Skip to main content

Advertisement

SpringerLink
Log in

Prognostic implications of BAX protein expression and microsatellite instability in all non-metastatic stages of primary colon cancer treated by surgery alone

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

Abstract

Purpose

This study examined whether the apoptosis-related protein, BAX, or the microsatellite-instability phenotype provide prognostic information in patients with resected colon cancer.

Methods

A total of 371 stage I–III patients that previously underwent radical surgery were included (mean follow-up 51.8 months). BAX expression was examined by immunohistochemical staining; high-frequency microsatellite instability (MSI+) was determined by assessing the specific marker, BAT26, using single-strand conformation polymorphism (SSCP)-based analysis.

Results

High BAX expression was found in 66.4% of patients. MSI+ tumors were observed in 14.8% of 344 patients. Univariate analysis showed that unlike MSI, low BAX expression was significantly correlated with poor disease-specific overall survival (OS) in stages I–III (p = 0.04). Multivariate subgroup analyses revealed that unlike MSI, low BAX was an independent predictor for OS in stage II (p = 0.009); however, in stages I or III, BAX or MSI were not independent predictors of OS.

Conclusions

In stage II colon cancer treated with surgery alone, BAX protein expression may be a predictor for prognosis.

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. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics 2007. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  2. Gill S, Loprinzi CL, Sargent DJ, Thomé SD, Alberts SR, Haller DG, Benedetti J, Francini G, shepherd LE, Seitz JF, Labianca R, Chen W, Cha SS, Heldebrant MP, Goldberg RM (2004) Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 22:1797–1806

    Article  PubMed  CAS  Google Scholar 

  3. Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ (2007) Adjuvant treatment for colorectal cancer. CA Cancer J Clin 57:168–185

    Article  PubMed  Google Scholar 

  4. Lindmark G, Bergström R, Pahlmann L, Glimelius B (1995) The association of preoperative serum tumor markers with Duke’s stage and survival in colorectal cancer. Br J Cancer 71:1090–1094

    PubMed  CAS  Google Scholar 

  5. Greene FL, Stewart AK, Norton J (2002) A new TNM staging strategy for node positive (stage III) colon cancer. Ann Surg 4:416–421

    Article  Google Scholar 

  6. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    Article  PubMed  CAS  Google Scholar 

  7. Perucho M (1996) Cancer of the microsatellite mutator phenotype. Biol Chem 377:675–684

    PubMed  CAS  Google Scholar 

  8. Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609–618

    Article  PubMed  CAS  Google Scholar 

  9. Kerr J, Wyllie A, Currie A (1972) Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer 26:239–257

    PubMed  CAS  Google Scholar 

  10. Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299

    Article  PubMed  CAS  Google Scholar 

  11. Hoang JM, Cottu PH, Thuille B, Salmon RJ, Thomas G, Hamelin R (1997) BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Res 57:300–303

    PubMed  CAS  Google Scholar 

  12. Loukola A, Eklin K, Laiho P, Solovaara R, Kristo P, Järvinen H, Mecklin JP, Launonen V, Aaltonen LA (2001) Microsatellite marker analysis in screening for hereditary nonpolyposis colorectal cancer (HNPCC). Cancer Res 61:4545–4549

    PubMed  CAS  Google Scholar 

  13. Jansson A, Sun XF (2002) BAX expression decreases significantly from primary tumor to metastasis in colorectal cancer. J Clin Oncol 20:811–816

    Article  PubMed  CAS  Google Scholar 

  14. Söreide K, Janssen EAM, Söiland H, Körner H, Baak JPA (2006) Microsatellite instability in colorectal cancer. Br J Surgery 93:395–406

    Article  Google Scholar 

  15. Sturm I, Köhne CH, Wolff G, Petrowsky H, Hillebrand T, Hauptmann S, Lorenz M, Dorken P, Daniel PT (1999) Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases. J Clin Oncol 17:1364–1374

    PubMed  CAS  Google Scholar 

  16. Schelwies K, Sturm I, Grabowski P, Scherubl H, Schindler I, Hermann S, Stein H, Buhr HJ, Riecken EO, Zeitz M, Dorken P, Daniel PT (2002) Analysis of p53/BAX in primary colorectal carcinoma: low BAX protein expression is a negative prognostic factor in UICC stage III tumours. Int J Cancer 99:589–596

    Article  PubMed  CAS  Google Scholar 

  17. Nehls O, Okech T, Hsieh CJ, Sarbia M, Borchard F, Gruenagel HH, Gaco V, Porschen R, Gregor M, Klump B (2005) Low BAX protein expression correlates with disease-recurrence in preoperatively irradiated rectal carcinoma. Int J Radiat Oncol Biol Phys 61:85–91

    PubMed  CAS  Google Scholar 

  18. Nehls O, Okech T, Hsieh CJ, Enzinger T, Sarbia M, Borchard F, Gruenagel HH, Gaco V, Hass HG, Arkenau HAT, Hartmann JT, Porschen R, Gregor M, Klump B (2007) Studies on p53, BAX, and Bcl-2 protein expression in stage III (UICC) colon cancer treated by adjuvant chemotherapy: Major prognostic impact of proapoptotic BAX pronounced by intact p53. Br J Cancer 96:1409–1418

    PubMed  CAS  Google Scholar 

  19. Sobin LH, Wittekind C (1997) TNM Classification of Malignant Tumours. UICC, International Union against cancer, 5th edn. Wiley-Liss, New York

    Google Scholar 

  20. Giatromanolaki A, Sivridis E, Stathopoulos GP, Fountzilas G, Kalofonos HP, Tsamandas A, Vrettou E, Scopa C, Polychronidis A, Simopoulos K, Koukourakis MI (2001) Bax protein expression in colorectal cancer: association with p53, bcl-2 and patterns of relapse. Anticancer Res 21:253–259

    PubMed  CAS  Google Scholar 

  21. Koda M, Reszec J, Sulkowska M, Kanczuga-Koda L, Sulkowski S (2004) Expression of the insulin-like growth factor-I receptor and proapoptotic BAX and Bak proteins in human colorectal cancer. Ann N Y Acad Sci 1030:377–383

    Article  PubMed  CAS  Google Scholar 

  22. Backus HHJ, van Groeningen CJ, Vos W, Dukers DF, Bloemena E, Wouters D, Pinedo HM, Peters GJ (2004) Differential expression of cell cycle and apoptosis related proteins in colorectal mucosa, primary colon tumours, and liver metastases. J Clin Pathol 55:206–211

    Google Scholar 

  23. Elsaleh H, Powell B, McCaul K, Grieu F, Grant R, Joseph D, Iacopetta B (2001) P53 alterations and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma. Clin Cancer Res 7:1343–1349

    PubMed  CAS  Google Scholar 

  24. Evertson S, Wallin A, Arbman G, Rütten S, Emterling A, Zhang H, Sun XF (2003) Microsatellite instability and MBD4 mutation in unselected colorectal cancer. Anticancer Res 23:3569–3574

    PubMed  CAS  Google Scholar 

  25. Wang C, van Rijnsoever M, Grieu F, Bydder S, Elsaleh H, Joseph D, Harvey J, Iacopetta B (2003) Prognostic significance of microsatellite instability and Ki-ras mutation type in stage II colorectal cancer. Oncology 64:259–265

    Article  PubMed  CAS  Google Scholar 

  26. Minamoto T, Esumi H, Ochiai A, Belitsky G, Mai M, Sugimura T, Ronai Z (1997) Combined analysis of microsatellite instability and k-ras mutation increases detection of normal samples from colorectal cancer patients. Clin Cancer Res 3:1413–1417

    PubMed  CAS  Google Scholar 

  27. Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. New Engl J Med 342:69–77

    Article  PubMed  CAS  Google Scholar 

  28. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S (2003) Tumor microsatellite instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. New Engl J Med 349:247–257

    Article  PubMed  CAS  Google Scholar 

  29. Nakata B, Muguruma K, Hirakawa K, Chung YS, Yamashita Y, Inoue T, Matsuoka T, Onoda N, Kato Y, Sowa M (1998) Predictive value of Bcl-2 and BAX protein expression for chemotherapeutic effect in gastric cancer. A pilot study. Oncology 55:543–547

    Article  PubMed  CAS  Google Scholar 

  30. Kang SY, Han JH, Lee KJ, Choi J-H, Park JI, Kim HI, Lee H-W, Jang JH, Park JS, Kim HC, Kang S, Oh YT, Chun M, Kim JH, Sheen SS, Lim H-Y (2007) Low expression of BAX predicts poor prognosis in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy. Clin Cancer Res 13:4146–4153

    Article  PubMed  CAS  Google Scholar 

  31. Theodorakis P, Lomonosova E, Chinnadurai G (2002) Critical requirement of BAX manifestation of apoptosis induced by multiple stimuli in human epithelial cancer cell lines. Cancer Res 62:3373–3376

    PubMed  CAS  Google Scholar 

  32. Schrag D, Cramer LD, Bach PB, Cohen AM, Warren JL, Begg CB (2000) Influence of hospital procedure volume on outcomes following surgery for colon cancer. JAMA 284:3028–3035

    Article  PubMed  CAS  Google Scholar 

  33. Rabeneck L, Davila JA, Thompson M, El-Serag HB (2004) Surgical volume and long-term survival following surgery for colorectal cancer in the Veterans Affairs Health-Care System. Am J Gastroenterol 99:668–675

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The last author is supported by a grant of the Deutsche Krebshilfe (702601) and the Interdisciplinary Center for Clinical Research Tübingen (IZKF IIIB2).

Author information

Authors and Affiliations

  1. Department of Internal Medicine I, University Hospital, 72076, Tübingen, Germany

    Oliver Nehls, Thomas Okech, Silke Zenner, Chih-Jen Hsieh, Vera Gaco, Michael Gregor & Bodo Klump

  2. Department of Internal Medicine II, University Hospital, 72076, Tübingen, Germany

    Oliver Nehls & Holger G. Hass

  3. Institute of Pathology, Lachnerstrasse, 80639, Munich, Germany

    Mario Sarbia

  4. Department of Pathology, Klinikum Aschaffenburg, 63739, Aschaffenburg, Germany

    Franz Borchard

  5. Department of Surgery, Evangelic Hospital, 40217, Düsseldorf, Germany

    Hans-Helmut Gruenagel

  6. Clinic of Internal Medicine, Central Hospital Bremen Ost, 28325, Bremen, Germany

    Rainer Porschen

  7. Medizinische Universitätsklinik und Poliklinik, Abteilung Innere Medizin I, Otfried-Müller-Str. 10, 72076, Tübingen, Germany

    Oliver Nehls

Authors
  1. Oliver Nehls
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Holger G. Hass
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Okech
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silke Zenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chih-Jen Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mario Sarbia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Franz Borchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hans-Helmut Gruenagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vera Gaco
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rainer Porschen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael Gregor
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bodo Klump
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oliver Nehls.

Additional information

Oliver Nehls and Holger G. Hass contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nehls, O., Hass, H.G., Okech, T. et al. Prognostic implications of BAX protein expression and microsatellite instability in all non-metastatic stages of primary colon cancer treated by surgery alone. Int J Colorectal Dis 24, 655–663 (2009). https://doi.org/10.1007/s00384-009-0635-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-009-0635-0

Keywords

Search

Navigation