Page 42 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 2
Although current evidence is limited, DNA methylation seems to be a promising prognostic biomarker and deserves more research in the future.
Viral factors
Viral genotype
The influence of HPV subtype on the risk of CIN development and progression has been established many years ago, leading to categorization of HPV into high-risk and low-risk types. (59) An increased risk for CIN progression was found for HPV16, -18, -31, -33, -52 and -58.(60- 62) HPV16 has been associated with a decreased rate of spontaneous regression. Trimble et al. followed 100 women with CIN 2/3 over a mean of 15 weeks.(8) Spontaneous regression occurred in 20.5% of those with single HPV16 infection as compared to 36.4% of those with an infection other than HPV16. Ovestad et al. followed 55 patients with histologically confirmed CIN 2-3 over a mean follow-up period of 12 weeks. 18% regressed, of which none contained HPV16. All 18 cases with HPV16 persisted.(7)
Viral DNA methylation
Clarke et al. reviewed the literature on viral DNA methylation in CIN diagnosis and concluded that the detection of methylation of CpG sites in the L1 gene may distinguish between HPV- infected women with CIN 2+ and without CIN.(33) The authors state that it is not yet clear whether methylation of HPV DNA reflects an early event that can be measured as a prognostic biomarker of later CIN 2+, or whether it is a late event that will serve only as a diagnostic biomarker. The evidence on the prognostic value of viral DNA methylation is limited. Mirabello et al. evaluated the prognostic value of DNA methylation in pre-diagnostic samples of CIN2+ lesions and found good performance of methylation of CpG sites in the L1 and L2 gene as prognostic markers for the development of CIN 2+.(63) Oka et al. is the only author that studied an association between viral DNA methylation and the natural history of histologically confirmed CIN. 15 patients were followed (10 patients with CIN 1, 4 patients with CIN 2 and one patient with CIN 3). Eight cases showed progression: all eight cases were CIN 1/2 and progressed to CIN3. The only case with CIN 3 regressed. Methylation rates of L1 gene were significantly higher in the progression group than in the regression group.(64)
Other factors
The HPV L1-gene encodes for the virus capsid protein. It represents about 90% of total protein on the surface of the virus and is typically evident during the reproductive phase of the HPV infection. (65) Several authors have found a correlation between loss of L1 capsid protein expression and disease grade.(65, 66) This seems logical, as L1-expession occurs in differentiating desquamating cells in the productive viral life cycle. A potential prognostic value of L1-expression in the natural history of CIN has been subject of study by several authors. Choi et al. found a positive association between L1 expression and disease regression of histologically confirmed CIN 1: the regression rate in HPV-L1 positive patients was 72,7% vs 38,1% in L1 negative patients. Progression did, however, occur in L1 positive patients and L1 negative patients also showed regression.(67) Rauber et al. followed 279 women with histologically confirmed CIN 1/2 during a mean of 25 months. Progression to CIN 3 was found in both L1 positive and L1 negative patients, but progression
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