Different DNA damage and cell cycle checkpoint control in low- and high-risk human papillomavirus infections of the vulva

Lindy Santegoets, Romy Baars, Annelinde Terlou, Claudia Antonissen, Sigrid Swagemakers, Peter van der Spek, Patricia Graham, M van Beurden, WI van der Meijden, Helmerhorst, Leen Blok

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26 Citations (Scopus)


Human papillomavirus (HPV) infections may result in benign hyperplasia, caused by low-risk HPV types, or (pre)malignant lesions caused by high-risk HPV types. The molecular basis of this difference in malignant potential is not completely understood. Here, we performed gene profiling of different HPV infected vulvar tissues (condylomata acuminata (n = 5), usual type vulvar intraepithelial neoplasia (uVIN) (n = 9)) and control samples (n = 14) using Affymetrix Human U133A plus 2 GeneChips. Data were analyzed using OmniViz (R), Partek (R) and Ingenuity (R) Software. Results were validated by real-time RT-PCR and immunostaining. Although similarities were observed between gene expression profiles of low- and high-risk HPV infected tissues (e.g., absence of estrogen receptor in condylomata and uVIN), high-risk HPV infected tissues showed more proliferation and displayed more DNA damage than tissues infected with low-risk HPV. These observations were confirmed by differential regulation of cell cycle checkpoints and by increased expression of DNA damage-biomarkers p53 and ?H2AX. Furthermore, FANCA, FANCD2, BRCA1 and RAD51, key players in the DNA damage response, were significantly upregulated (p < 0.05). In addition, we compared our results with publicly available gene expression profiles of various other HPV-induced cancers (vulva, cervix and head-and-neck). This showed p16INK4a was the most significant marker to detect a high-risk HPV infection, but no other markers could be found. In conclusion, this study provides insight into the molecular basis of low- and high-risk HPV infections and indicates two main pathways (cell cycle and DNA damage response) that are much stronger affected by high-risk HPV as compared to low-risk HPV.
Original languageUndefined/Unknown
Pages (from-to)2874-2885
Number of pages12
JournalInternational Journal of Cancer
Issue number12
Publication statusPublished - 2012

Research programs

  • EMC MGC-02-02-01
  • EMC MM-03-24-01
  • EMC MM-03-52-02-A

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