Skip to main content
SpringerLink
Log in

Prognostic significance of Bcl-2 and p53 expression in gastric cancer

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

Abstract

Background and aims

Apoptosis regulates cell death and influences cell proliferation and therefore may play an important role in development or growth of various malignant tumors. The Bcl-2 and p53 are closely linked in the regulation of apoptosis. We investigated the prognostic significance of Bcl-2 and p53 expression in patients with gastric cancer.

Patients and methods

Immunohistochemistry was used to study Bcl-2 and p53 expression in 308 consecutive patients with gastric cancer.

Results

Bcl-2 expression was positive in 39 patients (12.7%) and showed a significant negative correlation with depth of invasion and lymph node metastasis. p53 expression was observed in 105 patients (34.1%) and was significantly associated with depth of invasion, lymph node metastasis, distant metastasis, and intestinal type. Patients with Bcl-2+ tumors showed a trend to better 5-year survival rate (81%) than those with Bcl-2− negative tumors (71%). The 5-year survival rate in p53 positive cases (60%) was significantly lower than that in p53-negative cases (78%). In addition, p53 expression showed a significantly poorer prognosis in both diffuse and intestinal types. In multivariate analysis restricted to patients with R0 resection p53 expression was an independent prognostic factor (relative risk: 2.063). In combined assessment of p53 and Bcl-2 expression the group with p53+/Bcl-2− tumors showed significantly worse 5-year survival (57%) than the other groups, while best survival was seen in the group with p53+/Bcl-2+ tumors (100%).

Conclusion

p53 expression is an unfavorable prognostic factor in gastric cancer. Bcl-2 expression may have possible prognostic value when combined with p53 expression.

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. 1A–D.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  1. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336

    CAS  PubMed  Google Scholar 

  2. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukemic cells that is inhibited by interleutin-6. Nature 353:345–347

    Google Scholar 

  3. Fukuhara S, Rowley JD, Variakojis D, Golomb HM (1979) Chromosome abnormalities in poorly differentiated lymphocytic lymphoma. Cancer Res 39:3119–3128

    Google Scholar 

  4. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t (14;18) chromosome translocation. Science 226:1097–1099

    CAS  PubMed  Google Scholar 

  5. Cleary ML, Sklar J (1985) Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a chromosome 18. Proc Natl Acad Sci USA 82:7437–7443

    Google Scholar 

  6. Pezzella F, Tse AGD, Cordell JL, Pulford KAF, Gatter KC, Mason DY (1990) Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol 137:225–232

    CAS  PubMed  Google Scholar 

  7. Gaulard P, d'Agay MF, Peuchmaur M, Brousse N, Gisselbrecht C, Solal-Celigny P, Diebold J, Mason DY (1992) Expression of the bcl-2 gene product in follicular lymphoma. Am J Pathol 140:1089–1095

    CAS  PubMed  Google Scholar 

  8. Bissonnette RP, Echeverri F (1992) Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 359:552–554

    CAS  PubMed  Google Scholar 

  9. Korsmeyer S (1992) Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 80:879–886

    CAS  PubMed  Google Scholar 

  10. Saegusa M, Takano Y, Okayasu I (1995) Bcl-2 expression and its association with cell kinetics in human gastric carcinomas and intestinal metaplasia. J Cancer Res Clin Oncol 121:357–363

    CAS  PubMed  Google Scholar 

  11. Nakanishi H, Ohsawa M, Naka N, Uchida A, Ochi T, Aozasa K (1997) Immunohistochemical detection of bcl-2 and p53 proteins and apoptosis in soft tissue sarcoma: their correlations with prognosis. Oncology 54:238–244

    Google Scholar 

  12. Ishida H, Irie K, Itoh T, Furukawa T, Tokunaga O (1997) The prognostic significance of p53 and bcl-2 expression in lung adenocarcinoma and its correlation with Ki-67 growth fraction. Cancer 80:1034–1045

    Article  CAS  PubMed  Google Scholar 

  13. Pollina L, Pacini F, Fontanini G, Vignati S, Bevilacqua G, Basolo F (1996) bcl-2, p53 and proliferating cell nuclear antigen expression is related to the degree of differentiation in thyroid carcinomas. Br J Cancer 73:139–143

    Google Scholar 

  14. Silvestrini R, Veneroni S, Daidone MG, Benini E, Boracchi P, Mezzetti M, Di Fronzo G, Rilke F, Veronesi U (1994) The Bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients. J Natl Cancer Inst 86:499–504

    CAS  PubMed  Google Scholar 

  15. Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, Harris A, Gatter KC, Mason DY (1993) bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 329:690–694

    CAS  PubMed  Google Scholar 

  16. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML (1992) Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 52:6940–6944

    CAS  PubMed  Google Scholar 

  17. Manne U, Myers RB, Moron C, Poczatek RB, Dillard S, Weiss H, Brown D, Srivastava S, Grizzle WE (1997) Prognostic significance of Bcl-2 expression and p53 nuclear accumulation in colorectal adenocarcinoma. Int J Cancer 74:346–358

    Article  CAS  PubMed  Google Scholar 

  18. Müller W, Schneiders A, Hommel G, Gabbert H (1998) Prognostic value of bcl-2 expression in gastric cancer. Anticancer Res 18:4699–4704

    CAS  PubMed  Google Scholar 

  19. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancer. Science 253:49–53

    CAS  PubMed  Google Scholar 

  20. Yonish-Rouach E, Grunwald D, Wilder S, Kimchi A, May E, Lawrence JJ, May P, Oren M (1993) p53-mediated cell death: relationship to cell cycle control. Mol Cell Biol 13:1415–1423

    PubMed  Google Scholar 

  21. Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutation in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878

    CAS  PubMed  Google Scholar 

  22. Bass IO, Mulder J, Offerhaus G, Vogelstein B, Hamilton S (1994) An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms. J Pathol 172:5–12

    CAS  PubMed  Google Scholar 

  23. McLaren R, Kuzu I, Dunnill M, Harris A, Lane D, Gatter KC (1992) The relationship of p53 immuostaining to survival in carcinoma of the lung. Br J Cancer 66:735–738

    Google Scholar 

  24. Bell SM, Scott N, Cross D, Sagar P, Lewis FA, Blair GE, Taylor GR, Dixon MF, Quirke P (1993) Prognostic value of p53 expression and c-Ki-ras gene mutations in colorectal cancer. Gastroenterology 104:57–64

    CAS  PubMed  Google Scholar 

  25. Seshadri R, Leong ASY, McCaul K, Firgaira FA, Setlur V, Horsfall DJ (1996) Relationship between p53 gene abnormalities and other tumour characteristics in breast cancer prognosis. Int J Cancer 69:135–141

    Google Scholar 

  26. Jansen RL, Joosten-Achjanie SR, Volovics A, Arends JW, Hupperets PS, Hillen HF, Schouten HC (1998) Relevance of the expression of Bcl-2 in combination with p53 as a prognostic factor in breast cancer. Anticancer Res 18:4455–4462

    CAS  PubMed  Google Scholar 

  27. Martin HM, Filipe MI, Morris RW, Lane DP, Silvestre F (1992) p53 expression and prognosis in gastric carcinoma. Int J Cancer 50:859–862

    Google Scholar 

  28. Motojima K, Furui J, Kohara N, Ito T, Kanematsu T (1994) Expression of p53 protein in gastric carcinomas is not independently prognostic. Surgery 116:890–895

    CAS  PubMed  Google Scholar 

  29. Aizawa K, Ueki K, Suzuki S, Yabusaki H, Kanda T, Nishimaki T, Suzuki T, Hatakeyama K (1999) Apoptosis and Bcl-2 expression in gastric carcinoma: correlation with clinicopathological variables, p53 expression, cell proliferation and prognosis. Int J Oncol 14:85–91

    Google Scholar 

  30. Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi M, Angeletti CA, Basolo F, Bevilacqua G (1995) Bcl-2 protein: a prognostic factor inversely correlated to p53 in non-small-cell lung cancer. Br J Cancer 71:1003–1007

    PubMed  Google Scholar 

  31. Joensuu H, Pylkkänen L, Toikkanen S (1994) Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191–1198

    CAS  PubMed  Google Scholar 

  32. Hurlimann J, Larrinaga B, Vala DL (1995) bcl-2 protein in invasive ductal breast cancer patients. Virchows Arch 426:163–168

    CAS  PubMed  Google Scholar 

  33. Henriksen R, Wilander E, Oberg K (1995) Expression and prognostic significance of Bcl-2 in ovarian tumours. Br J Cancer 72:1324–1329

    Google Scholar 

  34. Inada T, Kikuyama S, Ichikawa A, Igarashi S, Ogata Y (1998) Bcl-2 expression as a prognostic factor of survival of gastric carcinoma. Anticaner Res 18:2003–2010

    CAS  Google Scholar 

  35. Pietenpol JA, Papadopoulos N, Markowitz S, Willson JKV, Kinzler KW, Vogelstein B (1994) Paradoxical inhibition of solid tumor cell growth by bcl2. Cancer Res 54:3714–3717

    CAS  PubMed  Google Scholar 

  36. Tormanen U, Eerola AK, Rainio P, Vahakangas K, Soini Y, Sormunen R, Bloigu R, Lehto VP, Paakko P (1995) Enhanced apoptosis predicts shortened survival in non-small cell lung carcinoma. Cancer Res 55:5595–5602

    PubMed  Google Scholar 

  37. van Slooten HJ, Clahsen PC, van Dierendonck JH, Duval C, Pallud C, Mandard AM, Delobelle-Deroide A, van de Velde CJ, van de Vijver MJ (1996) Expression of bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy. Br J Cancer 74:78–85

    Google Scholar 

  38. Diebold J, Baretton G, Felchner M, Meier W, Dopfer K, Schmidt M, Lohrs U (1995) Bcl-2 expression, p53 accumulation, and apoptosis in ovarian carcinomas. Am J Clin Pathol 105:341–349

    Google Scholar 

  39. Finlay CA, Hinds PW, Tan T-H, Eliyahu D, Oren M, Levine AJ (1988) Activating mutations for transformation by p53 produce a gene product that form and hsc 70-p53 complex with an altered half-life. Mol Cell Biol 8:531–539

    CAS  PubMed  Google Scholar 

  40. Levine AJ, Momand J, Finlay CA (1991) The p53 tumor suppressor gene. Nature 351:453–456

    CAS  PubMed  Google Scholar 

  41. Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245

    CAS  PubMed  Google Scholar 

  42. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF-1, a potential mediator of p53 tumor suppression. Cell 75:817–825

    CAS  PubMed  Google Scholar 

  43. Marchetti A, Buttitta F, Pellegrini S, Merlo G, Chella A, Angeletti CA, Bevilacqua G (1995) mdm-2 gene amplification and overexpression in non-small cell lung carcinomas with accumulation of the p53 protein in the absence of p53 gene mutation. Diagn Mol Pathol 4:93–97

    CAS  PubMed  Google Scholar 

  44. Starzyska T, Bromley M, Ghosh A, Stern PL (1992) Prognostic significance of p53 overexpression in gastric and colorectal carcinoma. Br J Cancer 66:558–562

    CAS  PubMed  Google Scholar 

  45. Joypaul BV, Hopwood D, Newman EL, Qureshi S, Grant A, Ogston SA, Lane DP, Cuschieri A (1994) The prognostic significance of the accumulation of p53 tumor-suppressor gene protein in gastric adenocarcinoma. Br J Cancer 68:943–946

    Google Scholar 

  46. Maehara Y, Okuyama T, Kakeji Y, Endo K, Yamamoto M, Sugimachi K (1995) A tumor-associated cell-surface glycoprotein accompanying p53 overexpression and higher growth potential for gastric cancer. Br J Cancer 71:999–1002

    Google Scholar 

  47. Mönig SP, Eidt S, Zirbes TK, Stippel D, Baldus SE, Pichlmaier H (1997) p53 expression in gastric cancer. Clinicopathologic correlation and prognostic significance. Dig Dis Sci 42:2463–2467

    Article  PubMed  Google Scholar 

  48. Maehara Y, Tomoda M, Hasuda S, Kabashima A, Tokunaga E, Kakeji Y, Sugimachi K (1999) Prognostic value of p53 protein expression for patients with gastric cancer-multivariate analysis. Br J Cancer 79:1255–1261

    Google Scholar 

  49. Schneider BG, Hilsenbeck SG, Hensel CH, Pekkel V, Shelton CH, Rodriguez-Martinez HA, Gutierrez-Diaz ME, Pulitzer DR, Allred DC (1994) p53 mutations in gastric and colorectal cancers in Texas Hispanics versus Anglos. Virchows Arch 424:187–193

    CAS  PubMed  Google Scholar 

  50. Gabbert HE, Müller W, Schneiders A, Meier S, Hommel G (1995) The relationship of p53 expression to the prognosis of 418 patients with gastric carcinoma. Cancer 76:720–726

    CAS  PubMed  Google Scholar 

  51. Shiao YH, Palli D, Buzard GS, Caporaso NE, Amorosi A, Saieva C, Fraumeni JF Jr, Anderson LM, Rice JM (1998) Implications of p53 mutation spectrum for cancer etiology in gastric cancers of various histologic types from a high-risk area of central Italy. Carcinogenesis 19:2145–2149

    Article  CAS  PubMed  Google Scholar 

  52. Roviello F, Marrelli D, Vindigni C, De Stefano A, Spina D, Pinto E (1999) p53 accumulation is a prognostic factor in intestinal-type gastric carcinoma but not in the diffuse type. Ann Surg Oncol 6:739–745

    CAS  PubMed  Google Scholar 

  53. Lee WJ, Shun CT, Hong RL, Wu MS, Chang KJ, Chen KM (1998) Overexpression of p53 predicts shorter survival in diffuse type gastric cancer. Br J Surg 85:1138–1142

    Article  CAS  PubMed  Google Scholar 

  54. Haldar S, Negrini M, Monne M, Sabbioni S, Croce CM (1994) Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res 54:2095–2097

    CAS  PubMed  Google Scholar 

  55. Watson AJ, Merritt AJ, Jones LS, Askew JN, Anderson E, Becciolini A, Balzi M, Potten CS, Hickman JA (1996) Evidence of reciprocity of bcl-2 and p53 expression in human colorectal adenomas and carcinomas. Br J Cancer 73:889–895

    Google Scholar 

  56. Kaklamanis L, Savage A, Whitehouse R, Doussis-Anagnostopoulou I, Biddolph S, Tsiotos P, Mortensen N, Gatter KC, Harris AL (1998) Bcl-2 protein expression: association with p53 and prognosis in colorectal cancer. Br J Cancer 77:1864–1869

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This study was supported by the Korean Foundation for Cancer Research Grant No. 20-12-4.

Author information

Author notes

  1. Hyeon Kook Lee

    Present address: Department of Surgery, College of Medicine, Ewha Womans University, Seoul, Korea

Authors and Affiliations

  1. Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, 110-744, Seoul, Korea

    Hyeon Kook Lee, Hye Seung Lee, Han-Kwang Yang, Woo Ho Kim, Kuhn Uk Lee, Kuk Jin Choe & Jin-Pok Kim

  2. Department of Surgery, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, 110-744, Seoul, Korea

    Hyeon Kook Lee, Han-Kwang Yang, Kuhn Uk Lee & Kuk Jin Choe

  3. Department of Pathology, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, 110-744, Seoul, Korea

    Hye Seung Lee & Woo Ho Kim

Authors
  1. Hyeon Kook Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hye Seung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Han-Kwang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Woo Ho Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kuhn Uk Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kuk Jin Choe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jin-Pok Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Han-Kwang Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, H.K., Lee, H.S., Yang, HK. et al. Prognostic significance of Bcl-2 and p53 expression in gastric cancer. Int J Colorectal Dis 18, 518–525 (2003). https://doi.org/10.1007/s00384-003-0491-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-003-0491-2

Keywords

Search

Navigation