (3) Classification of cervical cytology, LSIL is generally consistent with histopathologic grade in CINI, HSIL corresponding CINII and CINIII. TCT for CINI's diagnostic accuracy was 34.78%, CINII, CINIII the diagnostic accuracy was 37.83%, SCC of the diagnostic accuracy was 58.82%, the total detection rate is 43.82%.④3 ways to compare the efficiency of screening for cervical lesions, for the low-lesion group (CINI), three detection methods in terms of positive rate, sensitivity and specificity, the differences were not statistically significant (P>0.05). For a high degree of lesion group (CINII-SCC), FISH detection of abnormal gene amplification for the hTERC positive in 65 cases (59.1%), liquid-based cytology in HSIL was only 19 cases (17.3%), HR-HPV DNA-positive infections 66 cases (60.0%), pairwise comparison, only liquid-based cytology group's positve detection rate was significantly lower than FISH testing group and HPV testing group (P<0.05), three kinds of detection sensitivity and specificity were: FISH detection of group 82.7% and 73.6%, liquid-based cytology group 48.4% and 66.8%, HR-HPV DNA testing group to 86.5% and 46.5%, pairwise comparison the sensitivity of TCT group is lower than HPV group and the FISH group, specificity of HPV group is lower than TCT group and FISH testing group, the difference was statistically significant (P<0.05). Negative predictive value of the TCT group of the lowest in the three groups, HPV positive predictive value of the lowest group in the three groups, Youden index of FISH detection methods is higher than the other two groups, TCT was the lowest, the differences were statistically significant (P<0.05). Conclusion: l)In liquid-based cervical cytology and histological examination, hTERC gene amplification rate with the increase of the severity, especially in low-grade cervical lesions hTERC and high lesion group were significantly different gene expression, which can be applied FISH to detect abnormal hTERC gene amplification distinguish low-grade cervical lesions with high degree of lesions.2) hTERC gene amplification in the Uygur and Han nationalities in both groups increased with the severity of progress, amplification of hTERC gene and the signal ratio of polyploid types of high grade cervical lesions and cervical cancer in a high proportion, difference between low grade lesions and HSIL was significantly (P<0.05), hTERC gene amplification in high-risk HPV infection group was significantly higher than that of HPV-negative group, suggesting that high-risk HPV was associated with hTERC gene amplification, which can be as a progressive monitoring predictor of cervical precancerous lesions. Uygur patients with multiple HPV cervical lesions infected with a higher proportion of high-risk subtypes, leading to hTERC gene amplification obvious, may be one of the reasons the high incidence of cervical cancer in the Uygur than Han's.3) FISH technology because of its high specificity, sensitivity and speed, good stability, non-invasive and so on, to some extent make up for the current screening of cervical cancer and precancerous lesions of the limitations, it can be used as clinical cervical disease an important auxilury screening examinations. High risk of cervical cancer groups can be concentrated by genetic hTERC testing, which can increase the cervical cytology screening efficiency of cervical lesions, predict the development trend of cervical lesions.
引文
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