Cancer Letters

Cancer Letters

Volume 188, Issues 1–2, 15 December 2002, Pages 207-211
Cancer Letters

Proline homozygosity in codon 72 of p53: a risk genotype for human papillomavirus related cervical cancer in Indian women

https://doi.org/10.1016/S0304-3835(02)00430-5Get rights and content

Abstract

The objective of the present study was to determine the codon 72 genotypic frequencies of p53 in Indian women and to analyze the association of this polymorphism with human papillomavirus (HPV) related cervical cancer (CaCx). We used tissues derived from 55 women diagnosed with squamous cell carcinoma of the cervix (of whom 46 were HPV types 16/18 positive) and cervical scrapes derived from 201 cytologically normal women (of whom 84 were HPV types 16/18 positive) as controls. The DNA isolated from these samples was genotyped for p53 polymorphism by polymerase chain reaction and restriction fragment length polymorphism method. The genotypic frequency of homozygous arginine among women with CaCx was 27% and this did not differ with the controls. But, proline homozygosity of 33% in the malignant samples was significantly higher than controls (OR=2.23; 95% CI: 1.14–4.35; P=0.02). The associated risk of this genotype towards CaCx was more prominent (OR=2.67; 95% CI: 1.16–6.15; P=0.02) when analysis was restricted to HPV 16/18 positive women. Thus, proline homozygosity at codon 72 of p53 and not arginine homozygosity, could be a risk factor for development of CaCx associated with high risk HPV among 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.

Section snippets

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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