title: Immunohistochemical expression of p16(INK4a) is predictive of HR-HPV infection in cervical low-grade lesions.
abstract: The p16(INK4a) is a cyclin-dependent kinase inhibitor that decelerates the cell cycle by inactivating the cyclin-dependent kinases involved in the phosphorylation of the retinoblastoma protein (RB). Expression of E6 and E7 oncogenes of high-risk (HR) human papillomavirus (HPV), affecting the RB-p16 pathway, leads to p16 upregulation. Although it is widely reported that p16 is overexpressed in a high percentage of preneoplastic lesions and in almost all carcinomas of the uterine cervix, protein upregulation and its correlation with HPV infection in low-grade lesions is still being debated. In this study, we investigated in parallel, p16 expression and HPV infection in 100 cervical biopsies (17 normal tissues, 54 CIN1, 10 CIN2, 11 CIN3, eight invasive squamous cancers). Results obtained demonstrated that none of the 17 normal cervical tissues, evaluated by immunohistochemistry, presented p16 positivity whereas, starting from CIN1 (31%) to CIN2 (90%), CIN3 (100%) and carcinomas (100%), a constant and significant increase of protein overexpression (P<0.0001) was observed. In addition, p16 overexpression consistently showed elevated sensitivity (84%) and specificity (98%) in detecting HR-HPV infection with a high positive predictive value (97%) and negative predictive value (86%). Of interest, 93% of the p16-positive CIN1 were also HR-HPV infected. Our findings confirmed that p16 overexpression is associated to high-grade precancerous lesions and cervical carcinomas, and further demonstrated that immunohistochemical evaluation of p16 may be a useful biomarker in identifying HR-HPV-infected low-grade lesions.
authors.affiliation: Department of Pathology, Regina Elena Cancer Institute, Rome, Italy. benevolo@ifo.it
authors.forename: Maria
authors.initials: M
authors.lastname: Benevolo
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Marandino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vocaturo
authors.forename: Roberto
authors.initials: R
authors.lastname: Sindico
authors.forename: Giulia
authors.initials: G
authors.lastname: Piperno
authors.forename: Luciano
authors.initials: L
authors.lastname: Mariani
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.forename: Paola
authors.initials: P
authors.lastname: Canalini
authors.forename: Raffaele P
authors.initials: RP
authors.lastname: Donnorso
authors.forename: Amina
authors.initials: A
authors.lastname: Vocaturo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D045744:Cell Line, Tumor; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D005260:Female; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D027383:Papillomaviridae / Q000235:genetics* / Q000254:growth & development; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D011237:Predictive Value of Tests; D012307:Risk Factors; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral