Common polymorphisms in GSTM1, GSTT1, GSTP1, GSTA1 and susceptibility to colorectal cancer in the Central European population

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Abstract

Background

Central Europe presents with the highest incidence of sporadic colorectal cancer (CRC) worldwide. As sporadic CRC represents a typical multifactorial disease, it is characterized by intense interaction of the genetic background with the environment. Glutathione S-transferases could act as attractive susceptibility genes for CRC, as they are directly involved in conjugation between glutathione and chemotherapeutics, environmental pollutants and a wide spectrum of xenobiotics.

Methods

In this study, we investigated associations of polymorphisms in glutathione S-transferases ( GSTs) genes, that is GSTA1, GSTT1, GSTM1 and GSTP1, with CRC in a total of 197 cases and 218 controls originating from the Czech Central European population. Polymorphisms were assessed by polymerase chain reaction/restriction fragment length polymorphism-based methods, allele-specific multiplex and allelic discrimination by real-time polymerase chain reaction.

Results

None of investigated polymorphisms showed any associations with CRC, with the exception of GSTP1; where the heterozygote genotype Ile105Val was associated with decreased risk of CRC ( P = 0.043).

Conclusions

The frequencies observed in our study are in accordance with those from other European Caucasian populations. Based on our studies, examined variability in GST genes is not a major determinant of CRC susceptibility in the Central European population.

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Most cited references 17

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Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution.

Jeffrey A. Bell, Bob R. Stewart, Lorraine P. Smith … (1998)

The association between glutathione S-transferase (GST) activity as measured by 1-chloro-2,4-dinitrobenzene (CDNB) conjugation and genotype at exon 5 and exon 6 of the human GSTP1 gene was investigated in normal lung tissue obtained from 34 surgical patients. These samples were genotyped for previously identified polymorphisms in exon 5 (Ile105Val) and exon 6 (Ala114Val) by PCR-RFLP and direct sequencing. GST enzyme activity was significantly lower among individuals with the 105 Val allele. Homozygous Ile/Ile samples (n = 18) had a mean cytosolic CDNB conjugating activity of 74.9 +/- 3.8 nmol/mg per min; heterozygotes (n = 13) had a mean specific activity of 62.1 +/- 4.2 nmol/mg per min and homozygous Val/Val (n = 3) had a mean specific activity of 52.5 +/- 4.5 nmol/mg per min. The CDNB conjugating activity measured for the Ile/Ile genotype group was significantly different from that observed in the Ile/Val group (P = 0.03), and from Ile/Val and Val/Val genotypes combined (P = 0.009). Mean GST activity values were consistently lower in individuals with genotypes containing the 105 valine allele, regardless of smoking exposure. Genotypes at codon 114 were also assessed but the mean GST activity was not significantly lower in individuals with the 114 valine allele. A new haplotype, present in two samples who were homozygous 105Ile and had a 114Val, was identified and proposed as GSTP1*D. Frequencies of the exon 5 and exon 6 polymorphisms were determined in samples obtained from European-Americans, African-Americans and Taiwanese. The differences observed were highly significant suggesting the possibility of GSTP1 genotype-associated, ethnic differences in cancer susceptibility and chemotherapeutic response.

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Isothiocyanates as cancer chemopreventive agents: their biological activities and metabolism in rodents and humans.

C. Conaway, Yang-ming Yang, Fung-lung Chung (2002)

Isothiocyanates (ITCs) are a group of naturally occurring compounds that occur as thioglucoside conjugates, termed glucosinolates, in plants and cruciferous vegetables such as watercress, Brussels sprouts, broccoli, cabbage, kai choi, kale, horseradish, radish and turnip. ITCs inhibit the development of tumors in many of the experimental models investigated, and are being investigated as possible chemopreventive agents for specific human cancers. The goal of this review is to provide a mechanistic understanding for the biological activities of ITCs and to relate the metabolism of ITCs to their action as chemopreventive agents. In vivo animal studies have been conducted to address issues of tissue disposition, pharmacokinetics, and metabolism of ITCs. Methods for analysis of ITCs and their metabolites in urine and plasma have been developed. The metabolism of several naturally occurring ITCs as constituents of foodstuffs or as drugs has also been investigated in human studies. Finally, based on recent epidemiological studies, the role of dietary consumption of vegetables containing ITCs in prevention of human cancers and human cancer susceptibility is discussed.

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Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk.

D Ryberg, V Skaug, A Hewer … (1997)

The A-G polymorphism at codon 104 in the glutathione S-transferase P1 (GSTP1) gene was examined in 138 male lung cancer patients and 297 healthy controls. The patients had significantly higher frequency of the GG genotype (15.9%) and a lower frequency of AA (38.4%) than the controls (9.1% and 51.5%, respectively). The level of hydrophobic DNA-adducts were determined in lung tissue from 70 current smokers. Patients with the GG genotype had a significantly higher adduct level than patients with AA (15.5 +/- 10.2 vs 7.9 +/- 5.1 per 10(8) nucleotides, P = 0.006). We also analyzed the deletion polymorphism in the GSTM1 gene in 135 male patients and 342 controls. The patients were stratified according to histology, smoking dose, age, adduct level and mutational types found in the tumors (Ki-ras and p53 genes). The results consistently indicated that the GSTM1 null genotype was associated with a slightly increased lung cancer risk. When the combined GST M1 and P1 genotypes were examined, patients with the combination null and AG or GG had significantly higher adduct levels than all other genotype combinations (P = 0.011). The distribution of combined genotypes was also significantly different in cases and controls, mainly due to increased frequency of the combination GSTM1 null and GSTP1 AG or GG among patients.

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Author and article information

Journal

Journal ID (nlm-ta): Eur J Med Res

Journal ID (iso-abbrev): Eur. J. Med. Res

Title: European Journal of Medical Research

Publisher: BioMed Central

ISSN (Print): 0949-2321

ISSN (Electronic): 2047-783X

Publication date Collection: 2012

Publication date (Electronic): 14 June 2012

Volume: 17

Issue: 1

Page: 17

Affiliations

[1 ]Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic

[2 ]Department of Pathological Physiology, Medical Faculty, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic

[3 ]Department of Paediatric Oncology, Masaryk University affiliated Hospital, Cernopolni 22, 612 00, Brno, Czech Republic

[4 ]Central European Institute of Technology, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic

[5 ]Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Krízkovského 8, 771 47, Olomouc, Czech Republic

Article

Publisher ID: 2047-783X-17-17

DOI: 10.1186/2047-783X-17-17

PMC ID: 3480935

PubMed ID: 22697302

SO-VID: a4dd043a-e412-4d37-8a2c-9ee534fdcfbb

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Common polymorphisms in GSTM1, GSTT1, GSTP1, GSTA1 and susceptibility to colorectal cancer in the Central European population

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Abstract

Background

Methods

Results

Conclusions

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Most cited references 17

Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution.

Isothiocyanates as cancer chemopreventive agents: their biological activities and metabolism in rodents and humans.

Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk.

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