Physical status of human papillomavirus integration in cervical cancer is associated with treatment outcome of the patients treated with radiotherapy

PLoS One. 2014 Jan 10;9(1):e78995. doi: 10.1371/journal.pone.0078995. eCollection 2014.


Integration of human papillomavirus (HPV) DNA into the host genome is a critical aetiological event in the progression from normal cervix to intraepithelial neoplasm, and finally to invasive cervical cancer. However, there has been little work on how HPV integration status relates to treatment outcome for cervical carcinomas. In the current study, HPV E2 and E6 gene copy numbers were measured in 111 cervical cancer tissues using real-time QPCR. Integration patterns were divided into four groups: single copy-integrated with episomal components (group 1), single copy-integrated without episomal components (group 2), multicopy tandem repetition-integrated (group 3), and low HPV (group 4) groups. A relapse-predicting model was constructed using multivariable Cox proportional hazards model to classify patients into different risk groups for disease-free survival (DFS). The model was internally validated using bootstrap resampling. Oligonucleotide microarray analysis was performed to evaluate gene expression patterns in relation to the different integration groups. DFS rate was inferior in the order of the patients in group 4, group 2/3, and group 1. Multivariate analysis showed that histologic grade, clinical stage group, and integration pattern were significant prognostic factors for poor DFS. The current prognostic model accurately predicted the risk of relapse, with an area under the receiver operating characteristic curve (AUC) of 0.74 (bootstrap corrected, 0.71). In conclusion, these data suggest that HPV integration pattern is a potent prognostic factor for tailored treatment of cervical cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alphapapillomavirus / classification
  • Alphapapillomavirus / genetics*
  • Cluster Analysis
  • Female
  • Gene Dosage
  • Gene Expression Profiling
  • Humans
  • Middle Aged
  • Models, Statistical
  • Neoplasm Grading
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Oncogene Proteins, Viral / genetics
  • Papillomavirus Infections / complications*
  • Prognosis
  • Reproducibility of Results
  • Risk Factors
  • Treatment Outcome
  • Uterine Cervical Neoplasms / mortality
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / radiotherapy*
  • Uterine Cervical Neoplasms / virology*
  • Virus Integration*


  • Oncogene Proteins, Viral

Grant support

This work was supported by the National Cancer Center, Goyang, Korea (Grant 1310300 and 1110033). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.