Integration Sites and Genotype Distributions of Human Papillomavirus in Cervical Intraepithelial Neoplasia

  • Wang, Li (Qingdao University Medical College) ;
  • Dai, Shu-Zhen (Key Laboratory of Cervical Disease of Qingdao, Department of Obstetrics and Gynecology, Affiliated Hospital of Qingdao University Medical College, Qingdao University) ;
  • Chu, Hui-Jun (Key Laboratory of Cervical Disease of Qingdao, Department of Obstetrics and Gynecology, Affiliated Hospital of Qingdao University Medical College, Qingdao University) ;
  • Cui, Hong-Fei (Qingdao University Medical College) ;
  • Xu, Xiao-Yan (Qingdao University Medical College)
  • Published : 2013.06.30


Objectives: To analyse HPV integration prevalence and genotype distributions in cervical intraepithelial neoplasia (CIN) in east part of China, furthermore to assess preferential sites for common HPV integrations and provide baseline information for cervical abnormality screening and prevention. Methods: Integration of HPV in 113 paraffin-embedded cervical intraepithelial neoplasia samples was assessed using Gencap technology in Key Laboratory of Biotechnologies in BGI-Shenzhen. Results: 64 samples were HPV-integrated and as the cervical lesions increased, the integration rate became higher significantly (P=0.002). Fifteen different HPV genotypes were detected, 14 high-risk (16, 18, 31, 33, 51, 52, 56, 58, 66, 68) and 1 low-risk (11). The most common genotypes were HPV-16, 58, 33, 52, 66, and 56. Thirteen patients had co-integration involving mainly HPV-16 and 58. The frequency of HPV gene disruption was higher in L1 and E1 genes than in other regions of the viral genomes. Conclusion: Some 56.6% of CIN lesions in Qingdao had HPV integrations, and 67.2% of HPV-integrated patients were HPV-16 and 58, more prone to be integrated in younger patients below 45 years old. There exist preferential sites for HPV-16 and HPV-58 integration, and they are more likely to be disrupted in the L1 and E1 loci.


  1. Bao YP, Li N, Smith JS, Qiao YL (2008). Human papillomavirus type-distribution in the cervix of Chinese women: a metaanalysis. Int J STD AIDS, 19, 106-11.
  2. Bosch FX, Lorincz A, Munoz N, et al (2002). The causal relation between human papillomavirus and cervical cancer. J Clin Pathol, 55, 244-65..
  3. Bosch FX, de Sanjose S (2007). The epidemiology of human papillomavirus infection and cervical cancer. Dis Markers, 23, 213-27.
  4. Brown DR, Shew ML, Qadadri B, et al (2005). A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis, 191, 182-92.
  5. Clifford GM, Gallus S, Herrero R, et al (2005). Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet, 366, 991-8.
  6. Coutlee F, Ratnam S, Ramanakumar AV, et al (2011). Distribution of human papillomavirus genotypes in cervical intraepithelial neoplasia and invasive cervical cancer in Canada. J Med Virol, 83, 1034-41.
  7. Cricca M, Venturoli S, Leo E, et al (2009). Disruption of HPV 16 E1 and E2 genes in precancerous cervical lesions. J Virol Methods, 158, 180-3.
  8. Doorbar J (2007). Papillomavirus life cycle organization and biomarker selection. Dis Markers, 23, 297-313.
  9. Ho CM, Lee BH, Chang SF, et al (2011). Integration of human papillomavirus correlates with high levels of viral oncogene transcripts in cervical carcinogenesis. Virus Res, 161, 124-30.
  10. Li H, Yang Y, Zhang R, et al (2013). Preferential sites for the integration and disruption of human papillomavirus 16 in cervical lesions. J Clin Virol, 56, 342-7.
  11. Li J, Zhang D, Zhang Y, 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, 131-4.
  12. McCredie MR, Sharples KJ, Paul C, et al (2008). Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol, 9, 425-34.
  13. Nogara PR, Gimenes F, Consolaro ME (2012). Distribution of HPV genotypes and HPV-16 and HPV-18 E2 gene disruption in South Brazilian women with cervical abnormalities. Int J Gynaecol Obstet, 117, 289-90.
  14. Ochi H, Kondo K, Matsumoto K, et al (2008). Neutralizing antibodies against human papillomavirus types 16, 18, 31, 52, and 58 in serum samples from women in Japan with low-grade cervical intraepithelial neoplasia. Clin Vaccine Immunol, 15, 1536-40.
  15. Parkin DM, Bray F, Ferlay J, Pisani P (2005). Global cancer statistics, 2002. CA Cancer J Clin, 55, 74-108.
  16. Porras C, Rodriguez AC, Hildesheim A, et al (2009). Human papillomavirus types by age in cervical cancer precursors: predominance of human papillomavirus 16 in young women. Cancer Epidemiol Biomarkers Prev, 18, 863-5.
  17. Quek SC, Lim BK, Domingo E, et al (2013). Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical intraepithelial neoplasia across 5 countries in Asia. Int J Gynecol Cancer, 23, 148-56.
  18. Ramanakumar AV, Goncalves O, Richardson H, et al (2010). Human papillomavirus (HPV) types 16, 18, 31, 45 DNA loads and HPV-16 integration in persistent and transient infections in young women. BMC Infect Dis, 10, 326.
  19. Schiffman M and Rodriguez AC (2008). Heterogeneity in CIN3 diagnosis. Lancet Oncol, 9, 404-6.
  20. Shen Y, Gong JM, Li YQ, et al (2013). Epidemiology and genotype distribution of human papillomavirus (HPV) in women of Henan Province, China. Clin Chim Acta, 415, 297-301.
  21. Smith JS, Lindsay L, Hoots B, et al (2007). Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer, 121, 621-32.
  22. Walboomers JM, Jacobs MV, Manos MM, et al (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol, 189, 12-9.<12::AID-PATH431>3.0.CO;2-F
  23. Wang SS, Hildesheim A (2003). Chapter 5: Viral and host factors in human papillomavirus persistence and progression. J Natl Cancer Inst Monogr, 2003, 35-40.
  24. Wheeler CM, Hunt WC, Joste NE, et al (2009). Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst, 101, 475-87.

Cited by

  1. Genotype Distribution and Behavioral Risk Factor Analysis of Human Papillomavirus Infection in Uyghur Women vol.14, pp.10, 2013,
  2. Diagnosis of 25 genotypes of human papillomaviruses for their physical statuses in cervical precancerous/cancerous lesions: a comparison of E2/E6E7 ratio-based vs. multiple E1-L1/E6E7 ratio-based detection techniques vol.12, pp.1, 2014,
  3. Situation of HPV16 E2 Gene Status During Radiotherapy Treatment of Cervical Carcinoma vol.15, pp.6, 2014,
  4. Human Papillomavirus Genotype Distribution and E6/E7 Oncogene Expression in Turkish Women with Cervical Cytological Findings vol.15, pp.9, 2014,
  5. Human papillomavirus: Prevalence and factors associated in women prisoners population from the Eastern Brazilian Amazon vol.86, pp.9, 2014,
  6. Polymorphisms and Functional Analysis of the Intact Human Papillomavirus16 E2 Gene vol.15, pp.23, 2015,
  7. High-risk Human Papillomavirus Genotypes in Cervical Lesions and Vaccination Challenges in China vol.16, pp.6, 2015,
  8. Molecular approaches for HPV genotyping and HPV-DNA physical status vol.19, pp.1462-3994, 2017,
  9. Human papillomavirus genome integration in squamous carcinogenesis: what have next-generation sequencing studies taught us? vol.245, pp.1, 2018,
  10. Genome-wide profiling of human papillomavirus DNA integration in liquid-based cytology specimens from a Gabonese female population using HPV capture technology vol.9, pp.1, 2019,