Skip to main content

Advertisement

SpringerLink
Log in

Glutathione-S-transferase P1, T1 and M1 genetic polymorphisms in neoadjuvant-treated locally advanced gastric cancer: GSTM1-present genotype is associated with better prognosis in completely resected patients

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Objective

Neoadjuvant chemotherapy in gastric cancer is now standard in the Western world; however, only 30–40% of the patients respond to induction therapy. Pretherapeutic predictors of response and prognosis would be of utmost interest to individualize treatment. Glutathione-S-transferase enzymes detoxify therapeutic drugs such as platin derivates and may influence outcome of the treated patients. Therefore, glutathione-S-transferase (GST) polymorphisms were assessed as predictive markers in cisplatinum-based neoadjuvant-treated gastric cancer.

Materials and methods

DNA was isolated from 139 patients with locally advanced gastric cancer (cT3/4 anyN cM0) before chemotherapy. Multiplex polymerase chain reaction was used for GSTT1 and GSTM1 genes, and allelic discrimination assay with the TaqMan system for the GSTP1 gene.

Results

One hundred ten patients could be analyzed for GSTT1 (T-:23; T + 87), 112 for GSTM1 (M-:52; M +:60) and 132 for GSTP1 (Ile/Ile: 55; Ile/Val: 59; Val/Val: 18). There was no significant correlation between any of the GSTT1, GSTM1, or GSTP1 genotypes and patients’ characteristics or histopathological data; only the GSTM1+ genotype was associated with the non-intestinal subtype of the Lauren classification (p = 0.045). GSTT1, GSTM1, and GSTP1 genotypes were not correlated with response to chemotherapy (p = 0.57, p = 0.38, p = 0.33). In R0 resected patients, we found an improved survival for patients with the GSTM1-present genotype compared to patients with the GSTM1-null genotype (p = 0.017). Moreover, the GSTM1-present genotype showed a significantly better tumor-related (p = 0.017) and disease-free survival (p = 0.029).

Conclusion

None of the common GST polymorphisms predicts response in our study, but the GSTM1+ genotype was associated with a better prognosis in completely resected patients. Further investigations on chemotherapy-associated gene polymorphisms are warranted.

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

Similar content being viewed by others

References

  1. Cunningham D, Allum WH, Stenning SP, Thompson JN et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11–20

    Article  PubMed  CAS  Google Scholar 

  2. Boige V, Pignon J, Saint-Aubert B, Lasser P, Conroy T, Bouche O, Segol P, Bedenne L, Rougier P, Ychou M (2007) Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial. J Clin Oncol (Supplement) 25:18S (Abstract)

    Google Scholar 

  3. Ott K, Sendler A, Becker K, Dittler HJ et al (2003) Neoadjuvant chemotherapy with cisplatin, 5-FU, and leucovorin (PLF) in locally advanced gastric cancer: a prospective phase II study. Gastric Cancer 6:159–167

    Article  PubMed  CAS  Google Scholar 

  4. Lordick F, Stein HJ, Peschel C, Siewert JR (2004) Neoadjuvant therapy for oesophagogastric cancer. Br J Surg 91:540–551

    Article  PubMed  CAS  Google Scholar 

  5. Napieralski R, Ott K, Kremer M, Becker K et al (2007) Methylation of tumor-related genes in neoadjuvant-treated gastric cancer: relation to therapy response and clinicopathologic and molecular features. Clin Cancer Res 13:5095–5102

    Article  PubMed  CAS  Google Scholar 

  6. Ott K, Vogelsang H, Marton N, Becker K et al (2006) The thymidylate synthase tandem repeat promoter polymorphism: a predictor for tumor-related survival in neoadjuvant treated locally advanced gastric cancer. Int J Cancer 119:2885–2894

    Article  PubMed  CAS  Google Scholar 

  7. Seidegard J, Vorachek WR, Pero RW, Pearson WR (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 U S A 85:7293–7297

    Article  PubMed  CAS  Google Scholar 

  8. Srivastava SK, Singhal SS, Hu X, Awasthi YC et al (1999) Differential catalytic efficiency of allelic variants of human glutathione S-transferase Pi in catalyzing the glutathione conjugation of thiotepa. Arch Biochem Biophys 366:89–94

    Article  PubMed  CAS  Google Scholar 

  9. Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30:445–600

    Article  PubMed  CAS  Google Scholar 

  10. Dirven HA, Dictus EL, Broeders NL, van Ommen B et al (1995) The role of human glutathione S-transferase isoenzymes in the formation of glutathione conjugates of the alkylating cytostatic drug thiotepa. Cancer Res 55:1701–1706

    PubMed  CAS  Google Scholar 

  11. Weijl NI, Cleton FJ, Osanto S (1997) Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev 23:209–240

    Article  PubMed  CAS  Google Scholar 

  12. La Torre F, Silipigni AM, Orlando A, La T I et al (1997) [Role of free radicals, telomeres, and telomerases in aging and cancerogenesis]. Minerva Med 88:205–214

    PubMed  Google Scholar 

  13. Cullen KJ, Newkirk KA, Schumaker LM, Aldosari N et al (2003) Glutathione S-transferase pi amplification is associated with cisplatin resistance in head and neck squamous cell carcinoma cell lines and primary tumors. Cancer Res 63:8097–8102

    PubMed  CAS  Google Scholar 

  14. Goekkurt E, Hoehn S, Wolschke C, Wittmer C et al (2006) Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)—novel predictors for response and survival in gastric cancer patients. Br J Cancer 94:281–286

    Article  PubMed  CAS  Google Scholar 

  15. Okuyama T, Maehara Y, Endo K, Baba H et al (1994) Expression of glutathione S-transferase-pi and sensitivity of human gastric cancer cells to cisplatin. Cancer 74:1230–1236

    Article  PubMed  CAS  Google Scholar 

  16. Davies SM, Robison LL, Buckley JD, Tjoa T et al (2001) Glutathione S-transferase polymorphisms and outcome of chemotherapy in childhood acute myeloid leukemia. J Clin Oncol 19:1279–1287

    PubMed  Google Scholar 

  17. DeMichele A, Aplenc R, Botbyl J, Colligan T et al (2005) Drug-metabolizing enzyme polymorphisms predict clinical outcome in a node-positive breast cancer cohort. J Clin Oncol 23:5552–5559

    Article  PubMed  CAS  Google Scholar 

  18. Casson AG, Zheng Z, Chiasson D, MacDonald K et al (2003) Associations between genetic polymorphisms of Phase I and II metabolizing enzymes, p53 and susceptibility to esophageal adenocarcinoma. Cancer Detect Prev 27:139–146

    Article  PubMed  CAS  Google Scholar 

  19. Schuhmacher CP, Fink U, Becker K, Busch R et al (2001) Neoadjuvant therapy for patients with locally advanced gastric carcinoma with etoposide, doxorubicin, and cisplatinum. Closing results after 5 years of follow-up. Cancer 91:918–927

    Article  PubMed  CAS  Google Scholar 

  20. Ott K, Fink U, Becker K, Stahl A et al (2003) Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial. J Clin Oncol 21:4604–4610

    Article  PubMed  CAS  Google Scholar 

  21. Menzel C, Dobert N, Rieker O, Kneist W et al (2003) [18F-Deoxyglucose PET for the staging of oesophageal cancer: influence of histopathological subtype and tumour grading]. Nuklearmedizin 42:90–93

    PubMed  Google Scholar 

  22. Ott K, Dittler HJ, Helmberger H (2000) Preoperative chemotherapy of high dose 5-FU (HDFU) + folinic acid (HDFA) + biweekly Cisplatin without (group A) or with Paclitaxel (group B) in patients with locally advanced adenocarcinomas of the esophagus. Proc Am Soc Clin Oncol 19:287A (Abstract)

    Google Scholar 

  23. Becker K, Mueller JD, Schulmacher C, Ott K et al (2003) Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer 98:1521–1530

    Article  PubMed  Google Scholar 

  24. Ott K, Weber WA, Lordick F, Becker K et al (2006) Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction. J Clin Oncol 24:4692–4698

    Article  PubMed  Google Scholar 

  25. Ott K, Vogelsang H, Mueller J, Becker K et al (2003) Chromosomal instability rather than p53 mutation is associated with response to neoadjuvant cisplatin-based chemotherapy in gastric carcinoma. Clin Cancer Res 9:2307–2315

    PubMed  CAS  Google Scholar 

  26. Abdel-Rahman SZ, Anwar WA, Abdel-Aal WE, Mostafa HM et al (1998) GSTM1 and GSTT1 genes are potential risk modifiers for bladder cancer. Cancer Detect Prev 22:129–138

    Article  PubMed  CAS  Google Scholar 

  27. Ambrosone CB, Sweeney C, Coles BF, Thompson PA et al (2001) Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer. Cancer Res 61:7130–7135

    PubMed  CAS  Google Scholar 

  28. Sweeney C, McClure GY, Fares MY, Stone A et al (2000) Association between survival after treatment for breast cancer and glutathione S-transferase P1 Ile105Val polymorphism. Cancer Res 60:5621–5624

    PubMed  CAS  Google Scholar 

  29. Sweeney C, Nazar-Stewart V, Stapleton PL, Eaton DL et al (2003) Glutathione S-transferase M1, T1, and P1 polymorphisms and survival among lung cancer patients. Cancer Epidemiol Biomarkers Prev 12:527–533

    PubMed  CAS  Google Scholar 

  30. Choi SC, Yun KJ, Kim TH, Kim HJ et al (2003) Prognostic potential of glutathione S-transferase M1 and T1 null genotypes for gastric cancer progression. Cancer Lett 195:169–175

    PubMed  CAS  Google Scholar 

  31. Stoehlmacher J, Park DJ, Zhang W, Groshen S et al (2002) Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst 19(94):936–942

    Google Scholar 

  32. Lee JM, Wu MT, Lee YC, Yang SY et al (2005) Association of GSTP1 polymorphism and survival for esophageal cancer. Clin Cancer Res 11:4749–4753

    Article  PubMed  CAS  Google Scholar 

  33. Howells RE, Dhar KK, Hoban PR, Jones PW et al (2004) Association between glutathione-S-transferase GSTP1 genotypes, GSTP1 over-expression, and outcome in epithelial ovarian cancer. Int J Gynecol Cancer 14:242–250

    Article  PubMed  CAS  Google Scholar 

  34. Roder JD, Bottcher K, Siewert JR, Busch R et al (1993) Prognostic factors in gastric carcinoma. Results of the German Gastric Carcinoma Study 1992. Cancer 72:2089–2097

    Article  PubMed  CAS  Google Scholar 

  35. Yang G, Shu XO, Ruan ZX, Cai QY et al (2005) Genetic polymorphisms in glutathione-S-transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma. Cancer 103:52–58

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Katja Ott

  2. National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany

    Florian Lordick

  3. Directorate, University of Heidelberg, Heidelberg, Germany

    JörgRüdiger Siewert

  4. Department of Pathology, Technische Universitaet Muenchen, Munich, Germany

    Karen Becker, Heinz Höfler & Gisela Keller

  5. Institute for Medical Statistics and Epidemiology, Technische Universitaet Muenchen, Munich, Germany

    Kurt Ulm

Authors
  1. Katja Ott
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florian Lordick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karen Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kurt Ulm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. JörgRüdiger Siewert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heinz Höfler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gisela Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katja Ott.

Additional information

This study was supported by KKF 8744168.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ott, K., Lordick, F., Becker, K. et al. Glutathione-S-transferase P1, T1 and M1 genetic polymorphisms in neoadjuvant-treated locally advanced gastric cancer: GSTM1-present genotype is associated with better prognosis in completely resected patients. Int J Colorectal Dis 23, 773–782 (2008). https://doi.org/10.1007/s00384-008-0490-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-008-0490-4

Keywords

Search

Navigation