Page 39 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Identification of candidate prognostic biomarkers in the natural history of high-grade CIN
We aimed to identify biomarkers that predict the natural history of histologically confirmed 2 high-grade CIN (CIN 2-3). These must be biomarkers that predict spontaneous regression or progression of high-grade CIN. To this end, a search for promising biomarkers was conducted and
a critical appraisal was performed as described below.
Search strategy
A search was conducted on Pubmed using combinations of the following search terms: “cervical intraepithelial neoplasia”[MeSH Terms]; “biological markers”[MeSH Terms] OR (“biological”[All Fields] AND “markers”[All Fields]) OR “biological markers”[All Fields] OR “biomarker”[All Fields]; “natural history”[MeSH Terms] OR (“natural”[All Fields] AND “history”[All Fields]) OR “natural history”[All Fields]; “disease progression”[MeSH Terms] OR (“disease”[All Fields] AND “progression”[All Fields]) OR “disease progression”[All Fields] OR “progression”[All Fields] “regression”[All Fields]; (“humans”[MeSH Terms] OR “humans”[All Fields] OR “human”[All Fields]) AND (“papillomaviridae”[MeSH Terms] OR “papillomaviridae”[All Fields] OR “papillomavirus”[All Fields]). Language was restricted to English only. Those studies were selected that investigated prognostic biomarkers in histologically confirmed CIN lesions. Publications were first selected based on title and abstract. Final inclusion or exclusion was based on review of the full publication content. Additionally, relevant references from selected articles were also evaluated for inclusion.
Overview of candidate prognostic biomarkers in the natural history of high-grade CIN
As reviewed above, persistence or regression of HPV-induced lesions is determined by a complex interaction between the immune system, viral factors and different cellular functions. Understanding of the underlying biological mechanisms provides a rational basis for the selection of biomarkers with a clear role in cervical carcinogenesis and provides an extensive amount of candidate biomarkers.(40, 41) Candidate prognostic biomarkers of high-grade CIN can be categorized into three main areas: host factors, viral factors and cellular factors and will be discussed accordingly.
Host factors
Human Leukocyte Antigens (HLA) subtypes
Many viral infections are controlled by T-cells recognizing their antigen within the context of HLA class I and II molecules expressed on the cell surface. Evidence suggests a role for HLA polymorphisms in the individual risk of cervical cancer after HPV infection, based on case-control studies.(42) Two authors found an association between a certain HLA subtype and disease progression in histologically confirmed low-grade CIN. Matsumoto et al. found a protective effect of HLA-DRB1*1302 against progression of CIN 1/2 to CIN 3 in 454 patients.(43) Sastre-Garau et al. found an association between HLA-DRB1*13 and regression of CIN 1 in a cohort of 86 women with CIN 1. Disease regression was 71.8% in patients with HLA-DRB1*13 and 45.9% in patients with other genotypes. Regression reached 90.5% (38.9-98.5%) at 18 months in DRB1*13 patients with
A review of prognostic biomarkers
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