Page 35 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

by an increased expression of proliferation markers, such as Ki67, and increased expression of p16. P16 is a protein
that promotes cell cycle arrest through prevention of hyperphosphorylation of Rb. However, its function is bypassed
by HPV, because binding of E7 to pRb creates a phosphorylation independent release of E2F. The combined action of E6
and E7 proteins stimulate S-phase cell cycle entry and surpassing of cell cycle checkpoints, leading to cell proliferation 2 and immortalization. With additional accumulation of genomic instability, this forms the basis for cervical cancer development. Adapted from Litjens et al (86)
DNA integration
DNA integration occurs frequently in cervical carcinogenesis.(28, 29) Disruption of the viral genome takes place at fragile sites, often in the E1 and E2 gene sites. Viral integration leads to loss of E2 expression, which is responsible for repression of early gene expression. As a result, expression of the E6 and E7 genes is enhanced, leading to cell proliferation. Furthermore, cells with integrated viral DNA show increased genomic instability and therefore have a greater probability of malignant progression. Interestingly, viral integration is not present in all HPV-induced cervical malignancies. Whereas almost all HPV-18 positive cervical malignancies contain integrated DNA, it is found in only approximately 70% of HPV16 positive cervical malignancies. This indicates that viral integration may not to be essential for carcinogenesis and may be a consequence of the carcinogenic process rather than a cause.(31)
Epigenetic changes
Epigenetic changes in the host genome influence gene expression and disease control in many diseases. Although the exact mechanisms are not yet completely understood, the role of epigenetic modification by HPV in cervical oncogenesis has been established. (21, 29, 32) HPV induces modifications to the host DNA methylation status and aberrant miRNA expression, which results in silencing of tumour-suppressor genes and the overexpression of oncogenes. Recently, it has been suggested that methylation analysis may distinguish advanced high-grade CIN from those with a high probability of spontaneous regression.(21) This is understandable in view of the fact that accumulation of genetic and epigenetic changes in the host and/or viral genome are acknowledged to be involved in progression toward invasive cervical cancer. Methylation of viral DNA may also contribute to cervical oncogenesis. Methylation occurs at CpG sites and this process is thought to induce a transforming infection, leading to high-grade CIN.(33)
Natural history of high-grade CIN: what may influence disease regression or progression?
In conclusion, cervical intraepithelial neoplasia is the result of transforming infections by HPV, in which expression of E6 and E7 is deregulated in the basal cell layers. Oncogenesis is further aided by genomic instability, viral DNA integration and epigenetic modifications. However, only a minority of HPV infections persists and may result in high-grade CIN. Of these, only a subset will progress to invasive cervical cancer. As mentioned before, the natural history of HPV infection and CIN lesions is determined by a complex interaction between viral and host factors (figure 3). The immune system must ensure clearance of the infected cells before the effects of E6 and E7 in different important cellular functions will result in a CIN lesion that can no longer regress. Understanding of these influencing factors is essential for the potential identification of those
A review of prognostic biomarkers
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