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Early integration of high copy HPV16 detectable in women with normal and low grade cervical cytology and histology
  1. S-M A Kulmala1,
  2. S M Syrjänen1,
  3. U B Gyllensten2,
  4. I P Shabalova3,
  5. N Petrovichev3,
  6. P Tosi4,
  7. K J Syrjänen5,
  8. B C Johansson1
  1. 1Department of Oral Pathology, Institute of Dentistry, and MediCity Research Laboratory, University of Turku, Turku, Finland
  2. 2Department of Medical Genetics, Faculty of Medicine, University of Uppsala, Sweden
  3. 3N.N. Blokhin Cancer Research Centre of Russian Academy of Medical Sciences (RAMS), Moscow, Russia
  4. 4Russian Academy of Postgraduate Medical Education, Moscow, Russia
  5. 5Department of Pathology, University of Siena, Italy
  6. 6Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland
  1. Correspondence to:
 Professor Stina Syrjänen
 Institute of Dentistry and MediCity Research Laboratory, Faculty of Medicine, Lemminkäisenkatu 2, 20520 Turku, Finland; stina.syrjanen{at}


Background: Integration of human papillomavirus (HPV) DNA has been considered a late event in cervical carcinogenesis. However, integrated forms of HPV were recently detected in cancer precursor lesions using a new real time polymerase chain reaction (PCR) to detect the deletions at the 3362–3443 region of HPV16 E2

Objective: To study the frequency of HPV16 DNA integration in cervical lesions and compare the sensitivity of an additional upstream region of the E2 ORF (2962–3138) in detecting HPV integration.

Methods: Using the TaqMan based PCR, HPV16 positive DNA samples were analysed in 164 cervical scrapings from women participating in a multicentre screening trial. Biopsy confirmation was available in 62 cases.

Results: Primers targeting the 3362–3443 region detected the majority of E2 deletions. In only 23% of the samples was the E2 upstream region equal or better target than the 3362–3443 region. Mixed (episomal/integrated) pattern was the most prevalent physical state of HPV16, also present in PAP smears with normal morphology. Pure integrated form was most prevalent in HSIL and cancer lesions, but also detectable in low grade abnormalities (NSIL, ASC-US, LSIL). Women with only integrated HPV16 were almost 10 years older than those with episomal HPV16. Viral load of integrated HPV16 was related to cytological abnormality (p = 0.003) but not to histology.

Conclusions: Integrated HPV16 is present in low grade cervical lesions, mostly mixed with the episomal form. Women with the pure integrated form of HPV16 are older than those with the other forms.

  • ASC, atypical squamous cells
  • ASC-US, atypical squamous cells of undetermined significance
  • CIN, cervical intraepithelial neoplasia
  • HPV, human papillomavirus
  • HSIL, high grade squamous intraepithelial lesion
  • LCR, long control region
  • LSIL, low grade squamous intraepithelial lesion
  • NSIL, no sign of intraepithelial lesion
  • ORF, open reading frame
  • HPV16
  • CIN
  • cervical cancer
  • real time PCR

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