高危型HPV DNA整合导致宫颈癌的作用机制和临床检测进展

高危型人乳头瘤病毒(human papillomavirus,HPV)感染是宫颈癌发生发展的必要因素之一。病毒DNA整合到宿主基因组中被认为是导致宫颈癌最重要的病因。高危型HPV DNA整合往往导致其E1和E2区大部分缺失或中断,E6和E7致癌基因过表达,宿主致癌基因激活和抑癌基因失活。目前研究表明高危型HPV整合可作为优质宫颈病变筛查的预测生物标志物,且其检测的有效方法大都基于荧光原位杂交、实时荧光定量PCR和杂交捕获技术结合Sanger测序法等。本文重点阐述了高危型HPV整合导致宫颈癌的主要机制,描述了宫颈病变筛查标志物以及预防性HPV疫苗研发和推广的研究进展,并综述了高危型HPV DNA整合状态的检测方法。     

宫颈癌患者人乳头瘤病毒(HPV)主要型别及其感染研究

本文探讨了江西省和广东省宫颈癌患者人乳头瘤病毒(Human papillomavirus,HPV)感染及其型别分布,分析了高危型HPV对各种宫颈病变的感染情况,为宫颈癌的早期发现和临床诊治提供科学依据。首先采用细胞学、HPV DNA检测(第二代杂交捕获法,HC2)、电子阴道镜和宫颈化学着色方法筛查宫颈癌患者,经病理镜检确诊,然后用GP PCR-SBT法对宫颈癌患者进行HPV基因分型。江西省溪口镇、古市镇及修水县城宫颈癌癌前病变发生率为5．7‰。HC2方法发现宫颈癌患者13种高危型HPV DNA阳性率为89．9％,宫颈上皮内瘤样病变的为84．8％,对照组为24．5％。采用GP PCR-SBT方法进行基因分型发现,江西省宫颈癌患者存在HPV16、58、31、33、18、66、6、11、56和81十种型别,其中HPV81型在国内外鲜有报道。据此提出生殖道高危型HPV感染是妇女宫颈癌发病的重要因素。并发现江西省宫颈癌高发区妇女高危型HPV感染率为24．5％。建立了HPV基因分型的方法,对HPV致宫颈病变的分子机制进行了分析。     

HPV病毒感染与宫颈炎症及宫颈癌之间的关系及意义分析

目的研究人乳头瘤病毒(HPV)在宫颈炎症、宫颈癌前病变及宫颈癌中的水平及临床意义。方法分别选取宫颈炎症278例、宫颈癌前病变174例、宫颈腺癌82例、宫颈鳞癌183例患者,并以218例宫颈无病变的病例作为对照,所有患者均行薄层液基细胞学(TCT)检查及阴道镜下病理活检,检测各组患者间HPV阳性水平并对统计结果加以分析。结果 218例宫颈无病变病例中高危性HPV阳性率为9.6%(21/218),其余717例宫颈出现病变的患者中高危型HPV筛查结果阳性例数为405例,阳性检出率56.5%,且随着宫颈病变严重程度的加重,高危型HPV检出率逐渐升高(P0.01),但是宫颈腺癌和宫颈鳞癌组的高危型HPV阳性率比较差异无统计学意义(P0.05)。结论 HPV是宫颈癌前病变及宫颈癌的主要致病因素,对宫颈炎症、宫颈癌前病变及宫颈癌患者行HPV检测对于患者早日确诊及早日治疗具有重要意义。     

HPV病毒感染与宫颈病变发生发展关系的研究进展

宫颈病变是指在宫颈区域发生的各种病变,包括炎症、癌前病变、肿瘤等,人乳头瘤病毒(HPV)是引起多种宫颈病变的主要因素之一,尤其是高危型HPV病毒的持续感染更是宫颈病变的重要病因,目前高危型HPV病毒的检测已成为筛查宫颈癌前病变及宫颈癌的重要手段。现将近年来HPV病毒感染与宫颈病变发生发展关系的研究进展作一综述。     

HPV感染与宫颈癌预防的研究进展

宫颈癌在全球范围内依然是严重威胁妇女健康的常见恶性肿瘤之一。流行病学调查显示,高危型HPV持续感染是导致宫颈癌发病的主要原因,并且HPV感染具有显著的特点,因此,预防HPV感染是防治宫颈癌的主要途径。已明确性行为是促进HPV感染最重要的辅助因子,个体免疫力低下及年龄因素亦是促进HPV感染的重要因素。研究显示,在全球逐渐开展的预防措施包括对常见的高风险HPV类型进行预防性疫苗接种及包括HPV检测在内的宫颈癌筛查项目的实施已经在降低宫颈癌的发病率方面起到了很重要的作用。近些年来,人们越来越重视HPV检测在宫颈癌筛查程序中的应用。由于HPV的感染率具有显著的地域性差异,我们需要针对各地区的特点以完善相应的宫颈癌筛查程序,从而为宫颈癌防治工作的开展提供重要依据。     

宫颈癌中端粒酶的表达和高危型人乳头瘤病毒感染

目的:研究不同程度子宫颈病变中高危型人乳头瘤病毒HR-HPV感染和端粒酶活性的表达,以探讨两者在宫颈癌及宫颈上皮内瘤变中的作用及相关性。方法:采用第二代杂交捕获技术检测宫颈脱落细胞HPV-DNA含量,并用免疫组织化学EnVision二步法检测宫颈组织标本中端粒酶的表达。结果:(1)端粒酶阳性表达率在对照组、CINⅠ、CINⅡ、CINⅢ和宫颈癌组分别为10.00%、16.67%、40.00%、70.00%、95.00%,宫颈癌组高于CINⅢ,CINⅢ高于CINⅡ,CINⅡ高于CINⅠ,差异均有统计学意义(x2=4.329,P=0.037;x2=4.327,P=0.038;x2=4.022,P=0.045)。(2)随着宫颈病变级别的增加,高危型HPV的阳性率和病毒负荷量均增高。高危型HPV的阳性率在宫颈癌和CINⅢ组明显高于对照组、CINⅠ及CINⅡ(x2=29.501~7.414,P<0.01)。高危型HPV的病毒负荷量在对照组与其他4组比较,差异均有统计学意义(P<0.05);CINⅠ组分别与CINⅡ、CINⅢ及宫颈癌组比较差异均有统计学意义(P<0.05)。(3)随着宫颈病变级别的增加,高危型HPV的阳性率和端粒酶阳性表达率依次递增,两者有明显的相关性(r=0.943,P<0.01)。结论:高危型HPV感染和端粒酶活性均与宫颈癌前病变及宫颈癌的发生发展密切相关,有望作为子宫颈癌前病变和宫颈癌筛查的监测指标。     

四川地区宫颈癌HPV59型感染及其E6基因突变

宫颈癌是妇科常见的恶性肿瘤,特定型别的人乳头瘤病毒(HPV)感染是引发宫颈癌的主要因素[1].根据HPV致癌性的不同可分为高危型,低危型.Munoz N[2]等对来自9个国家的1918例宫颈癌组织进行各型HPV筛查,最终确认HPV-16、18、26、31、33、35、39、45、51、52、53、56、58、59、66、68、73及82型为高危型.李洁等[3]用核酸印迹技术对1986至1994年间来自我国14个省市自治区的1008宫颈癌组织进行HPV型别检测,发现HPV-16、18、31、35、51、58等型的存在,并发现各地区主要流行型别随地理位置有所差异.     

恒温扩增HPV检测技术应用于子宫颈癌筛查的效果评价研究

为了评价人乳头状瘤病毒(Human papillomavirus,HPV)恒温DNA扩增检测技术用于高危型HPV检测和宫颈癌早期及癌前病变筛查的准确性和可行性。本研究于2016年6月至8月,在我国内蒙古地区招募2 774例30-64岁有性生活史的妇女进行宫颈癌筛查;采用薄层液基细胞学技术完成细胞学诊断。采用恒温DNA扩增HPV检测技术(Isomega)和第二代杂交捕获技术(Hybrid Capture 2,HC2)平行检测宫颈标本;对于Isomega检测为HPV16/HPV18阳性的标本和两种方法检测不一致的标本,使用线性探针法(INNO-LiPA)进行分型验证。以病理诊断为金标准,评价Isomega用于筛查宫颈上皮内瘤变(Cervical Intraepithelial Neoplasia,CIN)2级及以上患者的灵敏度和特异度。结果表明,Isomega与HC2检测高危型HPV的总一致率为92.72%(Kappa=0.74),阳性一致率为86.78%,阴性一致率为93.77%;以INNO-LiPA分型结果为标准,Isomega检出HPV16和HPV18的准确率分别为96.97%和86.11%。以病理诊断为金标准,Isomega筛查CIN2+的灵敏度和特异度分别为87.76%和82.94%。Isomega能准确检测HPV16、HPV18和其他高危型别HPV,有较高的筛查灵敏度和特异度。     

生殖道感染与宫颈癌及宫颈癌前病变的相关性研究

目的:探讨生殖道感染与宫颈癌、宫颈癌前病变的相关性及危险因素分析。方法:选取我院收治的185例宫颈癌及宫颈癌前病变患者和同期206例健康体检者分为两组,对人乳头瘤病毒(HPV)、沙眼衣原体(CT)、细菌性阴道病(BV)、阴道滴虫进行检测,观察分析相应病原微生物导致的生殖道感染与宫颈癌及宫颈癌前病变的关系,同时根据HPV不同基因型在宫颈癌及宫颈癌前病变中的致癌作用和程度,判定危险程度。结果:宫颈癌及宫颈癌前病变患者上述指标感染检出率明显高于对照组,差异具有统计学意义(P=0.000、0.001、0.000、0.037),其中高危HPV感染率随宫颈上皮内瘤变级别的升高而呈明显上升趋势,CINⅠ～Ⅲ级感染率分别为57.1%、78.6%和82.9%,宫颈癌感染率最高达91.1%,高危HPV为高危因素。结论:生殖道HPV、CT、BV、滴虫感染与宫颈癌及CIN存在必然或一定相关性,加强对妇女生殖道病原体感染的重视和检测对防治宫颈癌及CIN具有积极意义。     

《柳叶刀-肿瘤学》：高危HPV DNA检测可初筛宫颈癌

高危型人乳头瘤病毒（HPV）DNA检测可作为宫颈癌初筛方法,用于中国及其他发展中国家宫颈癌的二级预防。这一结论来自题为《高危型人乳头瘤病毒DNA检测作为宫颈癌初筛方法的有效性研究——中国以人群为基础的17个筛查研究综合分析》的论文。     

人乳头瘤病毒分型检测在宫颈病变中的研究进展

宫颈癌是感染性疾病,HPV感染是宫颈癌发生的主要因素。宫颈上皮内留样病变(CIN)是宫颈浸润癌演变发展过程中的癌前病变阶段,研究发现大多数CIN伴有人乳头瘤病毒(HPV)感染,不同HPV亚型的致病力不同,因此不同亚型的HPV感染可以导致不同的宫颈病变。对CIN早诊、早治是降低宫颈癌发生率和死亡率的关键,临床上应用HPV亚型检测对宫颈病变的初筛及治疗追踪具有重要意义。     

Human papilloma virus type 16 infection and the early onset of cervical cancer

Human papilloma viruses (HPV), particularly type 16, have been associated with cervical cancer. It has been noted that the average onset of cervical cancer is occurring in younger women coupled with a higher prevalence of cervical HPV infection. However, the correlation between HPV 16 infection and the early onset of cervical cancer is still unclear. We hypothesize that HPV infection is an indicator of early onset of cervical cancer. To test this hypothesis, cervical smears from 197 women were evaluated by the polymerase chain reaction for HPV 16. These data revealed that the HPV 16-positive women were significantly younger than the HPV 16-negative women. Moreover, the average age of HPV 16-positive women with CIN 3 or invasive cancer was significantly younger compared with the other groups. These data clearly suggest that HPV 16 infection is a significant risk factor for the progression for cervical cancer in a young population of women.     

人乳头瘤病毒与宫颈癌关系研究进展

宫颈癌是一种严重危害女性健康的恶性肿瘤,其发病率较高,位居女性恶性肿瘤的第二位,仅次于乳腺癌。自从1977年德国学者ZurHausen等从宫颈癌标本中发现了人乳头瘤病毒(Human papillomavirus HPV)DNA,并推测HPV感染与宫颈癌发生有关后,许多学者对HPV与宫颈癌的相关性进行了大量的研究,并证实HPV感染是宫颈癌发病的必需因素。目前,对于宫颈HPV感染检测有多种手段,其中聚合酶链反应(PCR)和捕获杂交技术在实验室中应用较广泛。在宫颈癌筛查中联合应用HPV检测和细胞学,不仅可以提高敏感性,而且还可以减少随诊频率,从而大大降低了宫颈癌的发生。     

Uterine cervical carcinoma and human papillomaviruses]

For many years it has been thought that a significant proportion of cervical cancer could be attributed to sexually transmitted agents, such as sperm, smegma, Treponema pallidum, Gonococcus and herpes simplexvirus type 2. Recent advances of molecular biology, however, have revealed that human papillomavirus (HPV) might be the most causative virus of the disease. Since HPV type 16 DNA was found in a patient with cervical cancer in 1983, many HPV types have been cloned from cervical cancers, also from premalignant lesions (intraepithelial neoplasias). In Japan, we have found 6 new types of HPV (HPV 58, 59, 61, 62, 64, 67) in the female genital tract so far. Especially, HPV 58, which was cloned from a patient with cervical squamous cell carcinoma and was already fully sequenced, is thought to be an important agent for the development of cervical cancer as well as HPV 16. Now we are investigating extensively to clarify the real relationship between genital HPV infection and cervical cancer.     

Human papillomavirus (HPV) infection in Southern Africa: prevalence,immunity, and vaccine prospects

Human papillomavirus (HPV) associated cancers are more prevalent in developing countries compared to developed countries. The major cancer caused by HPV is cervical cancer. The humoral immune response to HPV can be a marker of past infection but may also reflect persistent infection and cervical disease. IgA antibodies to HPV in oral fluid were also found to be markers of cervical disease. Cell mediated immunity is important in clearing HPV infection and for regression of the associated lesions: this means that women infected with HIV have a high prevalence of co-infection with HPV. Good cervical screening programmes can control HPV associated cervical neoplasia. However, in countries such as South Africa, where these programmes are inadequate, there is a need for an HPV vaccine. The development of HPV vaccines is reviewed. There is a call for an inexpensive vaccine that will be accessible to the women that do not have access to adequate screening programmes and are therefore at the greatest risk of cervical cancer.     

Genetic alterations in cervical cancer

In the pathogenesis of cervical cancer the role of human papillomavirus (HPV) infection is well established. However, other than HPV infection the genetics of cervical cancer remains poorly understood. In the pathogenesis of cervical cancel three major factors are involved, two of which are related to the presence of HPV and the third is the recurrent genetic alterations not linked to HPV infection. Several chromosomal regions with recurrent loss of heterozygosity (LOH) in cervical cancer have been identified. However; the putative tumor suppressor genes located in these chromosomal locations are yet to be identified. Recurrent amplifications have been mapped to the short arm of chromosome 3 in invasive cancer. Microsatellite instability and mutator phenotype do not play a major role in cervical carcinogenesis. As in other cancers, cervical cancer too requires the accumulation of genetic alterations for carcinogenesis to occur. Identification of these alterations could help to provide a better understanding of the disease and thus improve treatment.     

我国宫颈癌疫苗市场分析及对策研究*

宫颈癌Cervical cancer是最常见的妇科恶性肿瘤,是威胁女性健康的第二大恶性肿瘤。宫颈癌疫苗是预防宫颈癌发病的有效途径。2019年以前葛兰素史克(GSK)和默沙东(MSD)垄断了全球宫颈癌疫苗药物市场。虽然国内宫颈癌疫苗起步较晚,但在国内创新政策驱动下,20种疫苗已进入临床阶段,特别是由厦门万泰联合厦门大学研发的馨可宁于2020年4月获批上市,它是我国首个自主研发、全球第三个的宫颈癌疫苗。相比较欧美等发达国家,我国在宫颈癌疫苗推广力度上还有较大差距,我国9~45岁女性的HPV疫苗接种率不足0.05%。面对HPV疫苗接种覆盖率低,提出了优化HPV疫苗审评审批流程、将HPV疫苗纳入国家免疫规划、提高女性对HPV疫苗的认识等对策建议。     

Acquired immune response to oncogenic human papillomavirus associated with prophylactic cervical cancer vaccines

Human papillomavirus (HPV) is a common infection among women and a necessary cause of cervical cancer. Oncogenic HPV types infecting the anogenital tract have the potential to induce natural immunity, but at present we do not clearly understand the natural history of infection in humans and the mechanisms by which the virus can evade the host immune response. Natural acquired immune responses against HPV may be involved in the clearance of infection, but persistent infection with oncogenic virus types leads to the development of precancerous lesions and cancer. B cell responses are important for viral neutralization, but antibody responses in patients with cervical cancer are poor. Prophylactic vaccines targeting oncogenic virus types associated with cervical cancer have the potential to prevent up to 80% of cervical cancers by targeting HPV types 16 and 18. Clinical data show that prophylactic vaccines are effective in inducing antibody responses and in preventing persistent infection with HPV, as well as the subsequent development of high-grade cervical intraepithelial neoplasia. This article reviews the known data regarding natural immune responses to HPV and those developed by prophylactic vaccination.