Role of Protein Biomarkers in the Detection of High-Grade Disease in Cervical Cancer Screening Programs

Table 1

Biomarkers used in cervical cancer screening and diagnosis.

Biomarker	Staining	Cellular process detected	Reported use of biomarker
	Pattern
Ki-67	Nuclear	Increased Ki-67 staining reflects increased epithelial cell proliferation found in HPV-infected tissues.	(i) Measure of cell proliferative capacity.; (ii) Recognizes tissues involved by HPV and extent of Ki-67 immunostaining generally parallels increasing grades of dysplasia.; (iii) Predominantly used in histology applications.
p16^INK4a	Nuclear and cytoplasmic	p16 levels increased in response to irregular cell cycle inactivation resulting from the disruption of interaction of pRb with transcription factor E2F in the presence by the HPV E7 oncogene.	(i) Detection can serve as a surrogate biomarker for persistent infection with high-risk HPV.; (ii) Triage of equivocal cytology findings can facilitate identification of abnormal cells in cytology preparations.; (iii) Aid in interpretation of histological material. Limited evidence for use as a predictor of disease progression in histology specimens.
BD ProEx C	Nuclear	Increased cellular levels of MCM2 and TOP2A due to aberrant transcription of S-phase proteins resulting from the interaction of HPV E6 and E7 oncoproteins with cell cycle proteins p53 and Rb.	(i) Marker of cells with proliferative capacity.; (ii) Triage from abnormal cytology to increase PPV over cytology alone or HPV triage for detection of CIN2+ disease. Can also facilitate identification of abnormal cells in cytology preparations.; (iii) Use in histology to distinguish true dysplasia from mimics such as reactive/reparative changes, immature squamous metaplasia, and atrophy.
Cytoactiv HPV L1	Nuclear	HPV L1 capsid protein found in mild-to-moderate dysplasias, but lost in higher-grade intraepithelial neoplasias.	(i) Possible prognostic marker to identify early dysplastic lesions most likely to progress to high-grade disease.