A prognostic marker predicting the progression or regression of the cervical intraepithelial neoplasia (CIN) would greatly impact cervical cancer screening. Proliferation markers like MIB 1 antibody Ki67, p16 showing HPV's oncogenic activity, and presence of the HPV DNA has been considered. However, the markers’ prognostic ability can reliably be assessed in prospective study only.

We established a model by selecting a patient material in relation to pregnancy as a treatment is usually postponed and the natural development of the lesion remains undisturbed for a limited period of time. The aim of the study was to investigate whether positivity for HPV type-specific DNA, p16, Ki67 indicates progression to a more severe lesion.

Material and methods: Through linkage between the Norwegian Medical Birth Registry and the Cancer Registry of Norway, all women with CIN grade I-III during pregnancy in 1996-1997 were identified. 149 women with minimum of two serial histology specimens were included into the study. From the national histology biobank, relevant formalin fixed paraffin embedded tissue blocs (altogether 400) were identified, collected and analyzed. Each case was judged from serial histology diagnoses to define progression, i.e. upward change of at least two CIN grades during the period of >6 month. For HPV DNA GP5+/6+ was used, followed by reverse line-blot for typing of 39 HPV types individually and pool of 6 rare HPV types. P16/Ki67 were detected immunohistochemically (Cell Marque, p16, 16P04 and Assey, Filled Disp., CONFIRM Anti-KI76 K-2, Ventana). Presence of biomarkers by dysplasia grade (normal, CINI-III) was estimated. Linear mixed models were used for the longitudinal analyses to accommodate somewhat unbalanced structure of the data. The outcome was degree of seriousness (CIN grade) in the histology-samples and the different biomarkers served as the time varying covariates.

Results and Conclusion: The mean age of subjects (at 1st visit) was 29 years. Prevalence of HPV DNA, Ki-67 and p16 increased by increasing grade of CIN lesion. By our criteria, 28 (18%) women showed progression. Ki67, overexpression of p16, presence of high risk HPV and HPV16 DNA showed strong association with CIN seriousness in longitudinal analyses while positivity for low risk HPV showed negative association (albeit not statistically significant). Further studies addressing progression and time-span of CIN are urgently needed to improve screening programs.

Citation Format: Mari Nygård, Ole Klungsøyr, Bjørn Hagmar. Role of different biomarkers for progression of the cervical dysplasia: a prospective molecular epidemiological study combining information from the nationwide registries and biobanks. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 124. doi:10.1158/1538-7445.AM2013-124