中国生殖器疣和子宫颈癌HPV感染型别流行病学研究
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摘要
研究背景HPV (Human Papillomavirus人乳头状瘤病毒)病毒是危害人类健康的重要感染因素之一,它是引发生殖器疣和子宫颈癌的主要病因。2003年中国疾病预防控制中心发表数据显示,生殖器疣新发病例数为154,922,发病率为12.02/10万。世界卫生组织IARC 2004年发表的数据显示中国每年有45689例新发子宫颈浸润癌,占全世界子宫颈新发病例的十分之一。随着医学科技进展,已经研发出有效的针对HPV感染的基因重组疫苗(recombinant vaccine),目前疫苗主要针对的HPV型别包括HPV16、18、6和11型。由于还没有采用标准化的、高灵敏度检测方法获得全国HPV型别分布的流行病学数据,尚不能对该疫苗推广后可能产生的预防效果做出准确的评价。
研究目的在中国不同地区开展以医院为基础的现况研究,调查具有生殖器疣、浸润性子宫颈癌(ICC)和CIN2以上的病例中HPV感染的流行情况和HPV的型别分布。
材料与方法采用分层抽样方法选择研究对象,按照地理分布将全国分为东北、华北、西北、华中、西南、华南和华东7个大区,在每个大区遴选合作医院,共选择18家医院提供确诊生殖器疣病人及其标本和19家医院提供确诊子宫颈病变病人及其组织蜡块。
疣体组织标本的HPV型别判定：采用酚-氯仿方法抽提DNA,使用通用引物MY09/11,MY09/GP5+和GP5+/GP6+以及巢式PCR扩增140-bp目标DNA。电泳分离后直接测序,如果是单一感染,直接用BLAST 2.0判定HPV型别；如果是多重感染,使用T-vector转化E.coli.,随机挑选五个克隆后测序,判定HPV型别。
宫颈病变组织蜡块标本的HPV型别判定：用三明治切片法,第一张和最后一张蜡卷用于HE染色,中间蜡卷用于DNA提取。HE切片由病理专家组完成诊断。将经过病理确认合格的蜡卷与蛋白酶k溶液混合,70度过夜消化,以SPF10为引物扩增,用DNA酶免疫分析(DEIA)判定是否存在HPV感染,用SPF10 LiPA25 (version1)试剂盒对扩增产物进行型别判断。
结果本研究获得1295例确诊的生殖器疣病人及其福尔马林固定的标本。因PCR扩增抑制或没有提取出足够量DNA,排除290例病人的标本,余下1005例病人标本符合本次实验的要求,用于本次的生殖器疣HPV感染的分析研究。生殖器疣患者的平均年龄为32岁,女性占55.3%(556/1005)多于男性的44.7%(449/1005)。1005例生殖器疣病人中HPV阳性者为891例,感染率为88.7%。在HPV阳性病例中,HPV6和HPV11分别占46.6%和42.4%,是最常见的HPV型别,其次是HPV16占11.8%；其它型别在HPV阳性病例中的比例均小于1%。891例病人中,单一型别HPV阳性率为97.2%,而多重感染比例仅为2.8%。多重感染的型别包括HPV6、11和16。HPV6、11和16型感染占全部生殖器疣HPV阳性病例的97.9%。未发现不同大区、城市和农村、不同性别和年龄组间HPV6和11型别分布存在统计学意义的差别。
本次研究共获得664例ICC病人,其中鳞癌(SCC)630例、腺癌(ADC)34例,并获得CIN 2/3病人569例。SCC病人HPV感染率为97.6%,ADC为85.3%,CIN2/3为98.9%。HPV16(76.7%)和HPV18(7.8%)是SCC病人中最常见的感染型别,两者合计占SCC病人的84.0%；其次是HPV31占3.2%,HPV52占2.2%,HPV58占2.2%。在不同地区间SCC病人HPV感染率差别没有统计学显著意义。但是,SCC病人中,≤49岁年龄组的HPV16感染率大于50岁年龄组(P=0.003),而HPV52,58和39在高年龄组有更高的感染率；相反在CIN2和CIN3病人中,≤34岁和35-49岁年龄组HPV16感染率小于50岁年龄组(P=0.01),而HPV52、58和39在低年龄组感染率更高。与SCC病人相比,CIN2/3病人有更高的HPV31、52和58感染率,而HPV16和18的感染率则低SCC病人。
结论HPV16和18是子宫颈病变病人中的最常见的型别,HPV6、11和16是生殖器疣病人中最常见的型别。提示目前的预防性疫苗能够达到很好的效果。
Backgroud HPV (Human Papillomavirus) is an important infectious agent that is related to cervical precancerous lesion, cervical cancer and genital warts etiologically. Tha data from China CDC National Center for AIDS/STD showed 154,922 new CA patients in 2003 (12.02/100,000). The data published by IARC WHO in 2004 shows 45,689 new invasive cancers comes from China, accounting for one tenth in whole world. With the development of biomolecular technology, recombinant vaccines against HPV, which can prevent HPV infection effectively, are available in the market. There are no evidences from well-designed epidemiology study using standardized and sensitive technology for HPV detection, which can facilitates accurate evaluation on prophylactic vaccine's effects.
Objectives Hospital-based epidemiology study across China are carried out to study HPV distribution in genital warts, invasive cervical cancer (ICC) and CIN2/3 samples.
Material and Methods Stratified sampling method was applied to get representive samples of the cases from the hospitals in 7 geographic regions, including Northeast, North, Northwest, Central, Southwest, South and East. Genital warts from the cases were provide by 18 hopitals, and archived paraffin blocks for cervical lesions are provided by 19 hospitals.
We employed standard phenol-chloroform extracting and ethanol precipitation procedures on genital wards to refine DNA. Consensus primers MY09/11, MY09/GP5+ and GP5+/GP6+and nested PCR are applied to amplify 140 bp target DNA segment. For single infection, the amplimor is separated by electrophoresis and sequenced. For multiple infections, the amplimor is inserted into T-vector for E. coli. transformation. Five single clones were randomly selected for sequencing separately. Sequence information was blasted with NCBI database to ascertain HPV types.
A sandwich technique was used to cut paraffin sections for Haematoxylin and Eosin (H&E) staining and paraffin sections for HPV DNA analysis from each cervical specimen. After confirmation of histological diagnosis, qualified cervical specimens were digested in Proteinase K buffer at 70 centigrade. SPF10 PCR on the 1:10 diluted DNA was applied to amplify HPV DNA and then the generic amplification products were detected by DNA enzyme immunoassay (DEIA). HPV-positive specimens were typed by reverse hybridization line probe assay SPF10 LiPA25 (version 1).
Results Among 1295 genital warts patients with genital tissues collected,290 subjects were excluded due to no beta-globin and cyt B amplification, or PCR inhibition, or insufficient DNA for further testing and 1005 subjects were qualified for this study. The mean age is 32 years, female GW patients (55.3%; 556/1005) are more than male (44.7%; 449/1005). HPV prevalence was 88.7%(N=1005); HPV6 (46.6%) and HPV11 (42.4%) were the most common HPV types, accounting for 87.3%, followed by HPV16 (11.8%). Other HPV types were less than 1.0%. Besides, single infection was 97.2% of the total HPV positive GW patients, comparing with 2.8% multiple infections composed of HPV6, HPV11 and/or HPV16. Cumulative prevalence of HPV 6,11, and 16 is 97.9%. Neither HPV6 nor HPV11 significantly differed by urban and rural, sex, age levels and geographical regions.
Archived paraffin blocks for 664 ICC (630 squamous cell carcinoma [SCC]; 34 adenocarcinoma [ADC]),569 CIN 2/3 cases from 7 regions of China were collected. HPV prevalence was 97.6% in SCC,85.3% in adenocarcinoma,98.9% in CIN 2/3. HPV16 (76.7%) and HPV18 (7.8%) were the most common, together accounting for 84.0% of SCC, followed by HPV31 (3.2%), HPV52 (2.2%), and HPV58 (2.2%). HPV prevalence in SCC did not differ notably by region. However, SCC cases from women≤34 years and 35-49 years had significantely higher HPV 16 prevalence than women over 50 years(P=0.003), among whom HPV52,58, and 39 were more common. In contrast to SCC, HPV16 prevalence in women over 50 years is singnificantely more than women≤34 years and 35-49 years, among whom HPV52,58, and 39 were more common. HPV16 and 18 were under-represented, whereas HPV31,52 and 58 were over-represented in CIN2/3(P=0.01),.
Conclusion HPV 16 and 18 are the most common types for cervcia cancer, and HPV 6, 11 and 18 are the most common types for genital warts. It was suggested that the potential impact of prophylactic HPV vaccines is estimated to be high.
研究目的在中国不同地区开展以医院为基础的现况研究,调查具有生殖器疣、浸润性子宫颈癌(ICC)和CIN2以上的病例中HPV感染的流行情况和HPV的型别分布。
材料与方法采用分层抽样方法选择研究对象,按照地理分布将全国分为东北、华北、西北、华中、西南、华南和华东7个大区,在每个大区遴选合作医院,共选择18家医院提供确诊生殖器疣病人及其标本和19家医院提供确诊子宫颈病变病人及其组织蜡块。
疣体组织标本的HPV型别判定：采用酚-氯仿方法抽提DNA,使用通用引物MY09/11,MY09/GP5+和GP5+/GP6+以及巢式PCR扩增140-bp目标DNA。电泳分离后直接测序,如果是单一感染,直接用BLAST 2.0判定HPV型别；如果是多重感染,使用T-vector转化E.coli.,随机挑选五个克隆后测序,判定HPV型别。
宫颈病变组织蜡块标本的HPV型别判定：用三明治切片法,第一张和最后一张蜡卷用于HE染色,中间蜡卷用于DNA提取。HE切片由病理专家组完成诊断。将经过病理确认合格的蜡卷与蛋白酶k溶液混合,70度过夜消化,以SPF10为引物扩增,用DNA酶免疫分析(DEIA)判定是否存在HPV感染,用SPF10 LiPA25 (version1)试剂盒对扩增产物进行型别判断。
结果本研究获得1295例确诊的生殖器疣病人及其福尔马林固定的标本。因PCR扩增抑制或没有提取出足够量DNA,排除290例病人的标本,余下1005例病人标本符合本次实验的要求,用于本次的生殖器疣HPV感染的分析研究。生殖器疣患者的平均年龄为32岁,女性占55.3%(556/1005)多于男性的44.7%(449/1005)。1005例生殖器疣病人中HPV阳性者为891例,感染率为88.7%。在HPV阳性病例中,HPV6和HPV11分别占46.6%和42.4%,是最常见的HPV型别,其次是HPV16占11.8%；其它型别在HPV阳性病例中的比例均小于1%。891例病人中,单一型别HPV阳性率为97.2%,而多重感染比例仅为2.8%。多重感染的型别包括HPV6、11和16。HPV6、11和16型感染占全部生殖器疣HPV阳性病例的97.9%。未发现不同大区、城市和农村、不同性别和年龄组间HPV6和11型别分布存在统计学意义的差别。
本次研究共获得664例ICC病人,其中鳞癌(SCC)630例、腺癌(ADC)34例,并获得CIN 2/3病人569例。SCC病人HPV感染率为97.6%,ADC为85.3%,CIN2/3为98.9%。HPV16(76.7%)和HPV18(7.8%)是SCC病人中最常见的感染型别,两者合计占SCC病人的84.0%；其次是HPV31占3.2%,HPV52占2.2%,HPV58占2.2%。在不同地区间SCC病人HPV感染率差别没有统计学显著意义。但是,SCC病人中,≤49岁年龄组的HPV16感染率大于50岁年龄组(P=0.003),而HPV52,58和39在高年龄组有更高的感染率；相反在CIN2和CIN3病人中,≤34岁和35-49岁年龄组HPV16感染率小于50岁年龄组(P=0.01),而HPV52、58和39在低年龄组感染率更高。与SCC病人相比,CIN2/3病人有更高的HPV31、52和58感染率,而HPV16和18的感染率则低SCC病人。
结论HPV16和18是子宫颈病变病人中的最常见的型别,HPV6、11和16是生殖器疣病人中最常见的型别。提示目前的预防性疫苗能够达到很好的效果。
Backgroud HPV (Human Papillomavirus) is an important infectious agent that is related to cervical precancerous lesion, cervical cancer and genital warts etiologically. Tha data from China CDC National Center for AIDS/STD showed 154,922 new CA patients in 2003 (12.02/100,000). The data published by IARC WHO in 2004 shows 45,689 new invasive cancers comes from China, accounting for one tenth in whole world. With the development of biomolecular technology, recombinant vaccines against HPV, which can prevent HPV infection effectively, are available in the market. There are no evidences from well-designed epidemiology study using standardized and sensitive technology for HPV detection, which can facilitates accurate evaluation on prophylactic vaccine's effects.
Objectives Hospital-based epidemiology study across China are carried out to study HPV distribution in genital warts, invasive cervical cancer (ICC) and CIN2/3 samples.
Material and Methods Stratified sampling method was applied to get representive samples of the cases from the hospitals in 7 geographic regions, including Northeast, North, Northwest, Central, Southwest, South and East. Genital warts from the cases were provide by 18 hopitals, and archived paraffin blocks for cervical lesions are provided by 19 hospitals.
We employed standard phenol-chloroform extracting and ethanol precipitation procedures on genital wards to refine DNA. Consensus primers MY09/11, MY09/GP5+ and GP5+/GP6+and nested PCR are applied to amplify 140 bp target DNA segment. For single infection, the amplimor is separated by electrophoresis and sequenced. For multiple infections, the amplimor is inserted into T-vector for E. coli. transformation. Five single clones were randomly selected for sequencing separately. Sequence information was blasted with NCBI database to ascertain HPV types.
A sandwich technique was used to cut paraffin sections for Haematoxylin and Eosin (H&E) staining and paraffin sections for HPV DNA analysis from each cervical specimen. After confirmation of histological diagnosis, qualified cervical specimens were digested in Proteinase K buffer at 70 centigrade. SPF10 PCR on the 1:10 diluted DNA was applied to amplify HPV DNA and then the generic amplification products were detected by DNA enzyme immunoassay (DEIA). HPV-positive specimens were typed by reverse hybridization line probe assay SPF10 LiPA25 (version 1).
Results Among 1295 genital warts patients with genital tissues collected,290 subjects were excluded due to no beta-globin and cyt B amplification, or PCR inhibition, or insufficient DNA for further testing and 1005 subjects were qualified for this study. The mean age is 32 years, female GW patients (55.3%; 556/1005) are more than male (44.7%; 449/1005). HPV prevalence was 88.7%(N=1005); HPV6 (46.6%) and HPV11 (42.4%) were the most common HPV types, accounting for 87.3%, followed by HPV16 (11.8%). Other HPV types were less than 1.0%. Besides, single infection was 97.2% of the total HPV positive GW patients, comparing with 2.8% multiple infections composed of HPV6, HPV11 and/or HPV16. Cumulative prevalence of HPV 6,11, and 16 is 97.9%. Neither HPV6 nor HPV11 significantly differed by urban and rural, sex, age levels and geographical regions.
Archived paraffin blocks for 664 ICC (630 squamous cell carcinoma [SCC]; 34 adenocarcinoma [ADC]),569 CIN 2/3 cases from 7 regions of China were collected. HPV prevalence was 97.6% in SCC,85.3% in adenocarcinoma,98.9% in CIN 2/3. HPV16 (76.7%) and HPV18 (7.8%) were the most common, together accounting for 84.0% of SCC, followed by HPV31 (3.2%), HPV52 (2.2%), and HPV58 (2.2%). HPV prevalence in SCC did not differ notably by region. However, SCC cases from women≤34 years and 35-49 years had significantely higher HPV 16 prevalence than women over 50 years(P=0.003), among whom HPV52,58, and 39 were more common. In contrast to SCC, HPV16 prevalence in women over 50 years is singnificantely more than women≤34 years and 35-49 years, among whom HPV52,58, and 39 were more common. HPV16 and 18 were under-represented, whereas HPV31,52 and 58 were over-represented in CIN2/3(P=0.01),.
Conclusion HPV 16 and 18 are the most common types for cervcia cancer, and HPV 6, 11 and 18 are the most common types for genital warts. It was suggested that the potential impact of prophylactic HPV vaccines is estimated to be high.
引文
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47. Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions:a meta-analysis update. Int J Cancer 2007;121:621-32
48.吴令英,李楠,章文华,等.醋酸涂抹法在宫颈癌筛查中的应用价值.癌症2003；22(10)：1096-1098.
49. Yu MY, Tong JH, Chan PK, et al. Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers. Int J Cancer 2003;105:204-9
50. Peng HQ, Liu SL, Mann V, et al. Human papillomavirus types 16 and 33, herpes simplex virus type 2 and other risk factors for cervical cancer in Sichuan Province, China. Int J Cancer 1991;47:711-6
51. Wu Y, Chen Y, Li L, et al. Associations of high-risk HPV types and viral load with cervical cancer in China. J Clin Virol 2006;35:264-9
52. Huang S, Afonina I, Miller BA, et al. Human papillomavirus types 52 and 58 are prevalent in cervical cancers from Chinese women. Int J Cancer 1997;70:408-11
53. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005;97:1072-9
54.周雷,王耕辛,曹文枫.等.63例宫颈腺癌临床治疗和预后分析.中国肿瘤临床2004；31(13)：755-757.
55. Lee PW, Kwan TT, Tam KF, et al. Beliefs about cervical cancer and human papillomavirus (HPV) and acceptability of HPV vaccination among Chinese women in Hong Kong. Prev Med 2007;45:130-4
56. Iftner T, Villa LL. Chapter 12:Human papillomavirus technologies. J Natl Cancer Inst Monogr 2003:80-8
1. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27
2. Bosch FX, Manos MM, Munoz N, et al. Prevalence of human papillomavirus in cervical cancer:a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995;87:796-802
3. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993;85:958-64
4. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999:189:12-9
5. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human papillomavirus infection in young women:a longitudinal cohort study. Lancet 2001;357:1831-6
6. Liaw KL, Glass AG, Manos MM, et al. Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions. J Natl Cancer Inst 1999;91:954-60
7. Nobbenhuis MA, Walboomers JM, Helmerhorst TJ, et al. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening:a prospective study. Lancet 1999;354:20-5
8. Cuzick J, Szarewski A, Cubie H, et al. Management of women who test positive for high-risk types of human papillomavirus:the HART study. Lancet 2003;362:1871-6
9. Kjaer SK, van den Brule AJ, Paull G, et al. Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women:population based prospective follow up study. Bmj 2002;325:572
10. Cuzick J, Clavel C, Petry KU, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006;119:1095-101
11. IARC. IARC Handbooks of Cancer Prevention:Cervical Cancer Screening. Vol.10. Lyon:IARC Press, 2005
12.乔友林,章文华,李凌,等.山西子宫颈癌筛查方法的横断面研究.中国医学科学院学报2002；24：50-53
13.赵方辉,李楠,马俊飞,等.山西襄垣妇女HPV感染与宫颈癌的研究.中华流行病学杂志2001；5：375-378
14. Levert M, Clavel C, Graesslin O, et al. Human papillomavirus typing in routine cervical smears. Results from a series of 3778 patients. Gynecol Obstet Fertil 2000:28:722-8
15. Solomon D, Schiffman M and Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance:baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293-9
16. Schneider A, Hoyer H, Lotz B, et al. Screening for high-grade cervical intra-epithelial neoplasia and cancer by testing for high-risk HPV, routine cytology or colposcopy. Int J Cancer 2000;89:529-34
17. Vince A, Kutela N. Iscic-Bes J. et al. Clinical utility of molecular detection of human papillomavirus in cervical samples by hybrid capture technology. J Clin Virol 2002;25 Suppl 3:S109-12
18. Poljak M, Marin IJ, Seme K and Vince A. Hybrid Capture Ⅱ HPV Test detects at least 15 human papillomavirus genotypes not included in its current high-risk probe cocktail. J Clin Virol 2002;25 Suppl 3:S89-97
19. Schlecht NF, Trevisan A, Duarte-Franco E, et al. Viral load as a predictor of the risk of cervical intraepithelial neoplasia. Int J Cancer 2003; 103:519-24
20. Stevens MP, Garland SM, Rudland E, Tan J, Quinn MA and Tabrizi SN. Comparison of the Digene Hybrid Capture 2 assay and Roche AMPLICOR and LINEAR ARRAY human papillomavirus (HPV) tests in detecting high-risk HPV genotypes in specimens from women with previous abnormal Pap smear results. J Clin Microbiol 2007;45:2130-7
21. van Hamont D, van Ham MA, Bakkers JM, Massuger LF and Melchers WJ. Evaluation of the SPF10-INNO LiPA human papillomavirus (HPV) genotyping test and the roche linear array HPV genotyping test. J Clin Microbiol 2006;44:3122-9
22. Kleter B. van Doom LJ, Schrauwen L, et al. Development and clinical evaluation of a highly sensitive PCR-reverse hybridization line probe assay for detection and identification of anogenital human papillomavirus. J Clin Microbiol 1999:37:2508-17
23. Castle PE, Sadorra M, Lau T, Aldrich C, Garcia FA and Komegay J. Evaluation of a prototype real-time PCR assay for carcinogenic human papillomavirus (HPV) detection and simultaneous HPV genotype 16 (HPV16) and HPV18 genotyping. J Clin Microbiol 2009;47:3344-7
24.胡兴文.荧光定量多重PCR检测13种高危型人乳头瘤病毒.实用医技杂志.2008,15(33)：4761-4762.
25.廖光东,张小燕,高玉华,等.流式荧光杂交法检测高危型人乳头瘤病毒的临床验证试验.中国 医学科学院学报2007；29：603-607
26. Tyagi S, Kramer FR. Molecular beacons:probes that fluoresce upon hybridization. Nat Biotechnol 1996:14:303-8
27. Jeantet D, Schwarzmann F, Tromp J, et al. NucliSENS EasyQ HPV vl test-Testing for oncogenic activity of human papillomaviruses. J Clin Virol 2009;45 Suppl 1:29-37
28. Szarewski A, Ambroisine L, Cadman L. et al. Comparison of predictors for high-grade cervical intraepithelial neoplasia in women with abnormal smears. Cancer Epidemiol Biomarkers Prev 2008:17:3033-42
29. Clausen T. Southan C and Ehrmann M. The HtrA family of proteases:implications for protein composition and cell fate. Mol Cell 2002:10:443-55
30. Jelen F, Oleksy A, Smietana K and Otlewski J. PDZ domains-common players in the cell signaling. Acta Biochim Pol 2003;50:985-1017
31. Schlieker C, Mogk A and Bukau B. A PDZ switch for a cellular stress response. Cell 2004; 117:417-9
32. Songyang Z, Fanning AS, Fu C, et al. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 1997;275:73-7
33. Kim E, Sheng M. PDZ domain proteins of synapses. Nat Rev Neurosci 2004;5:771-81
34. Alvarez-Salas LM, Cullinan AE, Siwkowski A, Hampel A and DiPaolo JA. Inhibition of HPV 16 E6/E7 immortalization of normal keratinocytes by hairpin ribozymes. Proc Natl Acad Sci U S A 1998;95:1189-94
35. Yugawa T, Kiyono T. Molecular mechanisms of cervical carcinogenesis by high-risk human papillomaviruses:novel functions of E6 and E7 oncoproteins. Rev Med Virol 2009:19:97-113
36. Sanclemente G, Gill DK. Human papillomavirus molecular biology and pathogenesis. J Eur Acad Dermatol Venereol 2002; 16:231-40
37. ACOG Practice Bulletin:clinical management guidelines for obstetrician-gynecologists. Number 45, August 2003. Cervical cytology screening (replaces committee opinion 152, March 1995). Obstet Gynecol 2003; 102:417-27
38. Clavel C, Masure M, Bory JP, et al. Human papillomavirus testing in primary screening for the detection of high-grade cervical lesions:a study of 7932 women. Br J Cancer 2001;84:1616-23
39.李淑敏,章文华,吴令英,等.人乳头状瘤病毒负荷量与子宫颈癌及其癌前病变关系的初步研究.中华妇产科杂志2004；39：400-402
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41. Belinson JL, Qiao YL, Pretorius RG, et al. Shanxi Province cervical cancer screening study II: self-sampling for high-risk human papillomavirus compared to direct sampling for human papillomavirus and liquid based cervical cytology. Int J Gynecol Cancer 2003;13:819-26
42.沈艳红,陈凤,黄曼妮,等.我国山西省子宫颈癌高发区人乳头瘤病毒感染调查.中国医学科学 院学报2003；25：381-385
43.刘彬,陈汶,任生达,等.液基细胞学剩余标本筛查子宫颈病变中人乳头瘤病毒DNA的应用.中华检验医学杂志2005；28：495-497
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16. Jacobs MV, Snijders PJ, van den Brule AJ, et al. A general primer GP5+/GP6(+)-mediated PCR-enzyme immunoassay method for rapid detection of 14 high-risk and 6 low-risk human papillomavirus genotypes in cervical scrapings. J Clin Microbiol 1997;35:791-5
17. Gravitt PE, Burk RD, Lorincz A. et al. A comparison between real-time polymerase chain reaction and hybrid capture 2 for human papillomavirus DNA quantitation. Cancer Epidemiol Biomarkers Prev 2003;12:477-84
18. Brown TJ, Yen-Moore A, Tyring SK. An overview of sexually transmitted diseases. Part II. J Am Acad Dermatol 1999;41:661-77; 678-80
19. Handsfield HH. Clinical presentation and natural course of anogenital warts. Am J Med 1997;102:16-20
20.龚向东,叶顺章,张君炎,等.1991-2001年我国性病流行病学分析.疾病监测2002；35：172-182
21.徐文严,邵长庚.近20年来我国性病的流行情况.中华医学杂志1997；77：157-159
22. Partridge JM, Koutsky LA. Genital human papillomavirus infection in men. Lancet Infect Dis 2006;6:21-31
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24. Wu Y, Chen Y, Li L, Yu G, He Y and Zhang Y. Analysis of mutations in the E6/E7 oncogenes and L1 gene of human papillomavirus 16 cervical cancer isolates from China. J Gen Virol 2006;87:1181-8
25. von Krogh G Lacey CJ, Gross G, et al. European course on HPV associated pathology:guidelines for primary care physicians for the diagnosis and management of anogenital warts. Sex Transm Infect 2000;76:162-8
26. Aubin F, Pretet JL, Jacquard AC, et al. Human papillomavirus genotype distribution in external acuminata condylomata:a Large French National Study (EDiTH IV). Clin Infect Dis 2008;47:610-5
27. Chan PK, Luk AC, Luk TN, et al. Distribution of human papillomavirus types in anogenital warts of men. J Clin Virol 2009;44:111-4
28. Garland SM, Steben M, Sings HL, et al. Natural history of genital warts:analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6,11,16, and 18) vaccine. J Infect Dis 2009;199:805-14
29. Frazer IH, Thomas R, Zhou J, et al. Potential strategies utilised by papillomavirus to evade host immunity. Immunol Rev 1999; 168:131-42
30. Arany I, Tyring SK. Status of local cellular immunity in interferon-responsive and-nonresponsive human papillomavirus-associated lesions. Sex Transm Dis 1996;23:475-80
31. Vandepapeliere P, Barrasso R, Meijer CJ, et al. Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine:infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005; 192:2099-107
32. Castle PE, Gravitt PE, Solomon D, et al. Comparison of linear array and line blot assay for detection of human papillomavirus and diagnosis of cervical precancer and cancer in the atypical squamous cell of undetermined significance and low-grade squamous intraepithelial lesion triage study. J Clin Microbiol 2008;46:109-17
33. Coutlee F, Gravitt P, Kornegay J, et al. Use of PGMY primers in L1 consensus PCR improves detection of human papillomavirus DNA in genital samples. J Clin Microbiol 2002;40:902-7
34. Woo YL, Damay I, Stanley M, et al. The use of HPV Linear Array Assay for multiple HPV typing on archival frozen tissue and DNA specimens. J Virol Methods 2007; 142:226-30
35.田子强,刘俊峰,张少为,等.普通甲醛固定石蜡包埋组织DNA提取方法的探讨.癌症2004；23(3)：342-435
36. Giovannelli L, Lama A, Capra G. et al. Detection of human papillomavirus DNA in cervical samples:analysis of the new PGMY-PCR compared to the hybrid capture Ⅱ and MY-PCR assays and a two-step nested PCR assay. J Clin Microbiol 2004;42:3861-4
37. Kornegay JR, Roger M, Davies PO. et al. International proficiency study of a consensus L1 PCR assay for the detection and typing of human papillomavirus DNA:evaluation of accuracy and intralaboratory and interlaboratory agreement. J Clin Microbiol 2003;41:1080-6
38. Cutts FT, Franceschi S, Goldie S, et al. Human papillomavirus and HPV vaccines:a review. Bull World Health Organ 2007:85:719-26
39. Lo KW, Wong YF, Chan MK, et al. Prevalence of human papillomavirus in cervical cancer:a multicenter study in China. Int J Cancer 2002:100:327-31
40. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12-9
41. Kleter B, van Doom LJ, Schrauwen L. et al. Development and clinical evaluation of a highly sensitive PCR-reverse hybridization line probe assay for detection and identification of anogenital human papillomavirus. J Clin Microbiol 1999;37:2508-17
42. Bao YP, Li N, Smith JS, et al. Human papillomavirus type-distribution in the cervix of Chinese women:a meta-analysis. Int J STD AIDS 2008; 19:106-11
43. van Ham MA, Bakkers JM. Harbers GK,et al. Comparison of two commercial assays for detection of human papillomavirus (HPV) in cervical scrape specimens:validation of the Roche AMPLICOR HPV test as a means to screen for HPV genotypes associated with a higher risk of cervical disorders. J Clin Microbiol 2005;43:2662-7
44. Liu J, Rose B, Huang X, et al. Comparative analysis of characteristics of women with cervical cancer in high-versus low-incidence regions. Gynecol Oncol 2004;94:803-10
45. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003:348:518-27
46. Munoz N, Bosch FX, de Sanjose S, et al. Risk factors for cervical intraepithelial neoplasia grade Ⅲ/carcinoma in situ in Spain and Colombia. Cancer Epidemiol Biomarkers Prev 1993:2:423-31
47. Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions:a meta-analysis update. Int J Cancer 2007;121:621-32
48.吴令英,李楠,章文华,等.醋酸涂抹法在宫颈癌筛查中的应用价值.癌症2003；22(10)：1096-1098.
49. Yu MY, Tong JH, Chan PK, et al. Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers. Int J Cancer 2003;105:204-9
50. Peng HQ, Liu SL, Mann V, et al. Human papillomavirus types 16 and 33, herpes simplex virus type 2 and other risk factors for cervical cancer in Sichuan Province, China. Int J Cancer 1991;47:711-6
51. Wu Y, Chen Y, Li L, et al. Associations of high-risk HPV types and viral load with cervical cancer in China. J Clin Virol 2006;35:264-9
52. Huang S, Afonina I, Miller BA, et al. Human papillomavirus types 52 and 58 are prevalent in cervical cancers from Chinese women. Int J Cancer 1997;70:408-11
53. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005;97:1072-9
54.周雷,王耕辛,曹文枫.等.63例宫颈腺癌临床治疗和预后分析.中国肿瘤临床2004；31(13)：755-757.
55. Lee PW, Kwan TT, Tam KF, et al. Beliefs about cervical cancer and human papillomavirus (HPV) and acceptability of HPV vaccination among Chinese women in Hong Kong. Prev Med 2007;45:130-4
56. Iftner T, Villa LL. Chapter 12:Human papillomavirus technologies. J Natl Cancer Inst Monogr 2003:80-8
1. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27
2. Bosch FX, Manos MM, Munoz N, et al. Prevalence of human papillomavirus in cervical cancer:a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995;87:796-802
3. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993;85:958-64
4. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999:189:12-9
5. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human papillomavirus infection in young women:a longitudinal cohort study. Lancet 2001;357:1831-6
6. Liaw KL, Glass AG, Manos MM, et al. Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions. J Natl Cancer Inst 1999;91:954-60
7. Nobbenhuis MA, Walboomers JM, Helmerhorst TJ, et al. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening:a prospective study. Lancet 1999;354:20-5
8. Cuzick J, Szarewski A, Cubie H, et al. Management of women who test positive for high-risk types of human papillomavirus:the HART study. Lancet 2003;362:1871-6
9. Kjaer SK, van den Brule AJ, Paull G, et al. Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women:population based prospective follow up study. Bmj 2002;325:572
10. Cuzick J, Clavel C, Petry KU, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006;119:1095-101
11. IARC. IARC Handbooks of Cancer Prevention:Cervical Cancer Screening. Vol.10. Lyon:IARC Press, 2005
12.乔友林,章文华,李凌,等.山西子宫颈癌筛查方法的横断面研究.中国医学科学院学报2002；24：50-53
13.赵方辉,李楠,马俊飞,等.山西襄垣妇女HPV感染与宫颈癌的研究.中华流行病学杂志2001；5：375-378
14. Levert M, Clavel C, Graesslin O, et al. Human papillomavirus typing in routine cervical smears. Results from a series of 3778 patients. Gynecol Obstet Fertil 2000:28:722-8
15. Solomon D, Schiffman M and Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance:baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293-9
16. Schneider A, Hoyer H, Lotz B, et al. Screening for high-grade cervical intra-epithelial neoplasia and cancer by testing for high-risk HPV, routine cytology or colposcopy. Int J Cancer 2000;89:529-34
17. Vince A, Kutela N. Iscic-Bes J. et al. Clinical utility of molecular detection of human papillomavirus in cervical samples by hybrid capture technology. J Clin Virol 2002;25 Suppl 3:S109-12
18. Poljak M, Marin IJ, Seme K and Vince A. Hybrid Capture Ⅱ HPV Test detects at least 15 human papillomavirus genotypes not included in its current high-risk probe cocktail. J Clin Virol 2002;25 Suppl 3:S89-97
19. Schlecht NF, Trevisan A, Duarte-Franco E, et al. Viral load as a predictor of the risk of cervical intraepithelial neoplasia. Int J Cancer 2003; 103:519-24
20. Stevens MP, Garland SM, Rudland E, Tan J, Quinn MA and Tabrizi SN. Comparison of the Digene Hybrid Capture 2 assay and Roche AMPLICOR and LINEAR ARRAY human papillomavirus (HPV) tests in detecting high-risk HPV genotypes in specimens from women with previous abnormal Pap smear results. J Clin Microbiol 2007;45:2130-7
21. van Hamont D, van Ham MA, Bakkers JM, Massuger LF and Melchers WJ. Evaluation of the SPF10-INNO LiPA human papillomavirus (HPV) genotyping test and the roche linear array HPV genotyping test. J Clin Microbiol 2006;44:3122-9
22. Kleter B. van Doom LJ, Schrauwen L, et al. Development and clinical evaluation of a highly sensitive PCR-reverse hybridization line probe assay for detection and identification of anogenital human papillomavirus. J Clin Microbiol 1999:37:2508-17
23. Castle PE, Sadorra M, Lau T, Aldrich C, Garcia FA and Komegay J. Evaluation of a prototype real-time PCR assay for carcinogenic human papillomavirus (HPV) detection and simultaneous HPV genotype 16 (HPV16) and HPV18 genotyping. J Clin Microbiol 2009;47:3344-7
24.胡兴文.荧光定量多重PCR检测13种高危型人乳头瘤病毒.实用医技杂志.2008,15(33)：4761-4762.
25.廖光东,张小燕,高玉华,等.流式荧光杂交法检测高危型人乳头瘤病毒的临床验证试验.中国 医学科学院学报2007；29：603-607
26. Tyagi S, Kramer FR. Molecular beacons:probes that fluoresce upon hybridization. Nat Biotechnol 1996:14:303-8
27. Jeantet D, Schwarzmann F, Tromp J, et al. NucliSENS EasyQ HPV vl test-Testing for oncogenic activity of human papillomaviruses. J Clin Virol 2009;45 Suppl 1:29-37
28. Szarewski A, Ambroisine L, Cadman L. et al. Comparison of predictors for high-grade cervical intraepithelial neoplasia in women with abnormal smears. Cancer Epidemiol Biomarkers Prev 2008:17:3033-42
29. Clausen T. Southan C and Ehrmann M. The HtrA family of proteases:implications for protein composition and cell fate. Mol Cell 2002:10:443-55
30. Jelen F, Oleksy A, Smietana K and Otlewski J. PDZ domains-common players in the cell signaling. Acta Biochim Pol 2003;50:985-1017
31. Schlieker C, Mogk A and Bukau B. A PDZ switch for a cellular stress response. Cell 2004; 117:417-9
32. Songyang Z, Fanning AS, Fu C, et al. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 1997;275:73-7
33. Kim E, Sheng M. PDZ domain proteins of synapses. Nat Rev Neurosci 2004;5:771-81
34. Alvarez-Salas LM, Cullinan AE, Siwkowski A, Hampel A and DiPaolo JA. Inhibition of HPV 16 E6/E7 immortalization of normal keratinocytes by hairpin ribozymes. Proc Natl Acad Sci U S A 1998;95:1189-94
35. Yugawa T, Kiyono T. Molecular mechanisms of cervical carcinogenesis by high-risk human papillomaviruses:novel functions of E6 and E7 oncoproteins. Rev Med Virol 2009:19:97-113
36. Sanclemente G, Gill DK. Human papillomavirus molecular biology and pathogenesis. J Eur Acad Dermatol Venereol 2002; 16:231-40
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