HPV related VIN: Highly proliferative and diminished responsiveness to extracellular signals

Abstract

Vulvar intraepithelial neoplasia (VIN) is a premalignant disorder caused by human papillomaviruses. Basic knowledge about the molecular pathogenesis of VIN is sparse. Therefore, we have analyzed the gene expression profile of 9 VIN samples in comparison to 10 control samples by using genome wide Affymetrix Human U133A plus2 GeneChips. Results were validated by quantitative real-time RT-PCR analysis and immunostaining of a few representative genes (TACSTD1, CCNE2, AR and ESR1). Significance analysis of microarrays (SAM) showed that 1,497 genes were differentially expressed in VIN compared to controls. By analyzing the biological processes affected by the observed differences, we found that VIN appears to be a highly proliferative disease; many cyclins (CCNA, CCNB and CCNE) and almost all prereplication complex proteins are upregulated. Thereby, VIN does not seem to depend for its proliferation on paracrine or endocrine signals. Many receptors (for example ESR1 and AR) and ligands are downregulated. Furthermore, although VIN is not an invasive disease, the inhibition of expression of a marked number of cell-cell adhesion molecules seems to indicate development towards invasion. Upon reviewing apoptosis and angiogenesis, it was observed that these processes have not become significantly disregulated in VIN. In conclusion: although VIN is still a premalignant disease, it already displays several hallmarks of cancer. 1 Differentiated type VIN is mostly found in postmenopausal women and is associated with lichen sclerosus. In contrast, Usual type VIN (undifferentiated) is often diagnosed in premenopausal women and is strongly associated with sexually transmitted Human papilloma virus (HPV) infections. In this report, we will focus on HPVrelated, Usual Type VIN.During the last decade, VIN has been diagnosed with increasing frequency in relatively young women in western countries. This rise in incidence could be the result of a higher awareness and knowledge of VIN, but is more likely to be due to the overall increase in sexually transmitted diseases, and especially the rise in HPV infections. Around 40% of young, sexually active women are infected with high-risk HPV. 2 Fortunately most women are able to clear the infection, and less than 10% of infected women develop a persistent HPV infection which causes dysplasia of the lower genital tract and might cause VIN.3 Such a persistent infection with high-risk HPV (mostly HPV16, 18, 31 or 33) may trigger VIN to further develop into invasive vulvar cancer. What percentage of women with VIN eventually develop cancer is difficult to assess, because most patients with VIN will be treated effectively.van Seters et al. have reviewed data on 3,322 published patients with VIN and found 88 untreated patients, of whom 8 (9%) progressed to vulvar cancer. 4 A critical step in the defence against high-risk HPV is a good immune response. Accordingly, being immunocompromised is a risk factor for the development of VIN and subsequent vulvar cancer. For example, VIN is observed more often ...

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