HPV感染型别和吸烟与宫颈癌的关系及新筛查方法验证的研究
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摘要
研究目的：
利用来自中国5个现场的横断面研究数据确定15～54岁妇女宫颈脱落细胞中与疫苗相关型别的HPV感染状态、血清抗体检测水平和CIN中HPV型别分布。系统评价中国妇女吸烟和被动吸烟与HPV感染和CIN2+的关系。验证可用于发展中国家作为宫颈癌初筛检测试剂盒(careHPVTM Test)的可靠性,为宫颈癌的预防提供科学依据。
材料与方法：
1.利用以人群为基础的横断面研究资料,纳入4215例妇女。利用第二代杂交捕获试验捕获实验(hc2)检测宫颈脱落细胞的高危和低危HPV,抽取部分受试者采用Linear Array法进行HPV DNA分型,对病理诊断为CIN1+的蜡块使用INNO LiPA法分型,血清中的HPV6、11、16、18抗体使用荧光检测法进行检测。
2.汇总1999-2008年中国医学科学院肿瘤研究所/肿瘤医院(CICAMS)与国内外合作单位在全国8个省市15个地区开展的以人群为基础的15项子宫颈癌横断面筛查研究资料,以pooled分析方法,系统评价吸烟和被动吸烟与HPV感染和CIN2+的关联。
3.在山西省襄垣县的459例受检者中平行比较careHPVTM与hc2实验、HPV PCR检测方法的一致性,验证careHPVTM作为宫颈癌初筛检测手段的可靠性。
研究结果：
1.本研究共纳入4215例合格研究对象,平均年龄为37.5±9.7岁。
(1)共有4206位妇女有宫颈脱落细胞HPV DNA检测和血清抗体检测结果。HPV16的宫颈脱落细胞HPV DNA检出率在30-34岁达到最高峰,为4-3%,45-49岁为3.7%；HPV18的宫颈脱落细胞的HPV DNA检出率在40～44岁最高,为1.3%。多数妇女宫颈脱落细胞中HPV DNA和血清抗体均为阴性：HPV16为92.2%,HPV18为97.2%,HPV16和HPV18为90.2%,HPV6为92.0%,HPV11为96.6%,HPV6和HPV11为89.9%,HPV6、11、16、18为82.5%。
(2)在183例病理诊断为CIN1+的蜡块中,162例有明确的HPV DNA分型,153例为HPV阳性。在农村和城市地区,HPV16均是最常见的HPV型别；在CIN2和CIN3+中,HPV16和HPV18的感染率可达65.9%和75.0%。同时发现HPV31、33、52、58的感染率也较高,HPV31较易发生混合感染。
2.中国妇女吸烟率为2.6%,被动吸烟率为73.7%。吸烟与HPV感染(OR=1.06,95%CI：0.87～1.29)以及C1N2+无关联(OR=1.33,95%CI：0.83～2.13),被动吸烟与HPV感染存在关联(OR=1.15,95%CI：1.02～1.29),但与CIN2+无关联(OR=0.83,95%CI：0.62～1.13)。
3. careHFVTM与hc2的Kappa值为0.815(P<0.0001),一致率为92.6%(95%CI：89.8%～94.7%)；与HPV核酸扩增PCR荧光检测试剂盒的Kappa为0.765(P<0.0001),一致率为90.3%(95%CI：87.3%～92.8%)。
结论与建议：
1.中国妇女的HPV感染的流行病学调查：
(1)30～34岁时,HPV16和HPV18在宫颈脱落细胞中的HPV DNA检出率达到高峰,之后虽有下降,但基本持平,在30岁之前,感染HPV的风险较高,所以,在制定HPV预防性疫苗免疫规划策略时,需考虑优先给育龄期年轻妇女接种。中国妇女宫颈脱落细胞中HPV感染和血清抗体检出率较低,接种HPV预防性疫苗,将会产生较好的保护性。
(2)HPV预防性疫苗在中国的上市和接种,可有效降低中国宫颈癌方面的疾病负担。除了目前两种疫苗中已有的HPV型别,在二代疫苗研发过程中,可考虑将中国妇女较感染率较高的其他HPV型别引入,如HPV52、58、33、31。
2.中国妇女主动吸烟率低,但被动吸烟率较高,被动吸烟是HPV感染的主要危险因素。
3. careHPVTM与已被国家食品药品监督管理局(SFDA)批准的hc2试剂(Qiagen)、 HPV PCR试剂(港龙)具有高度的一致性。
Objectives
To evaluate the status of HPV DNA infection in exfoliated cell, serum antibody levels of HPV6\11\16\18and HPV type distribution in cervical intraepithelial neoplasia from a cross sectional study include5sites in China. The second objective is to access the association between smoking/passive smoking and human papillomavirus (HPV) infection/CIN2+in Chinese women. And to validate the reliability of careHPVTM as a cervical cancer and precancerous lesions screening method in the low resource setting, provide scientific evidence for cervical cancer prevention.
Materials and methods
1. Use the data of a cross sectional and population-base study, a total of4,215sexually active women were included. Low and high risk HPV types from cervical exfoliated cells were tested with hc2, and some samples were genotyping with Linear Array. CIN1+specimens were genotyping with INNO LiPA form paraffin block. HPV16,18,6and11serum antibodies were detected using a Luminex-based, competitive immunoassay.
2. Data were collected from15cross-sectional population-based studies conducted by CICAMS and its national or international collaborators in8provinces, which including15areas during1999to2008. Evaluate the association between smoking/passive smoking and HPV infection/CIN2+.
3. Compared three cervical cancer screening methods:careHPVTM, Hybrid Capture2High-Risk HPV DNA Test (hc2) and HPV PCR by evaluating the sensitivity and specificity for detecting high-grade cervical intraepithelial neoplasis (≥CIN2) among459women in Xiangyuan county of Shanxi province, to validate the reliability of careHPVTM.
Results
1. The average age was37.5±9.7years of women in this study.
(1) A total of4,206women with HPV DNA status in exfoliated cell and serum antibody results were included. HPV16prevalence in exfoliated cell peaked in women aged30-34years (4.2%) and45-49years (3.8%), while HPV18prevalence peaked at ages40-44years (1.3%). Most women were dually DNA and serum antibody negative:HPV16(92.2%),18(97.2%), HPV16and18(90.2%), HPV6(92.0%), HPV11(96.6%), HPV6and11(89.9%) and HPV16,18,6and11(82.5%).
(2)183cases were diagnosis as CIN2+,162(88.5) typable lesions,153(94.4%) were HPV positive. HPV16was the most prevalent type in lesions in both urban and rural settings. Combined, HPV16and18were attributable to65.9%and75.0%of HPV positive CIN2and CIN3lesions, respectively. In addition, HPV31,33,52and58were prevalent in CIN1+lesions. Though prevalent, HPV31always occurred as a co-infection with another HPV types.
3. Smoking rates was2.6%in Chinese women, and passive smoking rate was73.3%. We found no evidence to indicate that smoking is a risk factor for HPV infection (OR=1.06,95%CI:0.87～1.29) and CIN2+(OR=1.33,95%CI:0.83～2.13). Passive smoking was associated with HPV infection (OR=1.15,95%CI:1.02～1.29), but was not associated with CIN2+(OR=0.83,95%CI:0.62～1.13).
4. Kappa value and the agreement rate were0.815(P<0.0001), and92.6%(95%CI:89.8%-94.7%), respectively between careHPVTM and hc2; and Kappa value and the agreement rate were0.765(P<0.0001) and90.3%(95%CI:87.3%-92.8%), respectively between careHPVTM and PCR fluorescence detection kit for human papillomavirus.
Conclusions and suggestions
1. We found in the study of4215women:
(1)The HPV infection in cervical exfoliated cells of HPV16and HPV18reached peak at30-34age group, after that, althouth it decrese, but basicall the same as30-34. Before the age of30, there was a high risk to infection HPV16and HPV18. Future national HPV vaccination programs in China should target younger women before30year old. And the HPV prophylactic vaccine will provide a good effection, because the HPV infection rate in exfoliated cell and serum antibody was low.
(2) Our study findings suggest that a prophylactic vaccine against HPV16and18is expected to substantially reduce the burden of cervical lesions and cancer in China. In addition, other HPV types, such as33,52, and58play an important role in cervical disease in China, we could consider the introduction to these HPV types in the second-generation vaccine development process.
2. The rate of smoking is low in Chinese women, rate of passive smoking is high. Passive smoking is a risk factor of HPV infection.
4. careHPVTM is highly consistent with hc2and HPV PCR, which have been approved by State Food and Drug Administration (SFDA).
利用来自中国5个现场的横断面研究数据确定15～54岁妇女宫颈脱落细胞中与疫苗相关型别的HPV感染状态、血清抗体检测水平和CIN中HPV型别分布。系统评价中国妇女吸烟和被动吸烟与HPV感染和CIN2+的关系。验证可用于发展中国家作为宫颈癌初筛检测试剂盒(careHPVTM Test)的可靠性,为宫颈癌的预防提供科学依据。
材料与方法：
1.利用以人群为基础的横断面研究资料,纳入4215例妇女。利用第二代杂交捕获试验捕获实验(hc2)检测宫颈脱落细胞的高危和低危HPV,抽取部分受试者采用Linear Array法进行HPV DNA分型,对病理诊断为CIN1+的蜡块使用INNO LiPA法分型,血清中的HPV6、11、16、18抗体使用荧光检测法进行检测。
2.汇总1999-2008年中国医学科学院肿瘤研究所/肿瘤医院(CICAMS)与国内外合作单位在全国8个省市15个地区开展的以人群为基础的15项子宫颈癌横断面筛查研究资料,以pooled分析方法,系统评价吸烟和被动吸烟与HPV感染和CIN2+的关联。
3.在山西省襄垣县的459例受检者中平行比较careHPVTM与hc2实验、HPV PCR检测方法的一致性,验证careHPVTM作为宫颈癌初筛检测手段的可靠性。
研究结果：
1.本研究共纳入4215例合格研究对象,平均年龄为37.5±9.7岁。
(1)共有4206位妇女有宫颈脱落细胞HPV DNA检测和血清抗体检测结果。HPV16的宫颈脱落细胞HPV DNA检出率在30-34岁达到最高峰,为4-3%,45-49岁为3.7%；HPV18的宫颈脱落细胞的HPV DNA检出率在40～44岁最高,为1.3%。多数妇女宫颈脱落细胞中HPV DNA和血清抗体均为阴性：HPV16为92.2%,HPV18为97.2%,HPV16和HPV18为90.2%,HPV6为92.0%,HPV11为96.6%,HPV6和HPV11为89.9%,HPV6、11、16、18为82.5%。
(2)在183例病理诊断为CIN1+的蜡块中,162例有明确的HPV DNA分型,153例为HPV阳性。在农村和城市地区,HPV16均是最常见的HPV型别；在CIN2和CIN3+中,HPV16和HPV18的感染率可达65.9%和75.0%。同时发现HPV31、33、52、58的感染率也较高,HPV31较易发生混合感染。
2.中国妇女吸烟率为2.6%,被动吸烟率为73.7%。吸烟与HPV感染(OR=1.06,95%CI：0.87～1.29)以及C1N2+无关联(OR=1.33,95%CI：0.83～2.13),被动吸烟与HPV感染存在关联(OR=1.15,95%CI：1.02～1.29),但与CIN2+无关联(OR=0.83,95%CI：0.62～1.13)。
3. careHFVTM与hc2的Kappa值为0.815(P<0.0001),一致率为92.6%(95%CI：89.8%～94.7%)；与HPV核酸扩增PCR荧光检测试剂盒的Kappa为0.765(P<0.0001),一致率为90.3%(95%CI：87.3%～92.8%)。
结论与建议：
1.中国妇女的HPV感染的流行病学调查：
(1)30～34岁时,HPV16和HPV18在宫颈脱落细胞中的HPV DNA检出率达到高峰,之后虽有下降,但基本持平,在30岁之前,感染HPV的风险较高,所以,在制定HPV预防性疫苗免疫规划策略时,需考虑优先给育龄期年轻妇女接种。中国妇女宫颈脱落细胞中HPV感染和血清抗体检出率较低,接种HPV预防性疫苗,将会产生较好的保护性。
(2)HPV预防性疫苗在中国的上市和接种,可有效降低中国宫颈癌方面的疾病负担。除了目前两种疫苗中已有的HPV型别,在二代疫苗研发过程中,可考虑将中国妇女较感染率较高的其他HPV型别引入,如HPV52、58、33、31。
2.中国妇女主动吸烟率低,但被动吸烟率较高,被动吸烟是HPV感染的主要危险因素。
3. careHPVTM与已被国家食品药品监督管理局(SFDA)批准的hc2试剂(Qiagen)、 HPV PCR试剂(港龙)具有高度的一致性。
Objectives
To evaluate the status of HPV DNA infection in exfoliated cell, serum antibody levels of HPV6\11\16\18and HPV type distribution in cervical intraepithelial neoplasia from a cross sectional study include5sites in China. The second objective is to access the association between smoking/passive smoking and human papillomavirus (HPV) infection/CIN2+in Chinese women. And to validate the reliability of careHPVTM as a cervical cancer and precancerous lesions screening method in the low resource setting, provide scientific evidence for cervical cancer prevention.
Materials and methods
1. Use the data of a cross sectional and population-base study, a total of4,215sexually active women were included. Low and high risk HPV types from cervical exfoliated cells were tested with hc2, and some samples were genotyping with Linear Array. CIN1+specimens were genotyping with INNO LiPA form paraffin block. HPV16,18,6and11serum antibodies were detected using a Luminex-based, competitive immunoassay.
2. Data were collected from15cross-sectional population-based studies conducted by CICAMS and its national or international collaborators in8provinces, which including15areas during1999to2008. Evaluate the association between smoking/passive smoking and HPV infection/CIN2+.
3. Compared three cervical cancer screening methods:careHPVTM, Hybrid Capture2High-Risk HPV DNA Test (hc2) and HPV PCR by evaluating the sensitivity and specificity for detecting high-grade cervical intraepithelial neoplasis (≥CIN2) among459women in Xiangyuan county of Shanxi province, to validate the reliability of careHPVTM.
Results
1. The average age was37.5±9.7years of women in this study.
(1) A total of4,206women with HPV DNA status in exfoliated cell and serum antibody results were included. HPV16prevalence in exfoliated cell peaked in women aged30-34years (4.2%) and45-49years (3.8%), while HPV18prevalence peaked at ages40-44years (1.3%). Most women were dually DNA and serum antibody negative:HPV16(92.2%),18(97.2%), HPV16and18(90.2%), HPV6(92.0%), HPV11(96.6%), HPV6and11(89.9%) and HPV16,18,6and11(82.5%).
(2)183cases were diagnosis as CIN2+,162(88.5) typable lesions,153(94.4%) were HPV positive. HPV16was the most prevalent type in lesions in both urban and rural settings. Combined, HPV16and18were attributable to65.9%and75.0%of HPV positive CIN2and CIN3lesions, respectively. In addition, HPV31,33,52and58were prevalent in CIN1+lesions. Though prevalent, HPV31always occurred as a co-infection with another HPV types.
3. Smoking rates was2.6%in Chinese women, and passive smoking rate was73.3%. We found no evidence to indicate that smoking is a risk factor for HPV infection (OR=1.06,95%CI:0.87～1.29) and CIN2+(OR=1.33,95%CI:0.83～2.13). Passive smoking was associated with HPV infection (OR=1.15,95%CI:1.02～1.29), but was not associated with CIN2+(OR=0.83,95%CI:0.62～1.13).
4. Kappa value and the agreement rate were0.815(P<0.0001), and92.6%(95%CI:89.8%-94.7%), respectively between careHPVTM and hc2; and Kappa value and the agreement rate were0.765(P<0.0001) and90.3%(95%CI:87.3%-92.8%), respectively between careHPVTM and PCR fluorescence detection kit for human papillomavirus.
Conclusions and suggestions
1. We found in the study of4215women:
(1)The HPV infection in cervical exfoliated cells of HPV16and HPV18reached peak at30-34age group, after that, althouth it decrese, but basicall the same as30-34. Before the age of30, there was a high risk to infection HPV16and HPV18. Future national HPV vaccination programs in China should target younger women before30year old. And the HPV prophylactic vaccine will provide a good effection, because the HPV infection rate in exfoliated cell and serum antibody was low.
(2) Our study findings suggest that a prophylactic vaccine against HPV16and18is expected to substantially reduce the burden of cervical lesions and cancer in China. In addition, other HPV types, such as33,52, and58play an important role in cervical disease in China, we could consider the introduction to these HPV types in the second-generation vaccine development process.
2. The rate of smoking is low in Chinese women, rate of passive smoking is high. Passive smoking is a risk factor of HPV infection.
4. careHPVTM is highly consistent with hc2and HPV PCR, which have been approved by State Food and Drug Administration (SFDA).
引文
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38 Marais D J, et al. (2008). Cervical human papillomavirus (HPV) infection and HPV type 16 antibodies in South African women. J Clin Microbiol,46(2): 732-739
39 Monsonego J, et al. (2005). Performance of the Roche AMPLICOR human papillomavirus (HPV) test in prediction of cervical intraepithelial neoplasia (CIN) in women with abnormal PAP smear. Gynecol Oncol,99(1):160-168
40 Leinonen M, et al. (2009). Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J Natl Cancer Inst,101(23):1612-1623
41 Kitchener H C, et al. (2011). MAVARIC-a comparison of automation-assisted and manual cervical screening:a randomised controlled trial. Health Technol Assess,15(3):iii-iv, ix-xi,1-170
42 Dai M, et al. (2006). Human papillomavirus infection in Shanxi Province, People's Republic of China:a population-based study. Br J Cancer,95(1):96-101
43 Whitlock E P, et al. (2011). Liquid-based cytology and human papillomavirus testing to screen for cervical cancer:a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med,155(10):687-697, W214-685
44 Li C, et al. (2010). A population-based study on the risks of cervical lesion and human papillomavirus infection among women in Beijing, People's Republic of China. Cancer Epidemiol Biomarkers Prev,19(10):2655-2664
45 Wong H Y, et al. (2011). Risk factors for cervical abnormalities among Hong Kong Chinese women:a large-scale community-based cervical screening program. J Womens Health (Larchmt),20(1):53-59
46 Chan P K, et al. (2011). Attribution of human papillomavirus types to cervical intraepithelial neoplasia and invasive cancers in Southern China. Int J Cancer:
47 Zhao Y, et al. (2008). Distribution of HPV genotypes in uterine cervical lesions in Yanbian, northern China. Pathol Int,58(10):643-647
48 Chan P K, et al. (2009). Distribution of human papillomavirus types in cervical cancers in Hong Kong:current situation and changes over the last decades. Int J Cancer,125(7):1671-1677
49 Bosch F X, et al. (2008). Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine,26 Suppl 10:Kl-16
50 Li J, et al. (2011). Prevalence and genotype distribution of human papillomavirus in women with cervical cancer or high-grade precancerous lesions in Chengdu, western China. Int J Gynaecol Obstet,112(2):131-134
51 Wu D, et al. (2010). Prevalence of genital human papillomavirus infection and genotypes among women from Fujian province, PR China. Eur J Obstet Gynecol Reprod Biol,151(1):86-90
52 Castellsague X, et al. (2006). Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors:implications for screening and prevention. J Natl Cancer Inst,98(5):303-315
53 Winkelstein W, Jr. (1977). Smoking and cancer of the uterine cervix:hypothesis. Am J Epidemiol,106(4):257-259
54 Appleby P, et al. (2006). Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer,118(6):1481-1495
55 Burk R D, et al. (1996). Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women. J Infect Dis,174(4):679-689
56 Giuliano A R,et al. (2002). Clearance of oncogenic human papillomavirus (HPV) infection:effect of smoking (United States). Cancer Causes Control,13(9): 839-846
57 Ho G Y, et al. (1998). Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med,338(7):423-428
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59 Schiffman M H, et al. (1993). Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst,85(12):958-964
60 Fujita M, et al. (2008). Smoking, earlier menarche and low parity as independent risk factors for gynecologic cancers in Japanese:a case-control study. Tohoku J Exp Med,216(4):297-307
61 Zhao F H, et al. (2006). Risk factors for HPV infection and cervical cancer among unscreened women in a high-risk rural area of China. Int J Cancer,118(2): 442-448
62 Syrjanen K (2008). New concepts on risk factors of HPV and novel screening strategies for cervical cancer precursors. Eur J Gynaecol Oncol,29(3):205-221
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37 Naucler P, et al. (2007). Seroprevalence of human papillomaviruses and Chlamydia trachomatis and cervical cancer risk:nested case-control study. J Gen Virol,88(Pt 3):814-822
38 Marais D J, et al. (2008). Cervical human papillomavirus (HPV) infection and HPV type 16 antibodies in South African women. J Clin Microbiol,46(2): 732-739
39 Monsonego J, et al. (2005). Performance of the Roche AMPLICOR human papillomavirus (HPV) test in prediction of cervical intraepithelial neoplasia (CIN) in women with abnormal PAP smear. Gynecol Oncol,99(1):160-168
40 Leinonen M, et al. (2009). Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J Natl Cancer Inst,101(23):1612-1623
41 Kitchener H C, et al. (2011). MAVARIC-a comparison of automation-assisted and manual cervical screening:a randomised controlled trial. Health Technol Assess,15(3):iii-iv, ix-xi,1-170
42 Dai M, et al. (2006). Human papillomavirus infection in Shanxi Province, People's Republic of China:a population-based study. Br J Cancer,95(1):96-101
43 Whitlock E P, et al. (2011). Liquid-based cytology and human papillomavirus testing to screen for cervical cancer:a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med,155(10):687-697, W214-685
44 Li C, et al. (2010). A population-based study on the risks of cervical lesion and human papillomavirus infection among women in Beijing, People's Republic of China. Cancer Epidemiol Biomarkers Prev,19(10):2655-2664
45 Wong H Y, et al. (2011). Risk factors for cervical abnormalities among Hong Kong Chinese women:a large-scale community-based cervical screening program. J Womens Health (Larchmt),20(1):53-59
46 Chan P K, et al. (2011). Attribution of human papillomavirus types to cervical intraepithelial neoplasia and invasive cancers in Southern China. Int J Cancer:
47 Zhao Y, et al. (2008). Distribution of HPV genotypes in uterine cervical lesions in Yanbian, northern China. Pathol Int,58(10):643-647
48 Chan P K, et al. (2009). Distribution of human papillomavirus types in cervical cancers in Hong Kong:current situation and changes over the last decades. Int J Cancer,125(7):1671-1677
49 Bosch F X, et al. (2008). Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine,26 Suppl 10:Kl-16
50 Li J, et al. (2011). Prevalence and genotype distribution of human papillomavirus in women with cervical cancer or high-grade precancerous lesions in Chengdu, western China. Int J Gynaecol Obstet,112(2):131-134
51 Wu D, et al. (2010). Prevalence of genital human papillomavirus infection and genotypes among women from Fujian province, PR China. Eur J Obstet Gynecol Reprod Biol,151(1):86-90
52 Castellsague X, et al. (2006). Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors:implications for screening and prevention. J Natl Cancer Inst,98(5):303-315
53 Winkelstein W, Jr. (1977). Smoking and cancer of the uterine cervix:hypothesis. Am J Epidemiol,106(4):257-259
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55 Burk R D, et al. (1996). Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women. J Infect Dis,174(4):679-689
56 Giuliano A R,et al. (2002). Clearance of oncogenic human papillomavirus (HPV) infection:effect of smoking (United States). Cancer Causes Control,13(9): 839-846
57 Ho G Y, et al. (1998). Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med,338(7):423-428
58 Coker A L, et al. (1992). Active and passive cigarette smoke exposure and cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev,1(5): 349-356
59 Schiffman M H, et al. (1993). Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst,85(12):958-964
60 Fujita M, et al. (2008). Smoking, earlier menarche and low parity as independent risk factors for gynecologic cancers in Japanese:a case-control study. Tohoku J Exp Med,216(4):297-307
61 Zhao F H, et al. (2006). Risk factors for HPV infection and cervical cancer among unscreened women in a high-risk rural area of China. Int J Cancer,118(2): 442-448
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