p16 expression in patients with cervical cancer and its prognostic significance: meta-analysis of published literature

https://doi.org/10.1016/j.ejogrb.2014.10.016Get rights and content

Abstract

Objectives

p16, a tumour suppressor, is unable to express its suppressive effects following interaction with E7-retinoblastoma protein. Previous reports have suggested that p16 immunostaining allows precise identification of cervical intra-epithelial neoplasia and cervical cancer lesions in biopsies. The prognostic value of p16 expression in cervical cancers has been evaluated for several years, but the results remain controversial. As such, the authors undertook a systematic review and meta-analysis of studies assessing the impact of p16 expression on overall survival and disease-free survival.

Study design

Medline, Embase and China National Knowledge Infrastructures were searched to identify studies on the prognostic impact of p16 expression in patients with cervical cancer. In total, 1070 patients from 10 eligible studies were included in the analysis. Pooled risk ratios (RRs) with 95% confidence intervals (95% CI) were calculated.

Results

A significant association was found between p16 expression and increased disease-free survival (RR 0.60; 95% CI 0.44–0.82; p = 0.001). However, no significant association was found between p16 and overall survival.

Conclusion

p16 expression may be predictive of a favourable prognosis in patients with cervical cancer. However, large-scale, multicentre and well-matched cohort studies are warranted to confirm this finding.

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].

References (27)

  • M.K. Parmar et al.

    Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints

    Stat Med

    (1998)
  • J.P. Higgins et al.

    Measuring inconsistency in meta-analyses

    Br Med J

    (2003)
  • M. Egger et al.

    Bias in location and selection of studies

    Br Med J

    (1998)
  • Cited by (11)

    • Immunohistochemical markers Ki67 and P16 help predict prognosis in locally advanced cervical cancer

      2024, European Journal of Obstetrics and Gynecology and Reproductive Biology
    View all citing articles on Scopus
    View full text