Page 41 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

available evidence lacks consistency. As clearance of high-grade CIN is effected by the individual
immune response, using markers of this response as prognostic biomarkers seems sensible. More
research is required for application purposes. 2
Telomerase amplification
Telomerase is an enzyme complex that provides telomere maintenance, a process that is normally restricted by activation of pRb and p53. Oncogenesis is associated with increased telomerase activity. Telomerase consists of several subunits, of which the human telomerase gene (hTERC) serves as a template during telomere elongation. The amplification of hTERC can stop cell apoptosis, leading to tumour occurrence. Gain of hTERC has been shown to correlate with histological disease grade.(48) Only one author conducted a prospective study, evaluating the prognostic value of telomerase amplification in CIN. Lan et al. studied 54 patients with histologically confirmed CIN 1/2, during 24 months. All lesions were associated with low-risk HPV types. All patients that showed progression to CIN 3 displayed gain of hTERC, whereas progression did not occur in patients were hTERC had not been amplified.(49) As such, hTERC amplification may have diagnostic purposes, in differentiating between low-grade CIN lesions with low or high risk of disease progression. Given its clear and established role in carcinogenesis and its association with CIN grade, its function as a prognostic biomarker for the natural history of CIN deserves further research.
Other markers
Both HPV antibodies and cytokine profiles, as markers of the host immune response, have been associated with disease grade in CIN, making them potential diagnostic biomarkers.(38, 50) The evidence on their value in disease prognosis is limited, however. One author found a significantly higher regression rate of CIN in patients with a stronger Th-1 cytokine response.(51) The population size was limited, however, and disease severity was not documented. The evidence on HPV antibodies in the prognosis of CIN is limited and conflicting and does not identify HPV antibodies as a promising biomarker. One author found an association between IgG positivity and progression to CIN 3 in patients with HPV16 positive cytological abnormalities.(52) Another author evaluated the prognostic value of HPV antibodies in histologically confirmed CIN 1/2 and found no correlation between baseline IgG reactivity to HPV L1 capsid and disease regression.(53)
The role of HPV induced epigenetic changes in cervical carcinogenesis is receiving increasing attention. Both altered microRNA expression and host DNA methylation is found in CIN. The mechanisms by which HPV oncoproteins deregulate microRNA expression and associations between several microRNAs and cervical cancer are reviewed by others.(54, 55) MicroRNAs have not yet been proven useful as diagnostic or prognostic markers in cervical carcinogenesis, but deserve more research in the future. Host DNA methylation of several sites has been identified as a diagnostic biomarker in CIN.(56-58) Moreover, it has recently been postulated that the extent of DNA methylation may distinguish CIN lesions with high short-term progression risk from those with low risk, as more extensive methylation may reflect a longer existing, transforming infection instead of a productive infection.(21)
A review of prognostic biomarkers
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