Association of p53 Arg72Pro polymorphism and HPV status with the initiation, progression, and development of cervical cancer (CC): A meta-analysis.

Abstract

1597 Background: CC develops through progression from normal cervical epithelium through squamous intra-epithelial lesions (SILs) to cancer. CC is classically associated with oncogenic human papillomavirus (HPV). Yet, not all CC patients demonstrate HPV infection at diagnosis. HPV+ and HPV– subsets of CC patients may thus represent distinct entities. HPV binds to P53, promoting its degradation; the Arg variant of p53 Arg72Pro binds more ardently to HPV than the Pro variant. Although there have been meta-analyses of Arg72Pro in CC risk, none has evaluated the relationship between Arg72Pro and HPV status together. We hypothesize that p53 Arg72Pro modifies aspects of the carcinogenic process in HPV+ (but not HPV-) subsets of CC. Methods: Pubmed/Embase databases identified 1494 potential studies; 51 were eligible and included. Separate analyses were performed to evaluate CC risk (CC vs normal), initiation of cancer (SIL vs normal), and progression towards cancer (CC vs SIL), by HPV status. Pooled odds ratios (pOR) were generated using RevMan 5.1 software. Results: p53 Arg72Pro was not associated with CC risk in either HPV+ or HPV- patient subsets (pORs 0.92; 95%CI, 0.6-1.3 and pORs 1.07; 95%CI, 0.7-1.7, respectively). Similarly, there was no association with the initiation of disease (SIL vs normal): pORs 0.96; 95%CI, 0.7-1.3 (HPV+ subset); 1.11; 95%CI, 0.9-1.4 (HPV- subset). There was no association with disease progression from SIL to CC in the HPV- subset (pOR, 0.98; 95%CI, 0.7-1.4). However, in the HPV+ subset, comparing the progression from SIL through to CC, there was strong and significant association: pOR, 1.37; 95%CI, 1.2-1.6 (p=4.0x10E-4), with no evidence of heterogeneity (I2 = 0%) or bias (by funnel plot). Sensitivity analyses demonstrated similarly significant results, even after taking into account differing quality of methodological designs and type of biological sample analyzed (tumour vs. blood) of the underlying studies. Associations were mainly restricted to Caucasian studies. Conclusions: In this meta-analysis, the Arg variant of p53 Arg72Pro was associated with progression of SIL to CC only in HPV+ subsets, but not to disease initiation or risk of CC.