Overexpression of p16(ink4a) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

Cytological screening for cervical cancer or its precursors using Papanicol aou's smear test (Pap test) has been highly efficient to reduce the morbidi ty and mortality of cervical cancer. However, evaluation of the Pap test re lies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parame ters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for ma ny patients and the high screening costs associated with repeated testing. Cervi cal dysplasia is induced by persistent infections through highrisk ty pes of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is tr iggered by increasing expression of two viral oncogenes, E6 and E7, which b oth interact with various cell cycle-regulating proteins. Among these is th e retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin dependent kinase inhibitor gene p16(InK4a). In creasing expression of the viral oncogenes in dysplastic cervical cells mig ht thus be reflected by increased expression of p16(INKa4). I, line with th is hypothesis, we ob sewed marked overexpression of p16(INK4a) in all cervi cal intraepithelial neoplasm (CIN) 1 lesions (n = 47) except those associat ed with low-risk HPV types (n = 7), all CIN II lesions (n = 32), all CIN II I lesions (n = 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16(INK4a) was observed in normal cervical epithel ium (n 42), inflammatory lesions (n = 48) and low-grade cervical lesions (C IN I) associated with low-risk HPV types (n = 7). Dysplastic cells could al so be identified in cervical smears using a specific p16(INK4a) monoclonal antibody. These data demonstrate that p16(INK4a) is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samp les or cervical smears. (C) 2001 Wiley-Liss, Inc.