Down-regulated nucleoside diphosphate kinase nm23-H1 expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer. Issue 10 (14th March 2006)

• Record Type: Journal Article
• Authors: Branca, M; Giorgi, C; Ciotti, M; Santini, D; Di Bonito, L; Costa, S; Benedetto, A; Bonifacio, D; Di Bonito, P; Paba, P; Accardi, L; Mariani, L; Ruutu, M; Favalli, C; Syrjänen, K
• Other Names: group-author.
• Is Part Of: Journal of clinical pathology. Volume 59:Issue 10(2006)
• Page Start: 1044
• Page End: 1051
• Publication Date: 2006-03-14
• Subjects: CIN, cervical intraepithelial neoplasia -- ERK, extracellular signal-regulated kinase -- FIGO, International Federation of Gynecology and Obstetrics -- HPV, oncogenic human papillomavirus -- HR-HPV, high-risk human papillomavirus -- IHC, immunohistochemistry -- ISS, Istituto Superiore di Sanità -- LR-HPV, low-risk human papillomavirus -- MMP, matrix metalloproteinase -- NDP, nucleoside diphosphate -- NPV, negative predictive value -- PCR, polymerase chain reaction -- PPV, positive predictive value -- SCC, squamous cell carcinoma -- VEGF, vascular endothelial growth factor; Pathology -- Periodicals; Pathology, Molecular -- Periodicals; 616.0705
• DOI: 10.1136/jcp.2005.033142
• Languages: English
• ISSNs: 0021-9746

Abstract

Abstract : Objective: One of the factors leading to an invasive phenotype is the nm23 family of metastases-associated genes. Of the six known members, nm23-H1 is the most frequently studied potential anti-metastatic gene in cervical cancer. However, the possible molecular links to oncogenic human papillomavirus (HPV) are completely unexplored as yet. Materials and methods: As a part of the HPV-Pathogen Istituto Superiore di Sanità study, a series of 150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions were examined by immunohistochemical staining for nm23-H1, and tested for HPV by polymerase chain reaction (PCR) with three sets of primers (MY09/11, GP5 + /GP6 + and short PCR fragment). Follow-up data were available on all patients with SCC, and 67 CIN lesions were monitored by serial PCR for clearance or persistence of HPV after cone treatment. Results: A linear decrease (p = 0.001) was observed in nm23-H1 expression, starting from CIN1 (85% with normal expression), with the most dramatic down regulation on transition from CIN2 (70% normal) to CIN3 (39%) and further to SCC (25%). Reduced expression was associated with CIN3 or cancer at an odds ratio 8.72 (95% confidence interval 4.13 to 18.41). Nm23-H1 was of no use as a marker of the high-risk human papillomavirus (HR-HPV) type, and it did not predict clearance or persistence of HR-HPV after treatment of CIN. Importantly, nm23-H1 expression was a significant prognostic factor in cervical cancer, reduced expression being associated with lower survival (p = 0.022) in univariate analysis. In the multivariate (Cox) regression model, however, only the International Federation of Gynecology and Obstetrics stage (p = 0.001) and age (p = 0.011) remained independent prognostic predictors. Conclusions: Down-regulated nm23-H1 expression is markedly associated with progression from CIN2 to CIN3, and predicts poor prognosis in cervical cancer. Nm23-H1 down regulation is probably orchestrated by mechanisms independent of HR-HPV oncoproteins and is possibly related to the emergence of a proteolytic phenotype.