The Utility of [P16.Sup.Ink4a] in Discriminating Between Cervical Intraepithelial Neoplasia 1 and Nonneoplastic Equivocal Lesions of the Cervix (Original Articles) (Report)
Current literature suggests that the protein [p16.sup.Ink4a] may be used as a biomarker for the identification of cervical intraepithelial neoplasia (CIN) as well as a test to decrease interobserver variability in making the diagnosis of CIN lesions. (1-9) [p16.sup.Ink4a] is a cell-cycle regulatory protein that negatively influences cell proliferation through a reciprocal relationship with another tumor suppressor protein, retinoblastoma gene product (pRb). (1,5) The action of pRb is to inhibit cells from entering the S phase of the cell cycle and proliferating. (5) It is modified via phosphorylation by cyclin D1 complexed with other cyclin-dependent kinases (cdk 4 through 6). (1-3,5) In the presence of the human papillomavirus (HPV) oncoprotein E7, pRb is inactivated. (5) This inactivation of pRb allows for the transcription of genes required for DNA replication and the inappropriate shifting of the cell cycle past the G1/S restriction point into the S phase. (2-3-5) As pRb is functionally inactivated by HPV oncoprotein E7, there is a reciprocal overexpression of [p16.sup.Ink4a]. (1-3,5) Marked overexpression of the [p16.sup.Ink4a] protein can be demonstrated immunohistochemically using monoclonal antibodies. Studies of cervical carcinomas and preneoplastic lesions of the cervix resulting from high-risk human papillomavirus (HR-HPV) subtypes, specifically subtypes 16 and 18, have demonstrated a strong and diffuse nuclear and cytoplasmic immunoreactivity of [p16.sup.Ink4a] in these lesions. (2,3,5,8-10) Subtypes 16 and 18 are representative of HR-HPV and are the most clinically important HPV subtypes because infection by these subtypes is associated with an increased risk of cervical carcinoma. (2,4) Cervical lesions associated with low-risk HPV subtypes, specifically HPV 6 and 11, express focal and weak [p16.sup.Ink4a] immunohistochemical reactivity and are not associated with an increased risk of cervical carcinoma. (2,8,9)
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