Surrogate Biomarkers of HPV Infection in Cervical Neoplasia Screening and Diagnosis

Abstract

The current prevention of cervical cancer and elimination of its precursors is predicated on the identification of cervical cytologic abnormalities and their histologic confirmation. This strategy, although effective, depends on both sensitivity and specificity of cytology and precise histologic distinction between precursor lesions and their mimics during biopsy interpretation. The effective application of diagnostic criteria is operator dependent and varies as a function of experience and training. However, because human papilloma viruses (HPV) are causative agents and alter the cell cycle in cervical neoplasms, host genes interacting directly or indirectly with HPV oncoproteins have been identified in vitro. Recent research has centered on identifying the host genes upregulated in association with HPV infection, determining their suitability as "surrogate markers" for HPV infection, and using these markers to identify HPV-associated epithelial lesions in tissue or cytologic specimens. This review surveys recent advances in this field, summarizing the advantages and limitations of several candidate biomarkers, including PCNA, Ki-67, cyclin E, p16ink4, MN antigen, carcinoembryonic antigen (CEA), and telomerase in the recognition of preinvasive cervical neoplasia, and discusses their future potential in cervical cancer screening. Based on current studies, the strongest candidates for diagnosis and screening are p16 and cyclin E (squamous) and MN (glandular) biomarkers. As new genes are identified and tested, the concept of biomarkers as tools in primary screening and lesion recognition will continue to mature.

p16INK4a Expression Correlates with Degree of Cervical Neoplasia: A Comparison with Ki-67 Expression and Detection of High-Risk HPV Types

“…Although Ki-67 has been shown in several studies to be useful in diagnosing cervical neoplasia, our study shows that whereas Ki-67 expression is a sensitive marker of cervical neoplasia, overexpression is linked to both inflammation and reactive/atypical changes; p16 INK4a showed no such association (7,10,14,22). This is to be expected as inflammation is associated with increased cell turnover and reactive cervical squamous metaplasia has been shown to overexpress Ki-67 (10).…”

p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia

“…The relatively long half-life of PCNA coupled with rapid cell turnover resulted in such seemingly aberrant suprabasal staining. 39 In our study, PCNA expressing cells were located in the upper one-third in two cases or the lower one-third to one-half of the epithelium of CIN lesions in five cases. The positive rate of PCNA expression was significantly increased during progression from normal to CIN and was also increased from CIN to squamous cell carcinoma.…”

Endometrial Intraepithelial Neoplasia

“…p16, also known as CDKN2A, is a tumor supressor gene that had been extensively studied in the context of HPV-related cancers and their precursors (Keating, Cviko et al 2001;Keating, Ince et al 2001;Negri, Egarter-Vigl et al 2003). In cervical HPV-related cancers, the mechanism of p16 overexpression may be mediated by HPV E7 viral protein.…”