Page 83 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Introduction
High-grade Cervical Intraepithelial Neoplasia (CIN) is caused by Human Papillomavirus (HPV)-
infection and is considered to be the precursor of cervical carcinoma.[1] Approximately 30%
of high-grade lesions progresses to cervical cancer on the long term, whereas spontaneous
regression occurs in approximately 20-40%.[2-6] Conventional histopathological assessment is
unable to differentiate between high-grade lesions that will progress to cervical cancer and those
that will regress spontaneously. Consequently, most high-grade lesions are currently treated, 4 leading to significant overtreatment with associated side effects.[7] Ideally, the natural prognosis
of individual CIN lesions would be predictable, in order to select patients in whom spontaneous regression is expected for a wait-and-see policy.
It has been established that the development of CIN and concurrent progression to cervical cancer is influenced by a complex interaction between HPV, the host immune system and functional cellular mechanisms.[8, 9] Cervical oncogenesis is characterized by several genetic effects, among which are genomic instability, chromosomal aberrations and integration of viral DNA into the host genome. Markers of these processes have been identified as potential diagnostic or prognostic biomarkers in the diagnosis and prognosis of CIN.[10, 11] Among these is chromosomal region 3q gain, which is frequently found in cervical carcinomas and its precursor lesions.[12] The association between 3q gain and cervical oncogenesis may be caused by amplification of the human telomerase RNA gene (hTERC), which is localized on the 3q26 locus. The hTERC gene encodes for the RNA unit of telomerase, which maintains the length of telomeres through cellular divisions. Overexpression of hTERC leads to the avoidance of abnormal cells with critically short telomeres to undergo apoptosis, which is a contributing factor in oncogenesis. Gain of 3q26/hTERC or copy number variations has been shown to correlate with disease grade in cervical lesions and could function as a diagnostic tool in cervical pathology.[13-16] Several studies have addressed the prognostic properties of 3q26/hTERC gain in the natural prognosis of CIN, but most studies focussed on low-grade lesions and/or evaluated 3q gain in cytological specimen. Evidence on 3q gain in histologically confirmed high-grade CIN is very scarce. The goal of this study is to provide an overview of the literature on the prognostic properties of 3q26/hTERC gain in the natural prognosis of CIN and to investigate the predictive properties of 3q26 gain specifically in high-grade CIN.
Materials and methods
The study was performed according to the PROBE criteria for biomarker research.[17]
Patient population
For the pilot study, the patient population was extracted from a prospective population based cohort study, conducted at the Stavanger University Hospital, Norway.[5] The women in this cohort were diagnosed with a CIN2 or CIN 3 lesion in a diagnostic biopsy. All biopsies were stained for Hematoxylin Eosin, p16 and Ki67 and disease grade was based on the most severely dysplastic area with the most intensive Ki67 and p16 staining. Staining was assessed for disease grade by
3q26 as a prognostic biomarker
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