Abstract
Cervical cancer develops through progression from normal cervical epithelium through squamous intraepithelial lesions (SIL) to invasive cancer. Cervical cancer is associated with oncogenic human papillomavirus (HPV). The HPV E6 oncoprotein binds to the tumor suppressor gene product p53, promoting its degradation; the Arg allele of p53 Arg72Pro polymorphism binds more ardently with HPV E6 than the Pro variant. Here we evaluate the role of p53 Arg72Pro polymorphism and HPV status on the initiation, progression, and development of cervical cancer. A systematic review and meta-analysis were conducted. Events of interest were the initiation of neoplasia (SIL vs. normal), progression to invasive cancer (cervical cancer vs. SIL), and risk of invasive cancer (cervical cancer vs. normal) by HPV status. OR were extracted from individual studies and pooled using generic inverse variance and random effects modeling. Forty-nine studies were included. In individuals showing HPV positivity, there was a significantly higher odds of progression from SIL to cervical cancer with the p53 Arg allele [OR 1.37; 95% confidence intervals (CI), 1.15-1.62; P < 0.001]. This association was not seen in HPV-negative individuals. p53 Arg72Pro was not associated with the risk of cervical cancer or initiation of SIL in either HPV-positive or HPV-negative patient subsets. The Arg variant of p53 Arg72Pro is associated with progression of SIL to cervical cancer only in the presence of HPV positivity. There were no associations of this variant with overall risk or initiation of cancer in either HPV-positive or HPV-negative patients. Clin Cancer Res; 18(23); 6407-15.
Highlights
Human papillomavirus (HPV) is associated with cervical carcinogenesis
Eligible studies included those in which cases were either cervical cancer or squamous intraepithelial lesions (SIL); the TP53 polymorphism Arg72Pro had been genotyped and HPV status had been determined in the same patients genotyped for TP53
Our meta-analysis suggests that the TP53 Arg[72] variant confers an increased risk of cervical cancer development in patients with known SIL
Summary
Human papillomavirus (HPV) is associated with cervical carcinogenesis. One host gene that interacts with HPV and promotes cancer development is TP53. The TP53 gene product, p53, functions as a tumor suppressor, arresting the cell cycle in G1 so that DNA damage can be repaired before DNA replication (1). Translation of the high-risk HPV E6 viral oncogene leads to the proteasomal degradation of p53 (2, 3). One specific single-nucleotide polymorphism in p53 is the nonsynonymous G-to-C variation in exon 4 ( known as rs1042522; Arg72Pro), which results. Authors' Affiliations: 1Ontario Cancer Institute, Princess Margaret Hospital; 2Division of Medical Oncology and Hematology, Department of Medicine; 3Division of Biostatistics; 4Radiation Medicine Program; 5Department of Medical Biophysics; 6Department of Radiation Oncology, University of Toronto; and 7Division of Epidemiology, Dalla Lana School of Public Health, Toronto, Ontario, Canada. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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