Human Cell

, Volume 23, Issue 4, pp 119–125 | Cite as

Germline polymorphisms of glutathione-S-transferase GSTM1, GSTT1 and p53 codon 72 in cervical carcinogenesis

  • Masatsugu UedaEmail author
  • Eisaku Toji
  • Osamu Nunobiki
  • Naomi Sato
  • Shinji Izuma
  • Kiyo Torii
  • Yoshiaki Okamoto
  • Sadamu Noda
Research Article


The clinical significance of glutathione-S-transferase GSTM1, GSTT1 and p53 codon 72 polymorphisms in cervical carcinogenesis was investigated. Germline polymorphisms of GSTM1, GSTT1 and p53 codon 72 together with human papillomavirus (HPV) types were examined in a total of 457 blood and cervical smear samples from normal healthy women and the patients with premalignant and malignant cervical lesions. The 167 patients with low-grade squamous intraepithelial lesion (LSIL), 49 with high-grade SIL (HSIL) and 83 with squamous cell carcinoma (SCC) had significantly higher frequency of high-risk HPV than 1 58 controls. The 49 patients with HSIL and 83 with SCC had statistically higher frequency of null GSTT1 genotype than 158 controls. There was an increased odds ratio for null GSTT1 genotype in HSIL and SCC cases compared with controls among 191 patients with high-risk HPV. The 67 cases with HPV types 16 and/or 18 had higher frequency of the GSTT1 null genotype than 186 with other types of HPV. There was no statistical difference in the polymorphic frequency of GSTM1 and p53 codon 72 genotypes between SILs and controls with or without high-risk HPV. These results suggest that GSTT1 null genotype may increase the risk of cervical cancer particularly in the cases with high-risk HPV types in a Japanese population.


cervical cancer glutathione-S-transferase p53 polymorphism 


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  1. 1.
    zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000; 92: 690–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 1994; 54: 4313–20.PubMedGoogle Scholar
  3. 3.
    Singhal SS, Zimniak P, Awasthi S et al. Several closely related glutathione S-transferase isoenzymes catalysing conjugation of 4-hydroxynonenal are differentially expressed in human tissues. Arch Biochem Biophys 1994; 311: 242–50.CrossRefPubMedGoogle Scholar
  4. 4.
    Baez S, Segura-Aguilar J, Widersten M et al. Glutathione transferases catalyse the detoxification of oxidised metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochem J 1997; 324: 25–8.PubMedGoogle Scholar
  5. 5.
    Goodman MT, McDuffie K, Hernandez B et al. CYP1A1, GSTM1, and GSTT1 polymorphisms and the risk of cervical squamous intraepithelial lesions in a multiethnic population. Gynecol Oncol 2001; 81: 263–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Ara S, Lee PSY, Hansen MF et al. Codon 72 polymorphism of the TP53 gene. Nucleic Acids Res 1990; 18: 4961.CrossRefPubMedGoogle Scholar
  7. 7.
    Fan R, Wu MT, Miller D et al. The p53 codon 72 polymorphism and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2000; 9: 1037–42.PubMedGoogle Scholar
  8. 8.
    Liu G, Miller DP, Zhou W et al. Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma. Cancer Res 2001; 61: 8718–22.PubMedGoogle Scholar
  9. 9.
    Miller DP, Liu G, De Vivo I et al. Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. Cancer Res 2001; 62: 2819–23.Google Scholar
  10. 10.
    Lee JM, Lee YC, Yang SY et al. Genetic polymorphisms of p53 and GSTP1, but not NAT2, are associated with susceptibility to squamous-cell carcinoma of the esophagus. Int J Cancer 2000; 89: 458–64.CrossRefPubMedGoogle Scholar
  11. 11.
    Zehbe I, Voglino G, Wilander E et al. Codon 72 polymorphism of p53 and its association with cervical cancer. Lancet 1999; 354: 218–19.CrossRefPubMedGoogle Scholar
  12. 12.
    Storey A, Thomas M, Kalita A et al. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature (Lond) 1998; 393: 229–34.CrossRefGoogle Scholar
  13. 13.
    Warwick A, Sarhanis P, Redman C et al. Theta class glutathione S-transferase GSTT1 genotypes and susceptibility to cervical neoplasia: interactions with GSTM1, CYP2D6 and smoking. Carcinogenesis 1994; 15: 2841–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Chen C, Madeleine MM, Weiss NS et al. Glutathione S-transferase M1 genotypes and the risk of squamous carcinoma of the cervix: a population-based case-control study. Am J Epidemiol 1999; 150: 568–72.PubMedGoogle Scholar
  15. 15.
    Rosenthal AN, Ryan A, Al-Jehani RM et al. p53 codon 72 polymorphism and the risk of cervical cancer in UK. Lancet 1998; 352: 871–2.CrossRefPubMedGoogle Scholar
  16. 16.
    Lanham S, Campbell I, Watt P et al. p53 polymorphism and risk of cervical cancer. Lancet 1998; 352: 1631.CrossRefPubMedGoogle Scholar
  17. 17.
    Hayes VM, Hofstra RMW, Buys CHCM et al. Homozygous arginine-72 in wild type p53 and risk of cervical cancer. Lancet 1998; 352: 1756.CrossRefPubMedGoogle Scholar
  18. 18.
    Chen CL, Liu Q, Relling MV. Simultaneous characterization of glutathione S-transferase M1 and T1 polymorphisms by polymerase chain reaction in American whites and blacks. Pharmacogenetics 1996; 6: 187–91.CrossRefPubMedGoogle Scholar
  19. 19.
    Ueda M, Gemmill RM, West J et al. Mutations of the β- and γ-catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas. Br J Cancer 2001; 85: 64–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Nagano H, Yoshikawa H, Kawana T et al. Association of multiple human papillomavirus types with vulvar neoplasias. J Obstet Gynecol Res 1996; 22: 1–8.Google Scholar
  21. 21.
    Yoshikawa H, Kawana T, Kitagawa K et al. Detection and typing of multiple genital human papillomaviruses by DNA amplification with consensus primers. Jpn J Cancer Res 1991; 82: 524–31.PubMedGoogle Scholar
  22. 22.
    Meyer DJ, Christodoulides LG, Hong-Tan K et al. Isolation, properties and tissue distribution of rat glutathione transferase E. FEBS Lett 1984; 173: 327–30.CrossRefPubMedGoogle Scholar
  23. 23.
    Chen H, Sandler DP, Taylor JA et al. Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Lancet 1996; 347: 295–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Elexpuru-Camiruaga J, Buxton N, Kandula V et al. Susceptibility to astrocytoma and meningioma. Influence of allelism at glutathione S-transferase GSTT1 and GSTM1 and cytochrome P450 CYP2D6 loci. Cancer Res 1995; 55: 4237–9.PubMedGoogle Scholar
  25. 25.
    Joseph T, Chacko P, Wesley R et al. Germline genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes in Indian cervical cancer: associations with tumor progression, age and human papillomavirus infection. Gynecol Oncol 2006; 101: 411–17.CrossRefPubMedGoogle Scholar
  26. 26.
    Ueda M, Hung YC, Terai Y et al. Glutathione S-transferase GSTM1, GSTT1 and p53 codon 72 polymorphisms in human tumor cells. Hum Cell 2003; 16: 241–51.CrossRefPubMedGoogle Scholar
  27. 27.
    Marin MC, Jost CA, Brooks LA et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet 2000; 25: 47–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Brooks LA, Tidy JA, Gusterson B et al. Preferential retention of codon 72 arginine p53 in squamous cell carcinomas of the vulva occurs in cancers positive and negative for human papillomavirus. Cancer Res 2000; 60: 6875–7.PubMedGoogle Scholar
  29. 29.
    Koushik A, Platt RW, Franco EL. p53 codon 72 polymorphism and cervical neoplasia: a meta-analysis review. Cancer Epidemiol Biomarkers Prev 2004; 13: 11–22.CrossRefPubMedGoogle Scholar
  30. 30.
    Minaguchi T, Kanamori Y, Matsushima M et al. No evidence of correlation between polymorphism at codon 72 of p53 and risk of cervical cancer in Japanese patients with human papillomavirus 16/18 infection. Cancer Res 1998; 58: 4585–6.PubMedGoogle Scholar
  31. 31.
    Yamashita T, Yaginuma Y, Saitoh Y et al. Codon 72 polymorphism of p53 as a risk factor for patients with human papillomavirus-associated squamous intraepithelial lesions and invasive cancer of the uterine cervix. Carcinogenesis 1999; 20: 1733–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Klug SJ, Ressing M, Koenig J et al. TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies. Lancet Oncol 2009; 10: 772–84.CrossRefPubMedGoogle Scholar

Copyright information

© Society and Springer Japan 2010

Authors and Affiliations

  • Masatsugu Ueda
    • 1
    Email author
  • Eisaku Toji
    • 1
  • Osamu Nunobiki
    • 2
  • Naomi Sato
    • 1
  • Shinji Izuma
    • 1
  • Kiyo Torii
    • 1
  • Yoshiaki Okamoto
    • 1
  • Sadamu Noda
    • 1
  1. 1.Cytopathology and GynecologyOsaka Cancer Prevention and Detection CenterOsakaJapan
  2. 2.Department of Medical TechnologyKobe Tokiwa UniversityHyogoJapan

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