Skip to main content

Advertisement

SpringerLink
Log in

GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis

  • Review
  • Published:
Tumor Biology

A Commentary to this article was published on 21 July 2016

Abstract

Observational studies have reported controversial results on the association between GSTT1 and GSTM1 genotypes and treatment outcome of breast cancer. The purpose of this study is to evaluate the association between GSTT1 and GSTM1 and treatment outcome in breast cancer patients. Eligible studies were searched in PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure databases. A random-effect model or fixed-effect model was used to calculate the overall combined risk estimates. Twenty-one studies with a total of 4990 patients were included in this meta-analysis. The GSTM1 null genotype (odds ratio (OR) = 1.33, 95 % confidence interval (CI) 1.01–1.75, P = 0.046) and GSTT1/GSTM1 double null genotype (OR = 2.22, 95 % CI 1.02–4.84, P = 0.045) were significantly associated with an increased tumor response. A reduced overall survival (hazard ratio (HR) = 0.84, 95 % CI 0.72–0.98, P = 0.024) was observed in GSTM1 null genotype, especially in mixed descent (HR = 0.77, 95 % CI 0.61–0.96, P = 0.018) and large sample size (HR = 0.85, 95 % CI 0.72–0.99, P = 0.033). Evidence of publication bias was observed in GSTM1 genotype rather than in GSTT1 genotype. This meta-analysis suggests that GSTM1 null and GSTT1/GSTM1 double null polymorphisms might be significantly associated with an increased tumor response. However, the GSTM1 null genotype might be significantly associated with a reduced overall survival. Future studies are warranted to confirm these findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.

    Article  PubMed  Google Scholar 

  2. Rodrigues FF, Santos RE, Melo MB, Silva MA, Oliveira AL, Rozenowicz RL, et al. Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer. Genet Mol Res GMR. 2008;7(1):177–83.

    Article  CAS  PubMed  Google Scholar 

  3. Arun BK, Granville LA, Yin G, Middleton LP, Dawood S, Kau SW, et al. Glutathione-s-transferase-pi expression in early breast cancer: association with outcome and response to chemotherapy. Cancer Investig. 2010;28(5):554–9.

    Article  CAS  Google Scholar 

  4. Huang MY, Wang YH, Chen FM, Lee SC, Fang WY, Cheng TL, et al. Multiple genetic polymorphisms of GSTP1 313AG, MDR1 3435CC, and MTHFR 677CC highly correlated with early relapse of breast cancer patients in Taiwan. Ann Surg Oncol. 2008;15(3):872–80.

    Article  PubMed  Google Scholar 

  5. Strange RC, Spiteri MA, Ramachandran S, Fryer AA. Glutathione-S-transferase family of enzymes. Mutat Res. 2001;482(1-2):21–6.

    Article  CAS  PubMed  Google Scholar 

  6. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 2003;22(47):7369–75.

    Article  CAS  PubMed  Google Scholar 

  7. Cho SG, Lee YH, Park HS, Ryoo K, Kang KW, Park J, et al. Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1. J Biol Chem. 2001;276(16):12749–55.

    Article  CAS  PubMed  Google Scholar 

  8. Khedhaier A, Remadi S, Corbex M, Ahmed SB, Bouaouina N, Mestiri S, et al. Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma. Br J Cancer. 2003;89(8):1502–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chacko P, Joseph T, Mathew BS, Rajan B, Pillai MR. Role of xenobiotic metabolizing gene polymorphisms in breast cancer susceptibility and treatment outcome. Mutat Res. 2005;581(1-2):153–63.

    Article  CAS  PubMed  Google Scholar 

  10. Tang JH, Zhao JH, Wu JZ, Lu JW, Pan LQ, Xu ZY. Establishment of a multiplex ligation-dependent SNP genotyping method and its application in the detection of genes related to chemotherapeutic drugs in breast cancer. Chin J Oncol. 2009;31(2):108–13.

    CAS  Google Scholar 

  11. Gor PP, Su HI, Gray RJ, Gimotty PA, Horn M, Aplenc R, et al. Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res BCR. 2010;12(3):R26.

    Article  PubMed  Google Scholar 

  12. Zhong SL, Jiang SG, Tang JH, Li J, Li WJ, Zhao JH. Association of GSTs gene polymorphism with response to chemotherapy in breast cancer. Chin J Clin Lab Sci. 2010;28(6):438–40.

    Google Scholar 

  13. Bai YL, Zhou B, Jing XY, Zhang B, Huo XQ, Ma C, et al. Predictive role of GSTs on the prognosis of breast cancer patients with neoadjuvant chemotherapy. Asian Pac J Cancer Prev APJCP. 2012;13(10):5019–22.

    Article  PubMed  Google Scholar 

  14. Lizard-Nacol S, Coudert B, Colosetti P, Riedinger JM, Fargeot P, Brunet-Lecomte P. Glutathione S-transferase M1 null genotype: lack of association with tumour characteristics and survival in advanced breast cancer. Breast Cancer Res BCR. 1999;1(1):81–7.

    Article  CAS  PubMed  Google Scholar 

  15. Ambrosone CB, Sweeney C, Coles BF, Thompson PA, McClure GY, Korourian S, et al. Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer. Cancer Res. 2001;61(19):7130–5.

    CAS  PubMed  Google Scholar 

  16. Yang G, Shu XO, Ruan ZX, Cai QY, Jin F, Gao YT, et al. Genetic polymorphisms in glutathione-S-transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma. Cancer. 2005;103(1):52–8.

    Article  CAS  PubMed  Google Scholar 

  17. Petros WP, Hopkins PJ, Spruill S, Broadwater G, Vredenburgh JJ, Colvin OM, et al. Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer. J Clin Oncol. 2005;23(25):6117–25.

    Article  CAS  PubMed  Google Scholar 

  18. Syamala VS, Sreeja L, Syamala V, Raveendran PB, Balakrishnan R, Kuttan R, et al. Influence of germline polymorphisms of GSTT1, GSTM1, and GSTP1 in familial versus sporadic breast cancer susceptibility and survival. Familial Cancer. 2008;7(3):213–20.

    Article  CAS  PubMed  Google Scholar 

  19. Oliveira AL, Rodrigues FF, Santos RE, Aoki T, Rocha MN, Longui CA, et al. GSTT1, GSTM1, and GSTP1 polymorphisms and chemotherapy response in locally advanced breast cancer. Genet Mol Res GMR. 2010;9(2):1045–53.

    Article  CAS  PubMed  Google Scholar 

  20. Mishra A, Chandra R, Mehrotra PK, Bajpai P, Agrawal D. Glutathione S-transferase M1 and T1 polymorphism and response to neoadjuvant chemotherapy (CAF) in breast cancer patients. Surg Today. 2011;41(4):471–6.

    Article  CAS  PubMed  Google Scholar 

  21. Saadat M, Khalili M, Nasiri M, Rajaei M, Omidvari S, Saadat I. Clinical response to chemotherapy in locally advanced breast cancer was not associated with several polymorphisms in detoxification enzymes and DNA repair genes. Biochem Biophys Res Commun. 2012;419(1):117–9.

    Article  CAS  PubMed  Google Scholar 

  22. Ji M, Tang J, Zhao J, Xu B, Qin J, Lu J. Polymorphisms in genes involved in drug detoxification and clinical outcomes of anthracycline-based neoadjuvant chemotherapy in Chinese Han breast cancer patients. Cancer Biol Ther. 2012;13(5):264–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tulsyan S, Chaturvedi P, Agarwal G, Lal P, Agrawal S, Mittal RD, et al. Pharmacogenetic influence of GST polymorphisms on anthracycline-based chemotherapy responses and toxicity in breast cancer patients: a multi-analytical approach. Mol Diagn Ther. 2013;17(6):371–9.

    Article  CAS  PubMed  Google Scholar 

  24. Duggan C, Ballard-Barbash R, Baumgartner RN, Baumgartner KB, Bernstein L, McTiernan A. Associations between null mutations in GSTT1 and GSTM1, the GSTP1 Ile(105)Val polymorphism, and mortality in breast cancer survivors. SpringerPlus. 2013;2:450.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liu J, Luo J, Wang Y, Li L, Yang S. Predictive potential role of glutathione S-transferases polymorphisms on prognosis of breast cancer. Int J Clin Exp Pathol. 2014;7(12):8935–40.

    PubMed  PubMed Central  Google Scholar 

  26. Zhao YJ, Liu XL. The research of the relationship between the polymorphisms of GSTM1, GSTT1 and GSTP1 with clinicopathology features, chemotherapy response and toxicities in breast cancer. 2014.

  27. Zhou L, Huang A, Zhang D, Yao J, Zhang Y, Li X. Genetic variability of glutathione S-transferases influences treatment outcome of breast cancer. Tumour Biol J Int Soc Oncodev Biol Med. 2015;36(8):5925–9.

    Article  CAS  Google Scholar 

  28. Yu KD, Huang AJ, Fan L, Li WF, Shao ZM. Genetic variants in oxidative stress-related genes predict chemoresistance in primary breast cancer: a prospective observational study and validation. Cancer Res. 2012;72(2):408–19.

    Article  CAS  PubMed  Google Scholar 

  29. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Alexander J, Sutton KRA, Jones DR, Sheldon TA, Song F. Methods for meta-analysis in medical research. Chichester: Wiley; 2000.

    Google Scholar 

  31. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  CAS  PubMed  Google Scholar 

  32. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.

    Article  CAS  PubMed  Google Scholar 

  34. Oliveira AL, Oliveira Rodrigues FF, Dos Santos RE, Rozenowicz RL. Barbosa de Melo M. GSTT1, GSTM1, and GSTP1 polymorphisms as a prognostic factor in women with breast cancer. Genet Mol Res GMR. 2014;13(2):2521–30.

    Article  CAS  PubMed  Google Scholar 

  35. Wei HB, Lu XS, Shang LH, Xu G, Hu J, Che DH, et al. Polymorphisms of ERCC1 C118T/C8092A and MDR1 C3435T predict outcome of platinum-based chemotherapies in advanced non-small cell lung cancer: a meta-analysis. Arch Med Res. 2011;42(5):412–20.

    CAS  PubMed  Google Scholar 

  36. Hayes JD, McLellan LI. Glutathione and glutathione-dependent enzymes represent a coordinately regulated defence against oxidative stress. Free Radic Res. 1999;31(4):273–300.

    Article  CAS  PubMed  Google Scholar 

  37. Lao X, Peng Q, Lu Y, Li S, Qin X, Chen Z, et al. Glutathione S-transferase gene GSTM1, gene-gene interaction, and gastric cancer susceptibility: evidence from an updated meta-analysis. Cancer Cell Int. 2014;14(1):127.

    Article  PubMed  PubMed Central  Google Scholar 

  38. He HR, You HS, Sun JY, Hu SS, Ma Y, Dong YL, et al. Glutathione S-transferase gene polymorphisms and susceptibility to acute myeloid leukemia: meta-analyses. Jpn J Clin Oncol. 2014;44(11):1070–81.

    Article  PubMed  Google Scholar 

  39. Liu K, Lin X, Zhou Q, Ma T, Han L, Mao G, et al. The associations between two vital GSTs genetic polymorphisms and lung cancer risk in the Chinese population: evidence from 71 studies. PLoS One. 2014;9(7):e102372.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sui C, Ma J, He X, Wang G, Ai F. Interactive effect of glutathione S-transferase M1 and T1 polymorphisms on hepatocellular carcinoma. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35(8):8235–41.

    Article  CAS  Google Scholar 

  41. Xiao Q, Deng D, Li H, Ye F, Huang L, Zhang B, et al. GSTT1 and GSTM1 polymorphisms predict treatment outcome for acute myeloid leukemia: a systematic review and meta-analysis. Ann Hematol. 2014;93(8):1381–90.

    Article  CAS  PubMed  Google Scholar 

  42. Yang Y, Xian L. The association between the GSTP1 A313G and GSTM1 null/present polymorphisms and the treatment response of the platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients: a meta-analysis. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35(7):6791–9.

    Article  CAS  Google Scholar 

  43. Wang Z, Chen JQ, Liu JL, Qin XG, Huang Y. Polymorphisms in ERCC1, GSTs, TS and MTHFR predict clinical outcomes of gastric cancer patients treated with platinum/5-Fu-based chemotherapy: a systematic review. BMC Gastroenterol. 2012;12:137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zareifar S, Monabati A, Saeed A, Fakhraee F, Cohan N. The association of glutathione S-transferase gene mutations (including GSTT1 and GSTM1) with the prognostic factors and relapse in acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2013;30(6):568–73.

    Article  CAS  PubMed  Google Scholar 

  45. Naoe T, Tagawa Y, Kiyoi H, Kodera Y, Miyawaki S, Asou N, et al. Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia: increased early death after chemotherapy. Leukemia. 2002;16(2):203–8.

    Article  CAS  PubMed  Google Scholar 

  46. Barragan E, Collado M, Cervera J, Martin G, Bolufer P, Roman J, et al. The GST deletions and NQO1*2 polymorphism confers interindividual variability of response to treatment in patients with acute myeloid leukemia. Leuk Res. 2007;31(7):947–53.

    Article  CAS  PubMed  Google Scholar 

  47. Shaikh RS, Amir M, Masood AI, Sohail A, Athar HU, Siraj S, et al. Frequency distribution of GSTM1 and GSTT1 null allele in Pakistani population and risk of disease incidence. Environ Toxicol Pharmacol. 2010;30(1):76–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all the people who provided technical support and useful discussion of the article.

Authors’ contributions

XYH and JM conceived the study, participated in the design, collected the data, and drafted the manuscript. XYH collected the data and performed statistical analyses. YZ and NBL helped collect the data. SLL and DKS conceived the study, participated in the design, and helped draft the manuscript. All authors read and approved the final manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Department of Radiology, Affiliated Oncology Hospital of Guangxi Medical University, 71 Hedi Road, Nanning, 530021, Guangxi, People’s Republic of China

      Xue-Ying Hu, Xiang-Yang Huang, Jie Ma, Yang Zuo, Ning-bin Luo, Shao-Lv Lai & Dan-Ke Su

    Authors
    1. Xue-Ying Hu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xiang-Yang Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jie Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yang Zuo
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ning-bin Luo
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Shao-Lv Lai
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Dan-Ke Su
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Dan-Ke Su.

    Ethics declarations

    Financial disclosure

    The study was supported by grants from the Guangxi Science and Technology Development Program (Gui Ke Gong14124004-1-11) and Guangxi Self-financing Scientific Research Subject (Z2013418). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Conflicts of interest

    None

    Additional information

    Xue-Ying Hu, Xiang-Yang Huang and Jie Ma contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Hu, XY., Huang, XY., Ma, J. et al. GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis. Tumor Biol. 37, 151–162 (2016). https://doi.org/10.1007/s13277-015-4401-3

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13277-015-4401-3

    Keywords

    Search

    Navigation