Abstract
The glutathione S-transferase (GST) supergene family is an important part of cellular enzyme defense against endogenous and exogenous chemicals, many of which have carcinogenic potential. The present investigation was conducted to detect a possible association between polymorphisms at the GSTM1, GSTT1, and GSTP1 genes and the interaction with cigarette smoking and colorectal cancer incidence. We examined 181 patients with colorectal cancer and 204 controls. DNA was extracted from whole blood, and the GSTM1, GSTT1, and GSTP1 polymorphisms were determined using a real-time polymerase chain reaction and fluorescence resonance energy transfer with a Light-Cycler instrument. Associations between specific genotypes and the development of colorectal cancer were examined by use of logistic regression analysis to calculate odds ratios (OR) and 95% confidence intervals (CI). The GSTM1 polymorphism was associated with an increased risk of developing colorectal cancer (OR = 1.62, 95% CI: 1.06–2.46). Also the risk of colorectal cancer associated with the GSTT1 null genotype was 1.64 (95% CI: 1.10–2.59). Statistically no differences were found between patients with colorectal cancer and control groups for the GSTP1 Ile/Ile, Ile/Val and Val/Val genotypes. In addition, the frequencies of the GSTM1 and GSTT1 deletion genotypes differed significantly between the cases and controls for current smokers; the GSTT1 null genotype especially is associated with a greater risk of colorectal cancer (OR = 2.44, 95% CI: 1.24–4.81). The GSTM1 and GSTT1 deletions were associated with an increased risk of developing a transverse or rectal tumor (OR = 1.86, 95% CI: 1.15–3.00; OR = 1.70, 95% CI: 1.02–2.84; respectively). The glutathione S-transferase polymorphisms were not associated with risk in patients stratified by age. The risk of colorectal cancer increased as putative high-risk genotypes increased for the combined genotypes of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity (OR = 2.69, 95% CI: 1.02–7.11). In conclusion, the results obtained in this study clearly suggest that those susceptibility factors related to different GST polymorphic enzymes are predisposing for colorectal cancer.
Similar content being viewed by others
References
Abdel-Rahman, S. Z., Soliman, A. S., Bondy, M. L., Wu, X., El-Badawy, S. A., Mahgoub, K. G., Ismail, S., Seifeldin, I. A., and Levin, B. (1999). Polymorphism of glutathione-S transferase loci GSTM1 and GSTT1 and susceptibility to colorectal cancer in Egypt. Cancer Lett. 142:97–104.
Ali-Osman, F., Akande, O., Antoun, G., Mao, J. X., and Buolamwini, J. (1997). Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J. Biol. Chem. 272:10004–100012.
Beckett, G. J., and Hayes, J. D. (1993). Glutathione S-transferases: biomedical applications. Adv. Clin. Chem. 30:281–380.
Board, P. G., Baker, J. T., Chelvanayagam, G., and Jermin, L. S. (1997). Zeta, a novel class of glutathione transferases in a range of species from plants to humans. Biochem. J. 328:929–935.
Butler, W. J., Ryan, P., and Roberts-Thomson, I. C. (1997). Metabolic genotypes and risk for colorectal cancer increased risk in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Gastroenterology 112:542.
Camdeviren, H., Ozkan, M., and Baspı nar, E. (2003). Biyoistatistik el kitabı. In H. de Camdeviren (ed.), Tı bbi Araştı rma Tipleri ve Sebep-Sonuç İlişkileri: Lojistik Regresyon analizi. Fersa Matbaacı lı k, Ankara, pp. 88–94.
Chenevix-Trench, G., Young, J., Coggan, M., and Board, P. (1995). Glutathione S-transferase M1 and T1 polymorphisms: susceptibility to colon cancer and age of onset. Carcinogenesis 16:1655–1657.
De Bruin, W. C., Wagenmans, M. J., and Peters, W. H. (2000). Expression of glutathione S-transferase alpha, P1-1, and T1-1 in the human gastrointestinal tract. Jpn J Cancer Res 91:2013–2316.
Deakin, M., Elder, J., Hendrickse, C., Peckham, D., Baldwin, D., Pantin, C., Wild, N., Leopard, P., Bell, D. A., Jones, P., Duncan, H., Brannigan, K., Alldersea, J., Fryer, A. A., and Strange, R. C. (1996). Glutathione S-transferase GSTT1 genotypes and susceptibility to cancer: Studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers. Carcinogenesis 17:881–884.
Garte, S., Gaspari, L., Alexandrie, A. K., Ambrosone, C., Autrup, H., Autrup, J. L., Baranova, H., Bathum, L., Benhamou, S., Boffetta, P., Bouchardy, C., Breskvar, K., Brockmoller, J., Cascorbi, I., Clapper, M. L., Coutelle, C., Daly, A., Dell’Omo, M., Dolzan, V., Dresler, C. M., Fryer, A., Haugen, A., Hein, D. W., Hildesheim, A., Hirvonen, A., Hsieh, L. L., Ingelman-Sundberg, M., Kalina, I., Kang, D., Kihara, M., Kiyohara, C., Kremers, P., Lazarus, P., Le Marchand, L., Lechner, M. C., van Lieshout, E. M., London, S., Manni, J. J., Maugard, C. M., Morita, S., NazarStewart, V., Noda, K., Oda, Y., Parl, F. F., Pastorelli, R., Persson, I., Peters, W, H., Rannug, A., Rebbeck, T., Risch, A., Roelandt, L., Romkes, M., Ryberg, D., Salagovic, J., Schoket, B., Seidegard, J., Shields, P. G., Sim, E., Sinnet, D., Strange, R. C., Stucker, I., Sugimura, H., To-Figueras, J., Vineis, P., Yu, M. C., and Taioli, E. (2001). Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol. Biomark. Prevent. 10:1239–1248.
Gertig, D. M., Stampfer, M., Haiman, C. H., Hennekens, C. H., Kelsey, K., and Hunter, D. J. (1998). Glutathione S-transferase GSTM1 and GSTT1 polymorphisms and colorectal cancer risk: A prospective study. Cancer Epidemiol. Biomark. Prevent. 7:1001–1005.
Harries, L. W., Stubbins, M. J., Forman, D., Howard, G. C., and Wolf, C. R. (1997). Identification of genetic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer. Carcinogenesis 18:641–644.
Hirata, S., Odajima, T., Kohama, G., Ishigaki, S., and Niitsu, Y. (1992). Significance of glutathione S-transferase-pi as a tumor marker in patients with oral cancer. Cancer 70:2381-2387.
Hirvonen, A. (1995). Genetic factors in individual responses to environmental exposures. J. Occup. Environ. Med. 37:37–43.
Katoh, T., Nagata, N., Kuroda, Y., Itoh, H., Kawahara, A., Kuroki, N., Ookuma, R., and Bell, D. A. (1996). Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis, 17:1855-1859.
Katoh, T., Kaneko, S., Takasawa, S., Nagata, N., Inatomi, H., Ikemura, K., Itoh, .H, Matsumoto, T., Kawamoto, T., and Bell, D. A. (1999). Human glutathione S-transferase P1 polymorphism and susceptibility to smoking-related epithelial cancer; oral, lung, gastric, colorectal and urothelial cancer. Pharmacogenetics 9:165–169.
Ko, Y., Koch, B., Harth, V., Schinidis, A., Thier, R., Vetter, H., Bolt, H. M., and Brüning, T. (2000). Rapid analysis of GSTM1, GSTT1 and GSTP1 polymorphisms using real-time polymerase chain reaction. Pharmacogenetics 10:1–4.
Lee, E., Huang, Y., Zhao, B., Seow-Choen, F., Balakrishnan, A., and Chan, S. H. (1998). Genetic polymorphism of conjugating enzymes and cancer risk: GSTM1, GSTT1, NAT1 and NAT2. J. Toxicol. Sci. 23:140–142.
Mannervik, B., and Danielson, U. H. (1988). Glutathione transferases: Structure and catalytic activity. CRC Crit. Rev. Biochem. 23:283–337.
Matthias, C., Bockmühl, U., Jahnke, V., Harries, L. W., Wolf, C. R., Jones, P. W., Alldersea, J., Worrall, S. F., Hand, P., Fryer, A. A., and Strange, R. C. (1998). The glutathione S-transferase GSTP1 polymorphism: Effects on susceptibility to oral/pharyngeal and laryngeal carcinomas. Pharmacogenetics 8:1–6.
Niitsu, Y., Takahashi, Y., Saito, T., Hirata, Y., Arisato, N., Maruyama, H., Kohgo, Y., and Listowsky, I. (1989). Serum glutathione-S-transferase-pi as a tumor marker for gastrointestinal malignancies. Cancer 63:317–323.
Parkin, D. M., Pisani, P., and Ferlay, J. (1993). Estimates of the worldwide incidence of eighteen major cancers in 1985. Int. J. Cancer 54:594–606.
Peters, W. H. M., Boon, C. E., Roelofs, H. M. J., Wobbes, T., Nagengast, F. M., and Kremers, P. G. (1992). Expression of drug-metabolizing enzymes and P-170 glycoprotein in colorectal carcinoma and normal mucosa. Gastroenterology 103:448–455.
Saadat, I., and Saadat, M. (2001). Glutathione S-transferase M1 and T1 null genotypes and the risk of gastric and colorectal cancers. Cancer Lett. 2001 August 10 169(1):21–26.
Seidegard, J., Vorachek, W. R., Pero, W. R., and Pearson, W. R. (1988). Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc. Natl. Acad. Sci USA 85:7293–7297.
Slattery, M. L., Potter, J. D., Samowitz, W., Bigler, J., Caan, B., and Leppert, M. (1998). NAT2, GSTM-1, cigarette smoking, and risk of colon cancer. Cancer Epidemiol. Biomark. Prevent. 7:1079–1084.
Sprenger, R., Schlagenhaufer, R., Kerb, R., Bruhn, C., Brockmoller, J., Roots, I., and Brinkmann, U. 2000. Pharmacogenetics 10:557–565.
Strange, C. G., Faulder, B. A., Davis, R., Hume, J. A. H., Brown, W. C., and Hopkinson, D. A. (1984). The human glutathione S-transferases: Studies on the tissue distribution and genetic variation of the GST1, GST2 and GST3 isoenzymes. Ann. Human Genet. 48:11–20.
Strange, R.C, Matharoo, B., Faulder, G. C., Jones, P., Cotton, W., Elder, J. B., and Deakin, M. (1991). The human glutathione S-transferases: A case-control study of the incidence of the GST1 0 phenotype in patients with adenocarcinoma. Carcinogenesis 12:25–28.
Van-Lieschout, E. M. M., Tiemessen, D. M., Roelofs, H. M. J., and Peters, W. H. M. (1998). Nonsteroidal anti-inflammatory drugs enhance glutathione S-transferase theta levels in rat colon. Biochim. Biophys. Acta. 1381:305–311.
Watson, M. A., Stewart, R. K., Smith, G. B., Massey, T. E., and Bell, D. A. (1998). Human glutathione S-transferase P1 polymorphisms: Relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis 19:275–280.
Welfare, M., Monesola-Adeokun, A., Bassendine, M. F., and Daly, A. K. (1999). Polymorphisms in GSTP1, GSTM1, and GSTT1 and susceptibility to colorectal cancer. Cancer Epidemiol. Biomark. Prevent. 8:289–292.
Zhong, S., Wyllie, A. H., Barnes, D., Wolf, C. R., and Spurr, N. K. (1993). Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis 14:1821–1824.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ateş, N.A., Tamer, L., Ateş, C. et al. Glutathione S-Transferase M1, T1, P1 Genotypes and Risk for Development of Colorectal Cancer. Biochem Genet 43, 149–163 (2005). https://doi.org/10.1007/s10528-005-1508-z
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10528-005-1508-z