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

Abstract

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 5), usual type vulvar intraepithelial neoplasia (uVIN) (n 5 9)) and control samples (n 5 14) using Affymetrix Human U133A plus 2 GeneChips. Data were analyzed using OmniViz V R , Partek V R and Ingenuity V 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 cH2AX. 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 p16 INK4a 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.Worldwide, human papillomavirus (HPV) is the most common sexually transmitted infection, with an 80% life-time infection risk. 1 Fortunately, the majority of these HPV infections ($ 90%) are cleared within one to two years, without further consequences for the host. 2 Persistent infections, however, are a well-established risk factor for a large spectrum of epithelial lesions, ranging from benign hyperplasia, caused by low-risk HPV types, to (pre)malignant lesions caused by high-risk HPV types.The best known high-risk HPV related disorder is the second most common cancer in women, namely cervical cancer, with 500,000 new cases each year worldwide resulting in 250,000 deaths every year. 3 Persistent HPV infections have also been associated with other anogenital squamous cell carcinomas, including vulvar, vaginal, anal and penile cancers and their precursors. Furthermore, recent epidemiological, molecular and clinical evidence indicate that high-risk HPV (especially HPV type 16) accounts for the development of approximately 20-30% of squamous cell carcinomas of the head-and-neck. 4,5 The molecular basis of the difference in malignant potential between low-and high-risk HPV infections is not

Integrative analyses reveal novel strategies in HPV11,-16 and -45 early infection

“…We propose that the increased activity of the DNA repair system in late stages of HPV infection and during HPV-driven carcinogenesis reported in previous studies6 is a secondary effect of substantial DNA damage present in the host cells and not induced by HPV. Contrarily, we suggest that HPV impairs the DNA damage detection and repair system early in infection, which allows the accumulation of mutations that can be beneficial for the initiation of a persistent viral infection and carcinogenesis process.…”

Design stars: how Small DNA Viruses Remodel the Host Nucleus

“…E7 is able to accelerate the degradation of claspin, a protein necessary for Chk1 activation [61]. Consistent with this, in a recent study comparing gene profiles between low- and high-risk HPV-infected vulvar tissues, the tissues that are infected with high-risk HPV appear to have more DNA damage and increased expression of DDR markers [62]. These data also suggest that the genome instability caused by HPV infection has multiple causes, and many DDR pathways may contribute to it.…”

Oral Human Papillomavirus Is Common in Individuals with Fanconi Anemia

“…These effects of E7 are due to inactivation of the Rb family of tumor suppressors that limit DNA damage (19). Microarray analysis of vulvar tissue infected with both low-risk and/or high-risk HPV types indicated that FANCA, FANCD2, and other DNA damage markers were significantly induced following high-risk HPV infection, along with increased DNA damage in the tissues (30). And finally, using a computational biology approach, a link between HPV16 and the FA DNA repair pathway was identified and then validated experimentally by evaluating the impact of overexpressing E6 or E7 proteins in primary fibroblasts and keratinocytes using global gene expression analysis (31).…”