Digestive Diseases and Sciences

, Volume 47, Issue 1, pp 114–121 | Cite as

p53 Mutation Pattern and Expression of c-erbB2 and c-met in Gastric Cancer: Relation to Histological Subtypes, Helicobacter pylori Infection, and Prognosis

  • Stefan Kubicka
  • Christiane Claas
  • Sven Staab
  • Florian Kühnel
  • Lars Zender
  • Christian Trautwein
  • Siegfried Wagner
  • Karl Lenhard Rudolph
  • Michael Manns


The molecular mechanisms of Helicobacter pylori associated tumor development are poorly understood. The spectra of genetic alterations in neoplasms may provide clues to the molecular carcinogenesis of a tumor and may be relevant for the prognosis of the patients. We investigated the p53 mutation pattern and the protein expression of p53, c-erbB2, and c-met in 42 gastric cancers and correlated these alterations with H. pylori infection, histological subtypes and survival of the patients after curative resection. There were no differences in the incidences of the expression of p53, c-erbB2, and c-met in the tumor tissues according to H. pylori infection. Fifteen p53 mutations in 12 (29%) tumors were identified. More p53 mutations were found in patients with positive serology for H. pylori (43% vs 14%). This difference was not significant, but the small sample size may be insufficient to detect a potential statistical difference. There was neither a H. pylori-associated p53 hot-spot codon mutation nor a H. pylori characteristic mutational pattern of p53. Positive lymph nodes (P = 0.0061) and p53 mutations (P = 0.0035) were the only significant bad prognostic markers for survival after curative resection of the gastric cancers in our study. Our study does not indicate a unique molecular mechanism of p53 mutagenesis through H. pylori infection. The fact that p53 mutations were significantly correlated with poor survival of patients after potentially curative resection of gastric cancer may have clinical implications for multimodal therapies.

gastric cancer Helicobacter pylori p53 mutations prognostic factor 


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  1. 1.
    Fuchs CS, Mayer RJ: Gastric carcinoma. N Engl J Med 333:32–41, 1995Google Scholar
  2. 2.
    Lauren P: The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Micobiol Immunol Scand 64:31–49, 1965Google Scholar
  3. 3.
    Correa P: Human gastric carcinogenesis: A multistep and multifactorial progress. Cancer Res 52:6735–6740, 1992Google Scholar
  4. 4.
    Forman D, Newwell DG, Fullerton F, Yarnell JW, Stacey AR, Wald N, Sitas F: Association between infection with Helicobacter pylori and risk of gastric cancer: Evidence from a prospective investigation. BMJ 302:1302–1305, 1991Google Scholar
  5. 5.
    Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK: Helicobacter pylori infection and risk of gastric carcinoma. N Engl J Med 325:1127–1131, 1991Google Scholar
  6. 6.
    Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ: Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Wawaii. N Engl J Med 325:1132–1136, 1991.Google Scholar
  7. 7.
    The EUROGAST Study Group: An international association between Helicobacter pylori infection and gastric cancer. Lancet 341:1359–1362, 1993Google Scholar
  8. 8.
    Tredaniel J, Boffetta P, Buiatti E, Saracci R, Hirsch A: Tobacco smoking and gastic cancer: Review and meta-analysis. Int J Cancer 72:565–573, 1997Google Scholar
  9. 9.
    Huang JQ, Sridhar S, Chen Y, Hunt RH: Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 114:1169–1179, 1998Google Scholar
  10. 10.
    Bechi P, Balzi M, Becciolini A, Maugeri A, Raggi CC, Amorosi A, Die R: Helicobacter pylori and cell proliferation of the gastric mucosa: Possible implications for gastric carcinogenesis. Am J Gastroenerol 91:271–276, 1996Google Scholar
  11. 11.
    Anti M, Armuzzi A, Gasbarrini A, Gasbarrini G: Importance of the chances in epithelial cell turnover during Helicobacter pylori infection in gastric carcinogenesis. Gut 43(suppl 1):S27–S32, 1998Google Scholar
  12. 12.
    Hongyo T, Buzard GS, Palli D, Weghorst CM, Amorosi A, Galli M, Caporaso NE, Fraumeni JF, Rice JM: Mutations of the K-ras and p53 genes in gastric adenocarcinomas from a high incidence region around Florence, Italy. Cancer Res 55:2665–2672, 1995Google Scholar
  13. 13.
    Shun CT, Wu MS, Lin JT, Chen SY, Wang HP, Lee WJ, Wang TH, Chuang SM: Relationship of p53 and c-erbB2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. Hepato-Gastroenterology 44:604–609, 1997Google Scholar
  14. 14.
    Wu MS, Shun CT, Wang HP, Sheu JC, Lee WJ, Wang TH, Lin JT: Genetic alterations in gastric cancer: Relation to histological subtypes, tumor stage, and Helicobacter pylori infection. Gastroenterology 112:1457–1465, 1997Google Scholar
  15. 15.
    Blok P, Craanen ME, Offerhaus GJ, Dekker W, Kuipers EJ, Meuwissen SG, Tytgat GN: Molecular alterations in early gastric carcinomas. Am J Clin Pathol 111:241–247, 1999Google Scholar
  16. 16.
    Stemmermann G, Heffelfinger SC, Noffsinger A, Hui YZ, Miller MA, Fenoglio-Preiser CM: The molecular biology of esophageal and gastric cancer and their precursors: Oncogenes, tumor suppressor genes, and growth factors. Hum Pathol 25:968–981, 1994Google Scholar
  17. 17.
    Yonemura Y, Ninomiya I, Yamaguchi A, Fushida S, Kimura H, Ohoyama S, Miyazaki I, Endou Y, Tanaka M, Sasaki T: Evaluation of immunoreactivity for erbB2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res 51:1034–1038, 1991Google Scholar
  18. 18.
    Motojima K, Furui J, Kohara N, Izawa K, Kanematsu T, Shiku H: erbB2 expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. Surgery 115:349–354, 1994Google Scholar
  19. 19.
    Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E: Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem Biophys Res Commun 189:227–232, 1992Google Scholar
  20. 20.
    Nakajima M, Sawada H, Yamada Y, Watanabe A, Tatsumi M, Yamashita J, Matsuda M, Sakaguchi T, Hirao T, Nakano H: The prognostic significance of amplification and overexpression of the c-met and the c-erbB2 in human gastric carcinomas. Cancer 85:1894–1902, 1999Google Scholar
  21. 21.
    Taniguchi K, Yonemura Y, Nojima N, Hirono Y, Fushida S, Fujimura T, Miwa K, Endo Y, Yamamoto H, Watanabe H: The relation between the growth pattern of gastric carcinoma and the expression of hepatocyte growth factor receptor (cmet), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor. Cancer 82:2112–2122, 1998Google Scholar
  22. 22.
    Hollstein M, Sidransky D, Vogelstein B: p53 mutations in human cancer. Science 253:49–53, 1991Google Scholar
  23. 23.
    Levine AJ, Momand J, Finlay CA: The p53 tumor suppressor gene. Nature 351:453–456, 1991Google Scholar
  24. 24.
    Kim JH, Takahashi T, Chiba I, Park JG, Birrer MJ, Roh JK, De Lee H, Kim JP, Minna JD, Gazdar AF: Occurrence of p53 gene abnormalities in gastric carcinoma tumors and cell lines. J Natl Cancer Inst 83:938–943, 1991Google Scholar
  25. 25.
    Tamura G, Kihana T, Nomura K, Terada M, Sugimura T, Hirohashi S: Detection of frequent p53 gene mutations in primary gastric cancer by cell sorting and polymerase chain reaction single-strand conformation polymorphism analysis. Cancer Res 51:3056–3058, 1991Google Scholar
  26. 26.
    Imazeki F, Omata M, Nose H, Ohto M, Isono K: p53 gene mutations in gastric and esophageal cancers. Gastroenterology 103:892–896, 1992Google Scholar
  27. 27.
    Matozaki T, Sakamoto C, Matsuda K, Suzuki T, Konda Y, Nakano O, Wada K, Uchida T, Nishisaki H, Nagao M: Missense mutations and a deletion of the p53 gene in human gastic cancer. Biochem Biophys Res Commun 182:215–223, 1992Google Scholar
  28. 28.
    Seruca R, David L, Holm R, Nesland JM, Fangan BM, Castedo S, Sobrinho-Simoes M, Borresen AL: p53 mutations in gastric carcinomas. Br J Cancer 65:708–710, 1992Google Scholar
  29. 29.
    Yokozaki H, Kuniyasu H, Kitadai Y, Nishimura K, Todo H, Ayhan A, Yasui W, Ito H, Tahara E: p53 point mutations in primary human gastric carcinomas. J Cancer Res Clin Oncol 119:67–70, 1992Google Scholar
  30. 30.
    Renault B, van den Broek M, Fodde R, Wijnen J, Pellegata NS, Amadori D, Khan PM, Ranzani GN: Base transitions are the most frequent genetic chenges at p53 in gastric cancer. Cancer Res 53:2641–2617, 1993Google Scholar
  31. 31.
    Uchino S, Noguchi M, Ochiai A, Saito T, Kobayashi M, Hirohashi S: p53 mutation in gastric cancer: A genetic model for carcinogenesis is common to gastric and colorectal cancer. Int J Cancer 54:759–764, 1993Google Scholar
  32. 32.
    Greenblatt MS, Bennett WP, Hollstein M, Harris CC: Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878, 1994Google Scholar
  33. 33.
    Beroud C, Verdier F, Soussi T: p53 gene mutation: Software and database. Nucleic Acids Res 1996; 24:147–150Google Scholar
  34. 34.
    Murakami K, Fujioka T, Okimoto T, Mitsuishi Y, Oda T, Nishizono A, Nasu M: Analysis of p53 gene mutations in Helicobacter pylori-associated gastritis mucosa in endoscopic biopsy specimens. Scand J Gastroenterol 34:474–477, 1999Google Scholar
  35. 35.
    Sipponen P, Kosunen TU, Valle J, Riihela M, Seppala K: Helicobacter pylori infection and chronic gastritis in gastric cancer. J Clin Pathol 45:319–323, 1992Google Scholar
  36. 36.
    Hu PJ, Mitchel HM, Li YY, Zhou MH, Hazell SL: Association of Helicobacter pylori with gastric cancer and observations on the detection of this bacterium in gastric cancer cases. Am J Gastroenterol 89:1806–1810, 1994Google Scholar
  37. 37.
    Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61:759–767, 1990Google Scholar
  38. 38.
    Barrett MT, Sanchez CA, Prevo LJ, Wong DJ, Galipeau PC, Paulson TG, Rabinovitch PS, Reid BJ: Evolution of neoplastic cell lineages in Barrett oesophagus. Nature Genetics 22:106–109, 1999Google Scholar
  39. 39.
    Kodama M, Fujioka T, Kodama R, Takahashi K, Kubota T, Murakami K, Nasu M: p53 expression in gastric mucosa with Helicobacter pylori infection. J Gastroenterol Hepatol 13:215–219, 1998Google Scholar
  40. 40.
    Martin HM, Filipe MI, Morris RW, Lane DP, Silvestre F: P53 expression and prognosis in gastric carcinoma. Int J Cancer 50:859–862, 1992Google Scholar
  41. 41.
    Starzynska T, Bromley M, Ghosh A, Stern PL: Prognostic significance of p53 overexpression in gastric and colorectal carcinoma. Br J Cancer 66:558–562, 1992Google Scholar
  42. 42.
    Sasano H, Date F, Imatani A, Asaki S, Nagura H: Double immunostaining for c-erbB2 and p53 in human stomach cancer cells. Hum Pathol 24:584–589, 1993Google Scholar
  43. 43.
    Lim BH, Soong R, Grieu F, Robbins PD, House AK, Iacopetta BJ: p53 accumulation and mutation are prognostic indicators of poor survival in human gastric carcinoma. Int J Cancer 69:200–204, 1996Google Scholar
  44. 44.
    Tsugawa K, Yonemura Y, Hirono Y, Fushida S, Kaji M, Miwa K, Miyazaki I, Yamamoto H: Amplification of the c-met, c-erbB2 and epidermal growth factor gene in human gastric cancers: correlation to clinical features. Oncology 55:475–481, 1998Google Scholar
  45. 45.
    Jain S, Filipe MI, Gullick WJ, Linehan J, Morris RW: C-erbB2 protooncogene expression and its relationship to survival in gastric carcinoma: An immunohistochemical study on archival material. Int J Cancer 48:668–671, 1991Google Scholar
  46. 46.
    Yonemura Y, Ninomiya I, Ohoyama S, Kimura H, Yamaguchi A, Fushida S, Kosaka T, Miwa K, Miyazaki I, Endou Y: Expression of c-erbb2 oncoprotein in gastric carcinoma. Cancer 67:2914–2918, 1991Google Scholar
  47. 47.
    Hilton DA, West KP: C-erbB2 oncogene product expression and prognosis in gastric carcinoma. J Clin Pathol 45:454–456, 1992Google Scholar
  48. 48.
    Uchino S, Tsuda H, Maruyama K, Kinoshita T, Sasako M, Saito T, Kobayashi M, Hirohashi S: Overexpression of c-erbB2 protein in gastric cancer its correlation with long term survival of patients. Cancer 72:3179–3148, 1993Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Stefan Kubicka
    • 1
  • Christiane Claas
    • 1
  • Sven Staab
    • 1
  • Florian Kühnel
    • 1
  • Lars Zender
    • 1
  • Christian Trautwein
    • 1
  • Siegfried Wagner
    • 1
  • Karl Lenhard Rudolph
    • 1
  • Michael Manns
    • 1
  1. 1.Department of Gastroenterology and HepatologyMedizinische HochschuleHannoverGermany

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