Proline homozygosity in codon 72 of p53: a risk genotype for human papillomavirus related cervical cancer in Indian women
Introduction
The prevalence of high risk human papillomavirus (HPV) infection in cervical cancer (CaCx) has been found to be over 95% and its contribution to the risk of disease development is much greater than any other recognized determinant [1]. A large number of sexually active women are infected with HPV. However, only a fraction of these women develop CaCx after a long latent period. This points to the role of genetic cofactors in carcinogenic transformation of HPV infected cervical epithelium.
The involvement of a common polymorphism of the p53 gene in exon 4 at codon 72, encoding either a proline, Pro (CCC) or arginine, Arg (CGC) amino acid, in the susceptibility to certain cancers has been investigated [2], [3], [4]. Recent in vitro functional data [2] showed that the arginine form of p53 protein was significantly more susceptible to high risk HPV E6 mediated degradation than the proline form. Subsequently, a number of differences at the biochemical and biological levels have also been detected for the two polymorphic forms of wild type p53 [5], which might influence the development of cancers harboring wild type p53. In case of CaCx, preliminary epidemiological data [2] showed that women with Arg/Arg genotypes were seven times more at risk to develop CaCx than those with Arg/Pro genotype. However, several larger studies that considered various populations have also failed to confirm [6], [7], [8], [9], [10], [11], [12] this finding, excepting a few who have supported [13], [14] this hypothesis. In this study, we determined the genotypic frequency of p53 codon 72 polymorphism and its association, if any, with HPV related CaCx among Indian women.
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Samples and subjects
We used DNA isolated from (i) tissues that were derived from 55 subjects with suspected malignancy (subsequently confirmed by histopathology as squamous cell carcinoma) of age 27–80 years, who were attending a cancer referral hospital; and (ii) from 201 cervical scrapes as controls. The scrapes (identified as normal from Pap smear tests) were derived from women aged 16–80 years, with no previous history of cervical dysplasia/malignancy, who were attending a Reproductive and Child Health Clinic
Results
The distribution of p53 codon 72 genotypes Arg/Arg, Arg/Pro and Pro/Pro and their frequencies are presented in Table 1. All groups showed a good fit to the Hardy–Weinberg equilibrium (χ2<3.84; df=1) excepting the HPV negative control group which showed a deviation (P=0.03). An increased frequency of the Pro/Pro genotype was observed in case of the malignants (32.7%) compared to the controls (17.9%) and this increase was statistically significant (OR=2.23; 95% CI: 1.14–4.35; P=0.02) as
Discussion
The genotypic distribution of p53 at codon 72 of exon 4 among normal women (n=201) in this study was 27.45% of Arg/Arg and 17.9% of Pro/Pro which was in Hardy–Weinberg equilibrium (Table 1). This was in agreement with data on Taiwanese women (n=71), where the distribution was 28.2% of Arg/Arg and 18.3% of Pro/Pro [19]. The profile of Korean women [20] was 47.5% of Arg/Arg and 11.6% of Pro/Pro in the normal population (n=181). Considering India, report from the Western part [21] showed 14% of
Acknowledgements
We thank Professor Partha P Majumder (Human Genetics Unit, Indian Statistical Institute, Kolkata, India), Dr Debapriya Sengupta (Stat-Math Unit, Indian Statistical Institute, Kolkata, India) and Dr Nitai P Bhattacharya (Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Kolkata, India) for their comments on the manuscript and for providing guidelines for statistical analysis of the data; Cancer Centre and Welfare Home (Thakurpukur, South 24 Parganas, West Bengal,
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A meta-analysis of human papillomavirus type-distribution in women from South Asia: Implications for vaccination
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Polymorphism p53 codon-72 and invasive cervical cancer: A meta-analysis
2004, International Journal of Gynecology and Obstetrics