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Frequency and spectrum of p53 mutations in gastric cancer — a molecular genetic and immunohistochemical study

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Abstract

The p53 tumour-suppressor gene plays an important role in gastric carcinogenesis. In an analysis of the spectrum of mutations of the p53 gene seen in 56 primary gastric carcinomas of various types and grades of differentiation, the entire coding sequence (exons 2–11) of the p53 gene was screened by single-strand conformation polymorphism analysis and direct genomic sequencing of polymerase chain reaction products. Intragenic restriction site polymorphisms and the probe YNZ22 were used for the detection of loss of heterozygosity (LOH) of the p53 gene locus on chromosome 17p. p53 overexpression was studied with the anti-p53 antibody CM-1. A total of 21 somatic alterations of the p53 gene were found. Twenty were base-pair substitutions, and one was an eight base-pair deletion. Six tumours with p53 mutations revealed LOH. Abnormalities in p53 expression were found in 17 tumour samples, of which 16 had gene mutations. The spectrum of mutations observed was consistent with the predicted spectrum for dietary mutagens associated with the metabolism of nitrogenous compounds, resulting in deamination of nucleic acids. Our findings suggest that p53 could be a primary target for mutations associated with dietary carcinogens in gastric carcinogenesis.

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References

  1. Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Wilson JKV, Hamilton S, Vogelstein B (1990) p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 50:7717–7722

    Google Scholar 

  2. Bankfalvi A, Riehemann K, Öfner D, Checci R, Morgan JM, Piffko J, Böcker W, Jasani B, Schmid KW (1994) Feuchtes Autoklavieren — Der einfachere Weg zur Antigendemaskierung. Pathologe 15:345–349

    Google Scholar 

  3. Bettendorf U (1984) Barrett-Syndrom (lower esophagus lined with columnar epithelium). In: Remmele W (ed) Pathologie 2: Verdauungsorgane einschließlich exokrines Pankreas, Leber, Gallenwege, Peritoneum, Retroperitoneum, Hernien. Springer, Berlin Heidelberg New York, pp 115–118

    Google Scholar 

  4. Bishop JM (1987) The molecular genetics of cancer. Science 235:305–311

    Google Scholar 

  5. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689 [published erratum appears in Cancer Res (1990); 50:1352]

    Google Scholar 

  6. Bos JL, Verlaan-de Vries M, Marshall CJ, Veeneman GH, Boom JH van, Eb AJ van der (1986) A human gastric carcinoma contains a single mutated and an amplified normal allele of the Ki-ras oncogene. Nucleic Acids Res 14:1209–1217

    Google Scholar 

  7. Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic diseae. Hum Genet 78:151–155

    Google Scholar 

  8. Correa P (1992) Human gastric carcinogenesis: A multistep and multifactoral process — first American cancer society award lecture on cancer epidemiology and prevention. Cancer Res 52:6735–6740

    Google Scholar 

  9. Coulondre C, Miller JH, Farabaugh PJ, Gilbert W (1978) Molecular basis of base substitution hotspots in Eschericia coli. Nature 274:775–780

    Google Scholar 

  10. Dockhorn-Dworniczak B, Poremba C, Dantcheva R, Stücker A, Brömmelkamp E, Blasius S, Mellin W, Roessner A, Yandell DW, Böcker W (1994) Rapid detection of loss of heterozygosity of chromosome 17p by polymerase chain reaction-based variable number of tandem repeat analysis and detection of single-strand conformation polymorphism of intragenic p53 polymorphisms. Virchows Arch 424:337–342

    Google Scholar 

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

    Google Scholar 

  12. Finlay CA, Hinds PW, Tan TH, Eliyahu D, Oren M, Levine AJ (1988) Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with altered half-life. Mol Cell Biol 8:531–539

    Google Scholar 

  13. Harris CC, Hollstein M (1993) Clinical implications of the p53 tumor-suppressor gene (review article). New Engl J Med 329:1318–1327

    Google Scholar 

  14. Hattori Y, Odagiri H, Nakatani H, Miyagawa K, Naito K, Sakamoto H, Katoh O, Yoshida T, Sugimura T, Terada M (1990) K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth-factor receptor genes. Proc Natl Acad Sci USA 87:5983–5987

    Google Scholar 

  15. Hollstein MC, Metcalf RA, Welsh JA, Montesano R, Harris CC (1990) Frequent mutation of the p53 gene in human esophageal cancer. Proc Natl Acad Sci USA 87:9958–9961

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Jiang W, Kahn SM, Guillem JG, Lu SH, Weinstein IB (1989) Rapid detection of ras oncogenes in human tumors: applications to colon, esophagous, and gastric cancer. Oncogene 4:923–928

    Google Scholar 

  18. Joypaul BV, Newman EL, Hopwood D, Grant A, Qureshi S, Lane DP, Cuschieri A (1993) Expression of p53 protein in normal, dysplastic, and malignant gastric mucosa: an immunohistochemical study. J Pathol 170:279–283

    Google Scholar 

  19. Kakeji Y, Korenaga D, Tsujitani S, Baba H, Anai H, Maehara Y, Sugimachi K (1993) Gastric cancer with p53 overexpression has high potential for metastasising to lymph nodes. Br J Cancer 67:589–593

    Google Scholar 

  20. Kappes S, Milde-Langosch K, Kressin P, Passlack B, Dockhorn-Dworniczak B, Röhlke P, Löning T (1995) p53 mutations in ovarian tumors- detected by temperature gradient gel electrophoresis, direct sequencing and immunohistochemistry. Int J Cancer 64:52–59

    Google Scholar 

  21. Kim JH, Takahashi T, Chiba I, Park JG, Birrer MJ, Roh JK, Lee HD, Kim JP, Minna JD, Gazdar AF (1991) Occurrence of p53 gene abnormalities in gastric carcinoma tumors and cell lines. J Natl Cancer Inst 83:938–943

    Google Scholar 

  22. Kneller RW, You WC, Chang YS, Liu WD, Zhang L, Zhao L, Xu GW, Fraumeni JF Jr, Blot WJ (1992) Cigarette smoking and other risk factors for progression of precancerous stomach lesions. J Natl Cancer Inst 84:1261–1266

    Google Scholar 

  23. Kraiss S, Spiess S, Reihsaus E, Montnarh M (1991) Correlation of metabolic stability and altered quaternary structure of oncoprotein p53 with cell transformation. Exp Cell Res 192:157–164

    Google Scholar 

  24. Kupryjanczyk J, Beauchamp R, Thor AD, Merritt V, Edgerton SM, Bell DA, Yandell DW (1993) p53 gene mutations and protein accumulation in human ovarian cancer. Proc Natl Acad Sci USA 90:4961–4965

    Google Scholar 

  25. Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand 64:31–49

    CAS  PubMed  Google Scholar 

  26. Levine AJ (1990) Tumor suppressor genes. Bioessays 12:60–66

    Google Scholar 

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

    Google Scholar 

  28. Maniatis T, Fritsch J, Sambrook J (eds) (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Press, pp 280–281

  29. 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 

  30. Mathlashewski GJ, Tuck S, Pim D, Lamb P, Schneider J, Crawford LV (1987) Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol 7:961–963

    Google Scholar 

  31. Matozaki T, Sakamoto C, Matsuda K, Suzuki T, Konda Y, Nakano O, Wada K, Uchida T, Nishisaki H, Nagao M, Kasuga M (1992) Missense mutations and a deletion of the p53 gene in human gastric cancer. Biochem Biophys Res Commun 182:215–223

    Google Scholar 

  32. Matozaki T, Sakamoto C, Suzuki T, Matsuda K, Uchida T, Nakano O, Wada K, Nishisaki H, Konda Y, Nagao M, Kasuga M (1992) p53 gene mutations in human gastric cancer: Wildtype p53 but not mutant p53 suppresses growth of human gastric cancer cells. Cancer Res 52:4335–4341

    Google Scholar 

  33. Milner J, Medcalf E, Cook A (1991) Tumor suppressor p53: analysis of wild-type and mutant p53 complexes. Mol Cell Biol 11:12–19

    Google Scholar 

  34. Ming SC (1977) Gastric carcinoma: a pathobiological classification. Cancer 39:2475–2485

    CAS  PubMed  Google Scholar 

  35. Mirvish SS (1971) Kinetics of nitrosamide formation from alkylureas, n-alkylurethans, and alkylguanidines: possible implications for the etiology of human gastric cancer. J Natl Cancer Inst 46:1183–1193

    Google Scholar 

  36. 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

    Google Scholar 

  37. Nakasoto F, Sakamoto H, Mori M, Hayashi K, Shimosato Y, Nishi M, Takao S, Nakatani K, Terada M, Sugimura T (1984) Amplification of the c-myc oncogene in human stomach cancers. Gann 75:737–742

    Google Scholar 

  38. Nakatsuru S, Yanagisawa A, Ichii S, Tahara E, Kato Y, Nakamura Y, Horii A (1992) Somatic mutation in the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma. Hum Mol Genet 1:559–563

    Google Scholar 

  39. Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR (1992) DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci USA 89:3030–3034

    Google Scholar 

  40. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B (1989) Mutations in the p53 gene occur in diverse human tumor types. Nature 342:705–708

    Google Scholar 

  41. Oota K (ed) (1977) Histological typing of gastric and oesophageal tumours. International histological classification of tumours, number 18. Geneva, World Health Organisation

    Google Scholar 

  42. Poremba C, Yandell DW, Spiro IJ, Heidl G, Böcker W, Dockhorn-Dworniczak B (1994) Hypervariable Regionen (HVR) als genetische Marker in the Tumordiagnostik — Methodische Grundlagen und ihre Anwendung in der pathologischen Diagnostik. Pathologe 15:113–118

    Google Scholar 

  43. Remmele W (1984) Bösartige epitheliale Tumoren/Magenkarzinom. In: Remmele W (ed) Pathologie 2: Verdauungsorgane einschließlich exokrines Pankres, Leber, Gallenwege, Peritoneum, Retroperitoneum, Hernien. Springer, Berlin Heidelberg New York, pp 213–215

    Google Scholar 

  44. Renauld B, Broek M van den, Fodde R, Wijnen J, Pellegata NS, Amadori D, Khan PM, Ranzani GN (1993) Base transitions are the most frequent genetic changes at p53 in gastric cancer. Cancer Res 53:2614–2617

    Google Scholar 

  45. Rideout WM III, Coetzee GA, Olumi AF, Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249:1288–1290

    Google Scholar 

  46. Rodrigues NR, Rowan A, Smith MEF, Kerr IB, Bodmer WF, Gannon JV, Lane DP (1990) p53 mutations in colorectal cancer. Proc Natl Acad Sci USA 87:7555–7559

    Google Scholar 

  47. Sano T, Tsujino T, Yoshida K, Nakayama H, Haruma K, Itoh H, Nakamura Y, Kajiyama G, Tahara E (1991) Frequent loss of heterozygosity on chromosomes 1q, 5q and 17p in human gastric carcinoma. Cancer Res 51:2926–2931

    Google Scholar 

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

    Google Scholar 

  49. Seruca R, David L, Holm R, Nesland JM, Fangan BM, Castedo S, Sobrinho-Simoes M, Borresen AL (1992) p53 mutations in gastric carcinomas. Br J Cancer 65:708–710

    Google Scholar 

  50. Shimaya K, Shiozaki H, Inoue M, Tahara H, Monden T, Shimano T, Mori T (1993) Significance of p53 expression as a prognostic factor in oesophageal squamous cell carcinoma. Virchows Arch [A] 422:271–276

    Google Scholar 

  51. Soussi T, Caron de Fromentel C, May P (1990) Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5:945–952

    Google Scholar 

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

    Google Scholar 

  53. Sugimura T, Fujimura S, Baba T (1970) Tumor production in the glandular stomach and alimentary tract of the rat by N-methyl-N'-nitro-N-nitrosoguanidine. Cancer Res 30:455–465

    Google Scholar 

  54. Tamura G, Kihana T, Nomura K, Terada M, Sugimura T, Hirohashi S (1991) 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

    Google Scholar 

  55. Thodo H, Yokozaki H, Haruma K, Kajiyama G, Tahara E (1993) p53 gene mutations in gastric adenomas. Virchows Arch [B] 63:191–195

    Google Scholar 

  56. Thor AD, Moore DH, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch HT, Marcus JN, Schwartz L, Chen LC, Mayall BH, Smith HS (1992) Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 84:845–855

    Google Scholar 

  57. Toguchida J, Yamaguchi T, Ritchie B, Beauchamp RL, Dayton SH, Herrera GE, Yamamuro T, Kotoura Y, Sasaki MS, Little JB, Weichselbaum RR, Ishizaki K, Yandell DW (1992) Mutation spectrum of the p53 gene in bone and soft tissue sarcomas. Cancer Res 52:6194–6199

    Google Scholar 

  58. Weinberg RA (1989) Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res 49:3713–3721

    Google Scholar 

  59. Wright PA, Williams GT (1993) Molecular biology and gastric carcinoma. Gut 34:145–147

    Google Scholar 

  60. Yamada Y, Yoshida T, Hayashi K, Sekiya T, Yokota J, Hirohashi S, Nakatani K, Nakano H, Sugimura T, Terada M (1991) p53 gene mutations in gastric cancer metastases and in gastric cancer cell lines derived from metastases. Cancer Res 51:5800–5805

    Google Scholar 

  61. Yandell DW, Dryja TP (1989) Detection of DNA sequence polymorphisms by enzymatic amplification and direct genomic sequencing. Am J Hum Genet 45:547–555

    Google Scholar 

  62. Yandell DW, Thor AD (1993) p53 analysis in diagnostic pathology — biologic implications and possible clinical applications. Diagn Mol Pathol 2:1–3

    Google Scholar 

  63. Yokota J, Yamamoto T, Miyajima N, Toyoshima K, Nomura N, Sakamoto H, Yoshida T, Terada M, Sugimura T (1988) Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by amplification of the v-erbA homologue. Oncogene 2:283–287

    Google Scholar 

  64. Yokozaki H, Kuniyasu H, Kitadai Y, Nishimura K, Todo H, Ayhan A, Yasui W, Ito H, Tahara E (1992) p53 point mutations in primary human gastric carcinomas. J Cancer Res Clin Oncol 119:67–70

    Google Scholar 

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Authors and Affiliations

  1. Gerhard-Domagk-Institute of Pathology, Westfälische Wilhelms University, Domagkstrasse 17, D-48149, Münster, Germany

    C. Poremba, K. Schmid, W. Böcker & B. Dockhorn-Dworniczak

  2. Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts, USA

    C. Poremba, D. Yandell & J. Little

  3. Department of Pathology, University of Vermont, Burlington, Vermont, USA

    D. Yandell & Q. Huang

  4. Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany

    W. Mellin

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  1. C. Poremba
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Poremba, C., Schmid, K., Böcker, W. et al. Frequency and spectrum of p53 mutations in gastric cancer — a molecular genetic and immunohistochemical study. Vichows Archiv A Pathol Anat 426, 447–455 (1995). https://doi.org/10.1007/BF00193167

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  • DOI: https://doi.org/10.1007/BF00193167

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