Genetic polymorphisms of p73 is associated with the risk of cervical cancer

Abstract

The p73 protein has a structural and functional homology with p53. Although p73 mutations are rare and occur in less than 2% of all cancers, lost of heterozygosity at the p73 locus are more common at various frequencies in different tumors, suggesting an important role of this gene in carcinogenesis. Nineteen single nucleotide polymorphisms were observed in p73 gene, and most of them were deleterious. Two single nucleotide polymorphisms at positions 4 (G→A) and 14 (C→T) in the uncoding region of exon 2 of the p73 gene are thought to affect p73 function by altering gene expression, perhaps by altering the efficiency of translational initiation. These two polymorphisms are in complete linkage disequilibrium with one another. The correlation of the p73 GC/AT polymorphism with cancer risk has been investigated in some cancers and the results were controversial. Functional analysis implies that this common p73 polymorphism may contribute to cancer development and progression.

The aim of this study was to investigate the association of the p73 G4C14-to-A4T14 nucleotide polymorphism with the risk of cervical cancer. Totally 504 cervical cancer patients and 716 normal control subjects were recruited for the study. The normal subjects had no history of cancer and were frequency-matched to the cancer subjects on age and residential area. The mean ages of patients and control subjects were 50.5 and 48.2 years, respectively. Genomic DNA was extracted from cancer specimens and control blood samples. p73 genotyping was performed using TaqMan SNP genotyping assay. The genotype distribution of controls was in agreement with Hardy-Weinberg equilibrium (p = 0.584). The genotyping frequencies of this polymorphism were 64.9% (GC/GC), 30.1% (GC/AT) and 5.0% (AT/AT) in patients, and 58.7% (GC/GC), 35.3% (GC/AT) and 6.0% (AT/AT) in controls, and the difference was not statistically significant (p = 0.089). Since the AT/AT variant homozygotes were relatively uncommon, we combined them with GC/ AT heterozygotes for further statistically analysis. The combined variant genotypes (GC/AT + AT/AT) was found significantly higher in controls than in patients (p = 0.032), suggesting that p73 AT variant might be a protective allele against cervical cancer. Compared to the p73 GC homozygotes, AT variant was associated with significantly decreased risk of cervical cancer (adjusted OR = 0.772, 95% CI = 0.609 - 0.978). However, no association of p73 polymorphism was observed with age in patients and controls, with cut-off points of <50 and ≥50 years (p = 1.0 and p = 0.758, respectively), as well as disease stages (p = 0.654) and cancer histological types (p = 0.503). Patients with the AT variant had a trend of better survival than patients with GC genotype (p = 0.068). These results suggested that the p73 polymorphism may have a role in cervical cancer susceptibility. Further studies are needed to elucidate potential functional relevance of the p73 AT variant allele.