J Korean Med Sci.  2014 Nov;29(11):1488-1492. 10.3346/jkms.2014.29.11.1488.

Association between Glutathione S-Transferase T1, M1, and P1 Genotypes and the Risk of Colorectal Cancer

• Cong N
• Liu L
• Xie Y
• Shao W
• Song J

• KMID: 2069929
• DOI: http://doi.org/10.3346/jkms.2014.29.11.1488

Abstract

Glutathione S-transferases (GSTs) are enzymes which play an important role in the neutralization of toxic compounds and eradication of electrophilic carcinogens. Genetic polymorphisms within the genes encoding for GSTs may therefore cause variations in their enzyme activity, which may in turn influence the interindividual susceptibility to cancers. In this study, we aimed to investigate the association between genetic polymorphisms of GSTT1, GSTM1, and GSTP1 and the risk of colorectal cancer (CRC) in 264 cases and 317 controls in a Chinese population. Genotyping was performed by using multiplex PCR (for GSTT1 and GSTM1) and PCR-RFLP (for GSTP1) methods. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Our results showed that individuals with GSTT1 and GSTM1 null genotypes exhibited a higher risk of CRC (GSTT1, OR,1.66; 95% CI, 1.20-2.31, P=0.003; GSTM1, OR,1.57; 95% CI,1.13-2.18, P=0.007), while no association was observed for GSTP1 (P(heterozygous)=0.790 or P(variant)=0.261). Furthermore, individuals who simultaneously carried the null genotypes for both GSTT1 and GSTM1 showed a stronger risk association (OR, 1.95; 95% CI, 1.33-2.85; P<0.001). In conclusion, the GSTT1 and GSTM1 polymorphisms, but not GSTP1, may modulate the CRC risk among Chinese.

Keyword

Colorectal Neoplasms; Glutathione S-Transferase; Polymorphism; Genetic; Risk; Disease Susceptibility

MeSH Terms

Aged
Alleles
Colorectal Neoplasms/*enzymology/*genetics/pathology
Female
*Genetic Predisposition to Disease
Genotype
Glutathione S-Transferase pi/*genetics
Glutathione Transferase/*genetics
Humans
Male
Middle Aged
Odds Ratio
Polymorphism, Genetic
Risk
Glutathione S-Transferase pi
Glutathione Transferase

Figure

• 

  Fig. 1 Representative genotyping result. Lane 1: DNA marker. Lane 2: GSTT1 non-null, GSTM1 non-null (459 bp, 268 bp, 219 bp). Lane 3: GSTT1 non-null, GSTM1 null (459 bp, 268 bp). Lane 4: GSTT1 null, GSTM1 non-null (268 bp, 219 bp). Lane 5: GSTT1 null, GSTM1 null (268 bp). Lane 6: GSTP1 Ile/Ile (329 bp, 104 bp). Lane 7: GSTP1 Val/Val (222 bp, 107 bp, 104 bp). Lane 8: GSTP1 Ile/Val (329 bp, 222 bp, 107 bp, 104 bp).

Reference

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, Cancer incidence and mortality worldwide: IARC CancerBase No. 10. accessed on 1 October 2014. Available at http://globocan.iarc.fr.

2. de la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer. 2004; 4:769–780.

3. Dong LM, Potter JD, White E, Ulrich CM, Cardon LR, Peters U. Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. JAMA. 2008; 299:2423–2436.

4. Mohd Suzairi MS, Tan SC, Ahmad Aizat AA, Mohd Aminudin M, Siti Nurfatimah MS, Andee ZD, Ankathil R. The functional -94 insertion/deletion ATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer. Cancer Epidemiol. 2013; 37:634–638.

5. Tan SC, Suzairi MS, Aizat AA, Aminudin MM, Nurfatimah MS, Bhavaraju VM, Biswal BM, Ankathil R. Gender-specific association of NFKBIA promoter polymorphisms with the risk of sporadic colorectal cancer. Med Oncol. 2013; 30:693.

6. Yang G, Gao YT, Shu XO, Cai Q, Li GL, Li HL, Ji BT, Rothman N, Dyba M, Xiang YB, et al. Isothiocyanate exposure, glutathione S-transferase polymorphisms, and colorectal cancer risk. Am J Clin Nutr. 2010; 91:704–711.

7. Koh WP, Nelson HH, Yuan JM, Van den Berg D, Jin A, Wang R, Yu MC. Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore. Carcinogenesis. 2011; 32:1507–1511.

8. Yeh CC, Hsieh LL, Tang R, Chang-Chieh CR, Sung FC. Vegetable/fruit, smoking, glutathione S-transferase polymorphisms and risk for colorectal cancer in Taiwan. World J Gastroenterol. 2005; 11:1473–1480.

9. Strange RC, Fryer AA. The glutathione S-transferases: influence of polymorphism on cancer susceptibility. IARC Sci Publ. 1999; 231–249.

10. Moyer AM, Salavaggione OE, Hebbring SJ, Moon I, Hildebrandt MA, Eckloff BW, Schaid DJ, Wieben ED, Weinshilboum RM. Glutathione S-transferase T1 and M1: gene sequence variation and functional genomics. Clin Cancer Res. 2007; 13:7207–7216.

11. Rebbeck TR. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 1997; 6:733–743.

12. Hirvonen A. Genetic factors in individual responses to environmental exposures. J Occup Environ Med. 1995; 37:37–43.

13. Cotton SC, Sharp L, Little J, Brockton N. Glutathione S-transferase polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol. 2000; 151:7–32.

14. Zimniak P, Nanduri B, Pikula S, Bandorowicz-Pikuła J, Singhal SS, Srivastava SK, Awasthi S, Awasthi YC. Naturally occurring human glutathione S-transferase GSTP1-1 isoforms with isoleucine and valine in position 104 differ in enzymic properties. Eur J Biochem. 1994; 224:893–899.

15. Chen K, Huang LR. A study on GSTT1 gene polymorphism and colorectal cancer susceptibility in smokers. Chin Foreign Med Res. 2009; 7:19–21.

16. Luo JG, He MJ, Liu XH. Relationship between polymorphisms in glutathione-S-transferase M1 gene and susceptibility to colorectal cancer. Anat Res. 2006; 28:52–54.

17. Wang J, Jiang J, Zhao Y, Gajalakshmi V, Kuriki K, Suzuki S, Nagaya T, Nakamura S, Akasaka S, Ishikawa H, et al. Genetic polymorphisms of glutathione S-transferase genes and susceptibility to colorectal cancer: a case-control study in an Indian population. Cancer Epidemiol. 2011; 35:66–72.

18. Vlaykova T, Miteva L, Gulubova M, Stanilova S. Ile105Val GSTP1 polymorphism and susceptibility to colorectal carcinoma in Bulgarian population. Int J Colorectal Dis. 2007; 22:1209–1215.

19. Hezova R, Bienertova-Vasku J, Sachlova M, Brezkova V, Vasku A, Svoboda M, Radová L, Kiss I, Vyzula R, Slaby O. Common polymorphisms in GSTM1, GSTT1, GSTP1, GSTA1 and susceptibility to colorectal cancer in the Central European population. Eur J Med Res. 2012; 17:17.