Breast Cancer Research and Treatment

, Volume 88, Issue 1, pp 55–62 | Cite as

Combined effect of GSTM1, GSTT1, and COMT genotypes in individual

  • Sue Kyung Park
  • Dong-seok Yim
  • Kyung-sik Yoon
  • In-mi Choi
  • Ji-yeob Choi
  • Keun-young Yoo
  • Dong-young Noh
  • Kuk-jin Choe
  • Sei-hyun Ahn
  • Ari Hirvonen
  • Daehee Kang


Our previous studies suggested that both catechol O-methyl transferase (COMT) and glutathione S-transferase (GST) M1 and T1 genotypes are associated with breast cancer risk. Here we extended the studies to evaluate the potential combined effect of these genotypes in individual breast cancer risk. Incident breast cancer cases (n = 202) and controls (n = 299) with no previous cancer were recruited from three teaching hospitals in Seoul in 1996-1999. Information on putative risk factors was collected by interviewed questionnaire. PCR-based methods were used for the genotyping analyses. Odds ratios (ORs) and 95% confidence (CIs) intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Among pre-menopausal women the low activity associated (COMT *L) allele containing genotypes and the GSTM1 null genotype posed increased risks of breast cancer with ORs of 1.7 (95% CI = 1.0 - 2.8) and 1.7 (95% CI = 1.0-2.8), respectively. A marginally significant effect of GSTT1 null genotype was also observed when the total study population was considered (OR = 1.3, 95% CI = 1.0-2.1). When the combined genotype effects were examined, the concurrent lack of GSTM1 and GSTT1 genes posed a more than 2-fold risk of breast cancer (OR = 2.2, 95% CI = 1.2-3.9); this effect was mainly attributable in pre-menopausal women (OR = 3.2, 95% CI = 1.5-7.2). Moreover, the breast cancer risk increased in parallel with the number of COMT, GSTM1, and GSTT1 at-risk genotypes (p for trend = 0.003). This association was particularly clear in pre-menopausal women among whom combination of all three high-risk genotypes posed a 4.1-fold breast cancer risk (95% CI = 1.4-12.7) compared with pre-menopausal women without at-risk genotypes (p for trend = 0.001). The trend was more pronounced in women with BMI greater than 22 kg/m2 (p for trend<0.001) and high-risk status of parity factor (nulliparous or women with the first full term pregnancy at age of over 25-year-old) (p for trend = 0.013). These results suggest the combined effect between reproductive factors and GSTM1, GSTT1 andCOMT genotypes in human breast carcinogenesis.

breast cancer genetic polymorphism GSTM1 GSTT1 COMT 


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  1. 1.
    Mitrunen K, Hirvonen A: Molecular epidemiology of sporadic breast cancer: the role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutat Res Rev 544: 9–41, 2003Google Scholar
  2. 2.
    Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF: A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8(10): 843–854, 1999Google Scholar
  3. 3.
    Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, Johansson SL, Patil KD, Gross ML, Gooden JK, Ramanathan R, Cerny RL, Rogan EG: Molecular origin of cancer: catechol estrogen-3,4–quinones as endogenous tumor initiators. Proc Natl Acad Sci USA 94(20): 10937–10942, 1997Google Scholar
  4. 4.
    Yager JD: Endogenous estrogens as carcinogens through metabolic activation. J Natl Cancer Inst Monogr 27: 67–73, 2000Google Scholar
  5. 5.
    Park SK, Yoo KY, Lee SJ, Kim SU, Ahn SH, Noh DY, Choe KJ, Strickland PT, Hirvonen A, Kang D: Alcohol consumption, glutathione S-transferase M1 and T1 genetic polymorphisms and breast cancer risk. Pharmacogenetics 10: 301–309, 2000Google Scholar
  6. 6.
    Yim DS, Park SK, Yoo KY, Yoon KS, Chung HH, Ahn SH, Noh DY, Choe KJ, Jang IJ, Shin SG, Stricklandi PT, Hirvonen A, Kang D: Relationship between the Val158Met polymorphism of catechol O-methyl transferase and breast cancer. Pharmacogenetics 11(4): 279–286, 2001Google Scholar
  7. 7.
    Cornfield J: A method of estimating comparative rates from clinical data: applications to cancer of lung, breast, and cervix. J Natl Cancer Inst 11: 1269–1275, 1951Google Scholar
  8. 8.
    Breslow NE, Day NE: Statistical Methods in Cancer Research. Vol. 1. The Analysis of Case Control Studies. Lyon: IARC Scientific Publications No. 32, 1980Google Scholar
  9. 9.
    Schlesselman JJ: Case–Control Studies. Design, Conduct, Analysis. Oxford University Press, New York, Oxford, 1982Google Scholar
  10. 10.
    Lavigne JA, Helzlsouer KJ, Huang HY, Strickland PT, Bell DA, Selmin O, Watson MA, Hoffmann S, Comstock GW, Yager JD: An association between the allele coding for a low activity variant of catechol o-methyltransferase and the risk for breast cancer. Cancer Res 57: 5493–5497, 1997Google Scholar
  11. 11.
    Mitrunen K, Kataja V, Eskelinen M, Kosma VM, Kang D, Benhamou S, Vainio H, Uusitupa M, Hirvonen A: Combined COMT and GST genotypes and hormone replacement therapy associated breast cancer risk. Pharmacogenetics 12(1): 67–72, 2002Google Scholar
  12. 12.
    Millikan R, Pittman G, Tse CK, Savitz DA, Newman B, Bell D: Glutathione S-transferases M1, T1, and P1 and breast cancer. Cancer Epidemiol Biomarkers Prev 9(6): 567–673, 2000Google Scholar
  13. 13.
    Kim WJ, Kim H, Kim CH, Lee MS, Oh BR, Lee HM, Katoh T: GSTT1–null genotype is a protective factor against bladder cancer. Urology 60(5): 913–918, 2002Google Scholar
  14. 14.
    Lee KA, Kim SH, Woo HY, Hong YJ, Cho HC: Increased frequencies of glutathione S-transferase (GSTM1 and GSTT1) gene deletions in Korean patients with acquired aplastic anemia. Blood 98(12): 3483–3485, 2001Google Scholar
  15. 15.
    Yim JJ, Park GY, Lee CT, Kim YW, Han SK, Shim YS, Yoo CG: Genetic susceptibility to chronic obstructive pulmonary disease in Koreans: combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and glutathione S-transferase M1 and T1. Thorax 55(2): 121–125, 2000Google Scholar
  16. 16.
    Bailey LR, Roodi CS, Verrier CS, Yee CJ, Dupont WD, Parl FF: Breast cancer and CYPIA1, GSTM1, and GSTT1 polymorphism: evidence of a lack of association in Caucasians and African Americans. Cancer Res 58: 65–70, 1998Google Scholar
  17. 17.
    Kelsey KT, Hankinson SE, Golditz GA, Springer K, Garcia-closas M, Spiegelman D, Manson JE, Garland M, Stampfer MJ, Willett WC, Speizer FE, Hunter DJ: Glutathione S-transferase classes deletion polymorphism and breast cancer: results from prevalent versus incident cases. Cancer Epidemiol Biomarkers Prev 6: 511–515, 1997Google Scholar
  18. 18.
    Zhong S, Wyllie AH, Barnes D, Wolf CR, Spurr NK: Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis 14(9): 1821–1824, 1993Google Scholar
  19. 19.
    Helzlsouer KJ, Sekmin O, Huang HY, Stricklan PT, Hoffman S, Alberg AJ, Watson M, Comstock GW, Bell D: Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer. J Natl Cancer Inst 90(7): 513–518, 1998Google Scholar
  20. 20.
    Maugard C, Charrier J, Bignon YJ: Allelic deletion at glutathione S-transferase M1 locus and its association with breast cancer susceptibility. Chemico-Biolog Interact 111–112: 365–375, 1998Google Scholar
  21. 21.
    Thompson PA, Shields PG, Freudenheim JL, Stone A, Vena JE, Marshall JR, Graham S, Laughlin R, Nemoto T, Kadlubar FF, Ambrosone CB: Genetic polymorphisms in catechol o-methyltransferase, menopausal status and breast cancer risk. Cancer Res 58: 2107–2110, 1998Google Scholar
  22. 22.
    Millikan RC, Pittman GS, Tse CKJ, Duell E, Newman B, Savitz D, Moorman PG, Boissy RJ, Bell DA: Catechol-Omethyltransferase and breast cancer risk. Carcinogenesis 19(11): 1943–1947, 1998Google Scholar
  23. 23.
    Park SK, Kang D, Noh DY, Lee KM, Kim SU, Choi JY, Choi IM, Ahn SH, Choe KJ, Hirvonen A, Strickland PT, Yoo KY: Reproductive factors, glutathione S-transferase M1 and T1 genetic polymorphism and breast cancer risk. Breast Cancer Res Treat 78(1): 89–96, 2003Google Scholar
  24. 24.
    Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C et al.: Endogenous Hormones Breast Cancer Collaborative Group: Body mass index, serum sex hormones, and breast cancer risk in post menopausal women. J Natl Cancer Inst 95(16): 1218–1226, 2003Google Scholar
  25. 25.
    Pike MC, Kralio MD, Henderson BE, Casagrande JT, Hoel DG: Hormonal risk factors, breast tissue age and the age-incidence of breast cancer. Nature 303: 767–770, 1983Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Sue Kyung Park
    • 1
    • 2
  • Dong-seok Yim
    • 1
  • Kyung-sik Yoon
    • 3
  • In-mi Choi
    • 1
  • Ji-yeob Choi
    • 1
  • Keun-young Yoo
    • 1
  • Dong-young Noh
    • 4
  • Kuk-jin Choe
    • 5
  • Sei-hyun Ahn
    • 6
  • Ari Hirvonen
    • 7
  • Daehee Kang
    • 8
    • 9
  1. 1.Department of Preventive Medicine Cancer Research InstituteSeoul National University College of MedicineChongno-GuKorea
  2. 2.Konkuk University, Institute of Medical ScienceKorea
  3. 3.Kyung Hee UniversityKorea
  4. 4.Department of SurgerySeoul National University College of MedicineKorea
  5. 5.Department of SurgerySeoul National University College of MedicineKorea
  6. 6.Asan Medical CenterKorea
  7. 7.Department of Industrial Hygiene and ToxicologyInstitute of Occupational HealthFinland
  8. 8.Department of Preventive MedicineKonkuk University College of MedicineKorea
  9. 9.Seoul National University, Cancer Research InstituteKorea

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