Immunohistochemical expression of p16INK4A is predictice of HR-HPV infection in cervical low grade lesions

Department of Pathology, Regina Elena Cancer Institute, Rome, Italy.
Modern Pathology (Impact Factor: 6.36). 04/2006; 19(3):384-91. DOI: 10.1038/modpathol.3800551
Source: PubMed

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.

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Available from: Isabella Sperduti, Apr 01, 2014
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    • "This PCR-based procedure can identify 22 mucosotropic HPV types, including 17 genotypes which are currently considered to be high-risk (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82), and 5 low-risk types (HPV 6, 11, 40, 43, and 44). Subsequent reverse dot blot hybridization, with sequencespecific oligonucleotide probes (Diatech), was done (Benevolo et al. 2006). As far as, the HR-HPV genotype frequency for the cases is concerned, 41% were found to be infected by genotype 16, 15% by genotype 18, 15% by genotype 33, 7% by genotype 31, and the remaining 12% were found to be infected by genotypes 50s. "
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    ABSTRACT: Human papillomavirus (HPV) infection is considered the major cause of cervical cancer (CC), but a number of infected women do not develop invasive lesions, suggesting the role of genetic susceptibility and environmental co-factors for cancer outbreak. The aim of this study was to investigate whether some GST polymorphisms could influence the risk to develop CC, either by themselves or in combination with smoking habit, in a cohort of high-risk HPV (HR-HPV) infected Italian women. The study population comprises 192 Italian women including 81 HR-HPV infected women bearing cervical lesions and 111 healthy controls. The cases include: 26 low-grade squamous intraepithelial lesions (LSILs), 30 high-grade-SIL, and 25 CCs, while controls were all negative for HPV. DNA was extracted from peripheral blood samples or cytobrush and individuals were genotyped for GSTM1, GSTT1, and GSTP1 polymorphisms using PCR and PCR/RFLP techniques. On studying the association of GSTs gene polymorphisms with cervical cancer lesions, the combination of GSTM1 null, GSTT1 null and GSTP1 AA genotypes, independently on smoking habit, seems to be related to a 5.7-fold increased risk of developing CLs with a considerable statistical significance (P = 0.0091). We suggest that the investigation of multiple gene polymorphisms, versus single genes, could contribute to a better understanding of the effect of susceptibility genes on cancer risk.
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    • "These criteria include nuclear with and without cytoplasmic staining, degree of intensity, basal and parabasal involvement, pattern of staining (focal or diffuse), and percentage of positive staining dysplastic cells. (Murphy et al., 2003; 2005; Lin et al., 2005; Wang et al., 2005; Benevolo et al., 2006; Carozzi et al., 2006; Queiroz et al., 2006; Focchi et al., 2007; Hariri et al., 2007; Yidiz et al., 2007). To address the issue of p16 immunoreactivity interpretation in cervical lesion, a group of Thai pathologists working in gynecologic pathology from 9 different institutes propose a combined scoring method for interpretation of p16 immunoreactivity and evaluate the interobserver reproducibility of this method. "
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