Elsevier

Gynecologic Oncology

Volume 96, Issue 3, March 2005, Pages 736-740
Gynecologic Oncology

Glutathione-S-transferase and p53 polymorphisms in cervical carcinogenesis

https://doi.org/10.1016/j.ygyno.2004.11.005Get rights and content

Abstract

Objective.

To investigate the clinical significance of glutathione-S-transferase GSTM1, GSTT1 and p53 codon 72 polymorphisms in cervical carcinogenesis.

Methods.

GSTM1, GSTT1 and p53 codon 72 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 198 cervical smear samples using multiplex polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism (RFLP) techniques.

Results.

Forty-two patients with high-grade squamous intraepithelial lesion (HSIL) had higher frequency of high-risk HPV and null GSTT1 genotype than 102 with low-grade SIL (LSIL) and 54 controls. Thirty-one patients with HSIL had also statistically higher frequency of null GSTT1 genotype than 28 with LSIL among 69 patients with high-risk HPV. There was no statistical difference in p53 Arg, Arg/Pro and Pro genotypes between SILs and controls with or without high-risk HPV.

Conclusion.

GSTT1 null genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population. The p53 codon 72 polymorphism is unlikely to be related to HPV status and the onset of cervical cancer.

Introduction

Cervical cancer is the second most common cancer in women worldwide, and is both a preventable and a curable disease especially if identified at an early stage. It is widely accepted that specific human papillomavirus (HPV) types are the central etiologic agent of cervical carcinogenesis. Recently, several candidate markers for cervical cancer risk, such as glutathione-S-transferase (GST) and p53, have been described [1], [2], [3], [4], [5]. Such markers could be used to direct high-risk women to more frequent cervical screening.

The genes of GST family encode enzymes that appear to be critical in cellular protection against the cytotoxic effects. GSTs play an important role in conjugating glutathione to the products of endogenous lipid peroxidation and inactivating organic hydroperoxides via selenium-independent glutathione peroxidase activity, thus protecting the cell from the deleterious effects of oxidative stress. GST classes mu (GSTM1) and theta (GSTT1) gene deletions may promote the development of cervical dysplasia by moderating the activation and detoxification of polycyclic hydrocarbons and other compounds that influence oxidative stress and DNA adduct formation [3]. A polymorphism at codon 72 of the p53 gene results in the substitution of arginine (Arg) for proline (Pro) in the gene product. It has been suggested that the homozygous Arg genotype increased the susceptibility of p53 protein to degradation by E6 protein derived from oncogenic HPV [4].

Despite extensive studies on germline polymorphisms of GSTM1, GSTT1 and p53 genes in the patients with premalignant and malignant cervical lesions, no correlation has been reported so far between genetic polymorphisms of these genes and increased risk of cervical cancer [1], [2], [3], [5], [6], [7]. In this study, we investigated GSTM1, GSTT1 and p53 codon 72 polymorphisms in exfoliated cervical cell samples from the patients with squamous intraepithelial lesion (SIL) of the cervix and evaluated the clinical significance of polymorphic frequency of these genes in cervical carcinogenesis.

Section snippets

Cell sample

We conducted GST and p53 genotype analysis together with HPV typing in a total of 198 cervical smear samples obtained from the patients with consent who received cervical cancer screening. They consist of 54 normal, 102 low-grade SIL (LSIL) and 42 high-grade SIL (HSIL). All of 198 patients were Japanese women who visited Osaka Medical College, Kansai Medical College or Osaka Cancer Prevention Center in the past 5 years. Final histologic diagnosis was confirmed by colposcopy-directed biopsy for

Results

Fig. 1A shows an example for genotyping of GSTM1 and GSTT1. The polymorphic deletion of the GSTM1 and GSTT1 genes was determined by multiplex PCR. The absence of 215- or 480-bp fragment indicated null GSTM1 or GSTT1 genotype, respectively. The polymorphic site in exon 4 (codon 72) of the p53 gene was achieved by PCR-RFLP. As shown in Fig. 1B, the fragment of 199 bp indicated the nondigested PCR product from the Pro allele. Fragments of 113 and 86 bp resulted from BstUI digestion of the Arg

Discussion

There is an expanding body of literature suggesting that host factors, including genetic polymorphisms, may explain some of the individual differences in cancer occurrence. A large number of previous studies have been conducted on the correlation between germline polymorphisms of cancer susceptibility genes and the higher risk of human malignant tumors.

The GSTM1 and GSTT1 gene products are thought to protect against somatic mutation in DNA by facilitating the conjugation and elimination of a

Acknowledgments

We are grateful to Dr. Ken Ueki, Department of Obstetrics and Gynecology, Osaka Medical College, for collecting clinical materials. We also thank Kumiko Sato for her technical assistance. This work was supported in part by High-Tech Research Program of Osaka Medical College.

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