Glutathione-S-transferase and p53 polymorphisms in cervical carcinogenesis
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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2013, Fertility and SterilityCitation Excerpt :The reason for this phenomenon may due to the difference between ethnic and geographical area. The Chinese population has a frequency of the GSTT1 null genotype of nearly 50% (47, 48), whereas in the Japanese population, the frequency is 44.4%–50.0% (49, 50). However, Indians have a lower frequency (14.5%–20.1%) (51–53), and the frequency of the GSTT1 null genotype in Caucasians is between 11.0% and 37.9% (54, 55).
Meta-analysis of association between GSTM1 gene polymorphism and cervical cancer
2012, Asian Pacific Journal of Tropical MedicineAssociation of glutathione S-transferase M1 and T1 null polymorphisms with the development of cervical lesions: A meta-analysis
2011, European Journal of Obstetrics and Gynecology and Reproductive BiologyCitation Excerpt :Therefore, it is necessary to conduct a more specific analysis of differential susceptibility to cervical cancer. Genetic alterations play important roles in susceptibility to cancer [4,6,12,13]. The present meta-analysis analysed the association of GSTM1 and GSTT1 null polymorphisms with the development of cervical lesions.
A common carcinogen benzo[a]pyrene causes p53 overexpression in mouse cervix via DNA damage
2011, Mutation Research - Genetic Toxicology and Environmental MutagenesisCitation Excerpt :Additionally, BaP, a potent inducer of carcinogenesis, has been detected in the cervical mucus of women [16–20]. Some reports have indicated that alterations in p53 expression are often observed in precancerous lesions and carcinomas of the uterine cervix [11–13,15]. However, the variation of p53 expression induced by BaP in cervical tissue is still unclear.
TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies
2009, The Lancet Oncology