title: Immunohistochemical expression of cyclin D1, p16Ink4a, p21WAF1, and Ki-67 correlates with the severity of cervical neoplasia.
abstract: High-risk human papillomaviruses are closely associated with cervical cancer and its precursor lesions through interactions between the E6 and E7 oncoproteins and the cell-cycle regulatory proteins, such as p53 and pRb, respectively. As other molecules involved in the cell-cycle control seem to be important for human papillomavirus (HPV)-mediated cervical carcinogenesis, we have analyzed the expression of p53, p21, p16, cyclin D1, and Ki-67 and the presence of HPV (HPV pool and HPV-16) by immunohistochemical studies using tissue microarray in low squamous intraepithelial lesions (n=50), high squamous intraepithelial lesions (n=98), and cervical carcinoma (n=18). We have found a significant increase in the expression of p16 and p21 (P<0.001) from low- to high-grade lesions and cancer. In contrast, cyclin D1 expression showed a significant decrease in more severe lesions (P<0.001). p16, Ki-67, p21, and p53 positivity increased with the cell-layer level and the lesion severity, with stronger correlations being observed for p16 and Ki-67. High positivity for HPV pool (96.3%) and HPV-16 (77.5%) immunostaining was detected in all cases, with an association between p16 and cyclin D1 expression and HPV-16 infection. Our tissue microarray results corroborate the usefulness of the immunohistochemical assessment of cell-cycle biomarkers in distinguishing different groups of precursor lesions of the cervix and cervical carcinoma.
authors.affiliation: Department of Pathology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Elyzabeth A
authors.initials: EA
authors.lastname: Portari
authors.forename: Fábio B
authors.initials: FB
authors.lastname: Russomano
authors.forename: Maria J
authors.initials: MJ
authors.lastname: de Camargo
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Machado Gayer
authors.forename: Heloísa C
authors.initials: HC
authors.lastname: da Rocha Guillobel
authors.forename: Cíntia B
authors.initials: CB
authors.lastname: Santos-Rebouças
authors.forename: Jacyara M
authors.initials: JM
authors.lastname: Brito Macedo
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001938:Brazil; D063646:Carcinogenesis; D002278:Carcinoma in Situ / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D052162:Human papillomavirus 16; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D027383:Papillomaviridae / Q000502:physiology*; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000473:pathology; D011230:Precancerous Conditions; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1