European Journal of Obstetrics & Gynecology and Reproductive Biology
p16 expression in patients with cervical cancer and its prognostic significance: meta-analysis of published literature
Introduction
Cervical cancer is the second most common cancer in women worldwide, and is the leading cause of cancer-related death in women in developing countries. Despite the public health importance of cervical cancer, factors that influence the outcome of these patients are not completely understood.
The tumour suppressor p16 is known to be overexpressed in cervical intra-epithelial neoplasia (CIN) and many invasive cervical carcinomas [1], [2]. It is a G1/S phase cell cycle inhibitor that arrests cell replication by binding to the cyclin D1-CDK4/CDK6 complex and inhibiting retinoblastoma (Rb) protein phosphorylation. As a result, p16 promotes the formation of a Rb-E2F – repressive complex that, in turn, blocks G1/S progression of the cell cycle [3]. In cases of human papilloma virus (HPV)-positive cervical cancer, overexpression of p16 is demonstrated as a result of functional inactivation of pRb by the HPV E7 protein [4].
Despite numerous studies on p16 and cervical cancer over recent years, precise conclusions regarding the clinical outcomes of this cancer remain uncertain. Several studies found that p16 expression was predictive of a positive outcome in particular subgroups of patients with cervical cancer, and other studies suggested a close relationship between p16 expression and prognosis but the results were not significant on multivariate analysis. As such, a meta-analysis of the published literature was conducted to estimate the prognostic value of p16 expression for overall survival (OS) and disease-free survival among patients with cervical cancer.
Section snippets
Publication selection
An electronic search of Medline, Embase and China National Knowledge Infrastructures was performed using the following keywords: ‘cervical neoplasm’, ‘cervical tumor’, ‘cervical carcinoma’, ‘cervical malignance’ or ‘cervical cancer’ and ‘p16INK4a’ or ‘p16’ and ‘prognosis’, ‘survival’ or ‘outcome’. The Cochrane Library was also reviewed for relevant articles. The references reported in the identified studies were also used to complete the search.
Studies were eligible for inclusion if: (1) they
Study characteristics
Fig. 1 shows the search strategy adopted in this study (Fig. 1). Ten publications met the inclusion criteria for this analysis [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. The total number of patients included was 1070, ranging from 39 to 212 patients per study. Among the 10 studies, five studies were performed in Asian populations, and five studies were performed in Caucasian patients. All patients in the eligible studies were determined by pathological stage. All of the studies
Comments
p16 is not only a bona fide inhibitor of cyclin D-CDK4/6 catalytic activity, but can also interfere with cyclin D-CDK4/6 assembly [20]. Recent immunohistochemical studies have demonstrated that p16 protein is highly overexpressed in dysplastic epithelial cells of the uterine cervix, but is not expressed in normal epithelium or benign lesions [21]. In HPV-positive tumours, p16 overexpression is observed due to loss of negative feedback by inactivation of pRb by HPV oncoprotein E7 [22].
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