Skip to main content
SpringerLink
Log in

The clinical significance of p53 aberrations in human tumours

  • Review Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

p53 aberrations are the most common genetic alteration found in human tumours and this review summarizes the current understanding of the clinical significance of p53 abnormalities. Immunohistochemical and molecular techniques can demonstrate alterations at the protein and gene level, respectively, but with a significant discordance between the findings of either technique. The tumours evaluated in this review include cancers of the breast, lung, gastrointestinal tract, genitourinary tract, and others. In most cases, only data on p53 protein are available and in each of these tumour types discrepant conclusions on the clinical value of p53 abnormalities as prognostic indicators have been reached. The role of p53 in the context of anticancer adjuvant therapy has also been analysed. Experimental data suggest that p53 affects the apoptotic response to anticancer agents, but this has not yet been proven in a clinical series where this demonstration and its effect on therapy could represent one of the most important endpoints in p53 clinical research. The use of standardized techniques to evaluate p53 gene mutation and protein accumulation within controlled clinical series of patients entering prospective trials is essential to answer the many remaining questions on the clinical significance of p53 aberrations.

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

Similar content being viewed by others

References

  1. Ahomadegbe JC, Barrois M, Fogel S, LeBihan ML, DoucRasy S, Duvillard P, Armand JP, Riou G (1995) High incidence of p53 alterations (mutation, deletion, overexpression) in head and neck primary tumors and metastases; absence of correlation with clinical outcome. Frequent protein overexpression in normal epithelium and in early non-invasive lesions. Oncogene 10:1217–1227

    Google Scholar 

  2. Allred DC, Clark GM, Elledge R, Fuqua SAW, Brown RW, Chamness GC, Osborne CK (1993) Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst 85:200–206

    Google Scholar 

  3. Andersen TI, Holm R, Nesland JM, Heimdal KR, Ottestad L, Borresen AL (1993) Prognostic significance of TP53 in breast carcinoma. Br J Cancer 68:540–548

    Google Scholar 

  4. Baas IO, Mulder IR, Offerhaus JA, Vogelstein B, Hamilton SR (1994) An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms. J Pathol 172:5–12

    Google Scholar 

  5. Barnes DM, Dublin EA, Fisher CJ, Levison DA, Millis RR (1993) Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum Pathol 24:469–476

    Google Scholar 

  6. Batsakis JG, El-Naggar AK (1995) p53: Fifteen years after discovery. Adv Anat Pathol 2:71–88

    Google Scholar 

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

    Google Scholar 

  8. Benhattar J, Losi L, Chaubert P, Givel J-C, Costa J (1993) Prognostic significance of k-ras mutations in colorectal carcinomas. Gastroenterology 104:1044–1048

    Google Scholar 

  9. Bodmer W, Bishop T, Karran P (1994) Genetic steps in colorectal cancer. Nat Genet 6:217–219

    Google Scholar 

  10. Bodner SM, Minna JD, Jensen SM, D'Amico D, Carbone D, Mitsudomi T, Fedorko J, Buchhagen DL, Nau MM, Gazdar AF, Linnolila RI (1992) Expression of mutant p53 proteins in lung cancer correlates with the class of p53 mutations. Oncogene 7:743–749

    Google Scholar 

  11. Bosari S, Lee AKC, Viale G, Heatley GJ, Coggi G (1992) Abnormal p53 immunoreactivity and prognosis in node-negative breast carcinomas with long-term follow-up. Virchows Arch [A] 421:291–295

    Google Scholar 

  12. Bosari S, Roncalli M, Viale G, Bossi P, Coggi G (1993) p53 immunoreactivity in inflammatory and neoplastic diseases of the uterine cervix. J Pathol 169:425–430

    Google Scholar 

  13. Bosari S, Viale G, Radaelli U, Bossi P, Bonoldi E, Coggi G (1993) p53 accumulation in ovarian carcinomas and its prognostic implications. Hum Pathol 24:1175–1179

    Google Scholar 

  14. Bosari S, Viale G, Bossi P, Maggioni M, Coggi G, Murray JJ, Lee AKC (1994) Cytoplasmic accumulation of p53 protein: an independent prognostic indicator in colorectal adenocarcinomas. J Natl Cancer Inst 86:681–687

    Google Scholar 

  15. Bosari S, Moneghini L, Graziani D, Lee AKC, Murray JJ, Coggi G, Viale G (1995) bcl-2 oncoprotein in colorectal hyperplastic polyps, adenomas and adenocarcinomas. Hum Pathol 26:534–540

    Google Scholar 

  16. Bosari S, Marchetti A, Buttitta F, Graziani D, Borsani G, Loda M, Bevilacqua G, Coggi G (1995) Detection of p53 mutations by single-strand conformation polymorphisms (SSCP) gel electrophoresis: a comparative study of radioactive and non-radioactive silver-stained SSCP analysis. Diagn Mol Pathol (in press)

  17. Bosari S, Viale G, Roncalli M, Graziani D, Borsani G, Lee AKC, Coggi G (1995) p53 gene mutations, p53 protein accumulation and compartmentalization in colorectal adenocarcinoma. Am J Pathol 147:790–798

    Google Scholar 

  18. Bot FJ, Godschalk JC, Kirshnadath KK, Kwast TH van der, Bosman FT (1994) Prognostic factors in renal-cell carcinoma: immunohistochemical detection of p53 protein versus clinicopathological parameters. Int J Cancer 57:634–637

    Google Scholar 

  19. Boyle JO, Hakim J, Kock W, Riet P van der, Hruban RH, Roa RA, Correo R, Elby YJ, Ruppert JM, Sidransky D (1993) The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res 53:4477–4480

    Google Scholar 

  20. Bronner MP, Culin C, Reed JC, Furth EE (1995) The bcl-2 proto-oncogene and the gastrointestinal epithelial tumor progression model. Am J Pathol 146:20–26

    Google Scholar 

  21. Bruner JM, Saya H, Moser RP (1991) Immunocytochemical detection of p53 in human gliomas. Mod Pathol 4:671–674

    Google Scholar 

  22. Bruner JM, Connelly JH, Saya H (1993) p53 protein immunostaining in routinely processed paraffin-embedded sections. Mod Pathol 6:189–194

    Google Scholar 

  23. Caleffi M, Teague MW, Jensen RA, Vnencak-Jones C, Dupont WD, Parl FF (1994) p53 gene mutations and steroid receptor status in breast cancer. Clinicopathologic correlations and prognostic assessment. Cancer 73:2147–2156

    Google Scholar 

  24. Chang F, Syrjanen S, Syrjanen K (1995) Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol 13:1009–1022

    Google Scholar 

  25. Cheng J, Haas M (1992) Sensitivity of detection of heterozygous point mutations in p53 cDNAs by direct PCR sequencing. PCR Methods Appl 1:199–201

    Google Scholar 

  26. Chin K-V, Ueda K, Pastan I, Gottesman MM (1992) Modulation of activity of the promoter of the human MDR1 gene by ras and p53. Science 255:459–462

    Google Scholar 

  27. Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH (1993) Thymocytes apoptotis induced by p53 dependent and independent pathways. Nature 362:849–852

    Article  CAS  PubMed  Google Scholar 

  28. Cripps KJ, Purdie CA, Carder PJ, White S, Komine K, Bird CC, Wylie AH (1994) A study of stabilization of p53 protein versus point mutation in colorectal carcinoma. Oncogene 9:2739–2743

    Google Scholar 

  29. Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582–1584

    Google Scholar 

  30. DeiTos AP, Doglioni C, Laurino L, Barbareschi M, Fletcher CDM (1993) p53 protein expression in non-neoplastic lesions and benign and malignant neoplasms of soft tissues. Histopathology 22:45–50

    Google Scholar 

  31. Dive C, Hickman JA (1991) Drug-target interactions: only the first step in commitment to programmed cell death? Br J Cancer 64:192–196

    Google Scholar 

  32. Dobashi Y, Sugimura H, Sakamoto A, Mernyei M, Mori M, Oyama T, Machinami R (1994) Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas. Diagn Mol Pathol 3:9–14

    Google Scholar 

  33. Domagala W, Striker G, Sdzadowska A, Dukowicz A, Harezga B, Osborn M (1994) p53 protein and vimentin in invasive ductal NOS breast carcinoma. Relationship with survival and site of metastases. Eur J Cancer 30:1527–1534

    Google Scholar 

  34. Ebina M, Steinberg SM, Mulshine JL, Linnoila RI (1994) Relationship of p53 overexpression and up-regulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancer. Cancer Res 54:2496–2503

    Google Scholar 

  35. Eliyahu D, Raz A, Gruss P, Givol D, Oren M (1984) Participation of p53 cellular tumor antigen in transformation of normal embryonic cells. Nature 312:646–649

    Google Scholar 

  36. Elledge RM, Fuqua SA, Clark GM, Pujol P, Allred DC (1993) The role and prognostic significance of p53 gene alterations in breast cancer. Breast Cancer Res Treat 27:95–102

    Google Scholar 

  37. Ellison J, Dean M, Goldman D (1993) Efficacy of fluorescent-based PCR-SSCP for detection of point mutations. Biotechniques 15:684–691

    Google Scholar 

  38. Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP, Chen S-C (1994) Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331:1259–1264

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  40. Field JK, Spandidos DA, Malliri A, Gosney JR, Yiagnisis M, Stell PM (1991) Elevated P53 expression correlates with history of heavy smoking in squamous cell carcinoma of the head and neck. Br J Cancer 64:573–577

    Google Scholar 

  41. Finkelstein SD, Sayegh R, Christensen S, Swalsky PA (1993) Genotypic classification of colorectal adenocarcinoma. Biologic behavior correlates with k-ras-2 mutation type. Cancer 71:3827–3838

    Google Scholar 

  42. Finlay CA, Hinds PW, Levine AJ (1989) The p53 proto-oncogene can act as a supressor of transformation. Cell 57:1083–1093

    Google Scholar 

  43. Fox SB, Persad RA, Royds J, Kore RN, Silcocks PB, Collins CC (1993) p53 and c-myc expression in stage A1 prostatic adenocarcinoma: useful prognostic determinants? J Urol 150:490–494

    Google Scholar 

  44. Frank JL, Bur ME, Garb JL, Kay S, Ware JL, Sismanis A, Neifeld JP (1994) p53 tumor suppressor oncogene expression in squamous cell carcinoma of the hypopharynx. Cancer 73:181–186

    Google Scholar 

  45. Friedmann T (1992) Gene therapy of cancer through restoration of tumor-suppressor function? Cancer 70:1810–1817

    Google Scholar 

  46. Fujiwara T, Grimm EA, Mukhopadhyay T, Zhang W-W, Owen-Schaub LB, Roth JA (1994) Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res 54:2287–2291

    Google Scholar 

  47. Fung CY, Fisher DE (1995) p53: from molecular mechanisms to prognosis in cancer (editorial). J Clin Oncol 13:808–811

    Google Scholar 

  48. Furihata M, Inoue K, Ohtsuki Y, Hashimoto H, Terao N, Fujita Y (1993) High-risk human papillomavirus infections and over-expression of p53 protein as prognostic indicators in transitional cell carcinoma of the urinary bladder. Cancer Res 53:4823–4827

    CAS  PubMed  Google Scholar 

  49. Furihata M, Ohtsuki Y, Ogoshi S, Takahashi A, Tamiya T, Ogata T (1993) Prognostic significance of human papillomavirus genome (type-16,-18) and aberrant expression of p53 protein in human esophageal cancer. Int J Cancer 54:226–230

    Google Scholar 

  50. Gapany M, Pavelic ZP, Gapany SR, Pavelic L, Li YG, Craven JM, Jones H, Biddinger P, Stambrook PJ, Gluckman JL (1993) Relationship between immunocytochemically detectable p53 protein and prognostic factors in head and neck tumors. Cancer Detect Prevent 17:379–386

    Google Scholar 

  51. Gasparini G, Weidner N, Bevilacqua P, Maluta S, Dalla Palma P, Caffo O, Barbareschi M, Boracchi P, Marubini E, Pozza F (1994) Tumor microvessel density, p53 expression, tumor size, and peritumoral vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol 12:454–466

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  53. Haerslev T, Jacobsen GK (1995) An immunohistochemical study of p53 with correlations to histopathological parameters, c-erbB-2, proliferating cell nuclear antigen, and prognosis. Hum Pathol 26:295–301

    Google Scholar 

  54. Hamelin R, Laurent-Puig P, Olshwang S, Jego N, Asselain B, Remvikos Y, Girodet J, Salmon RJ, Thomas G (1994) Association of p53 mutations with short survival in colorectal cancer. Gastroenterology 106:42–48

    Google Scholar 

  55. Hanzal E, Gitsch G, Kohlberger P, Dadak C, Miechowiecka N, Breitenecker G (1992) Immunohistochemical detection of mutant p53-suppressor gene product in patients with breast cancer: influence on metastasis-free survival. Anticancer Res 12:2325–2329

    Google Scholar 

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

    Google Scholar 

  57. Hartmann LC, Podratz KC, Keeney GL, Kamel NA, Edmonson JH, Grill JP, Su JQ, Katzmann JA, Roche PC (1994) Prognostic significance of p53 immunostaining in epithelial ovarian cancer. J Clin Oncol 12:64–69

    Google Scholar 

  58. Hartmann A, Blaszyk H, McGovern RM, Schroeder JJ, Cunningham J, DeVries EMG, Kovach JS, Sommer SS (1995) p53 gene mutations inside and outside of exons 5–8: the patterns differ in breast and other cancers. Oncogene 10:681–688

    Google Scholar 

  59. Hayashi K (1991) PCR-SSCP: a simple and sensitive method for detection of mutations in the genomic DNA. PCR Methods Appl 1:34–38

    Google Scholar 

  60. Hayashi K, Yandell DW (1993) How sensitive is PCR-SSCP? Hum Mutat 2:338–46

    Google Scholar 

  61. Hinds PW, Finlay CA, Levine AJ (1989) Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J Virol 63:739–746

    Google Scholar 

  62. Hinds PW, Finlay CA, Quartin RS, Baker SJ, Fearon ER, Vogelstein B, Levin AJ (1990) Mutant p53 DNA clones from human colon carcinomas cooperate with ras in transforming primary rat cells: a comparison of the “hot spot” mutant phenotypes. Growth Differ 1:571–580

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  64. Horio Y, Takahashi T, Kuroishi T, Hibi K, Suyama M, Niimi T, Shimokata K, Yamakawa K, Nakamura Y, Ueda R, Takahashi T (1993) Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res 53:1–4

    Google Scholar 

  65. Hurlimann J (1993) Prognostic value of p53 protein expression in breast carcinomas. Pathol Res Pract 189:996–1003

    Google Scholar 

  66. Hurlimann J, Saraga EP (1994) Expression of p53 protein in gastric carcinomas. Association with histologic type and prognosis. Am J Surg Pathol 18:1247–1253

    Google Scholar 

  67. Isola J, Visakorpi T, Holli K, Kallioniemi O-P (1992) Association of overexpression of tumor suppressor gene protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst 84:1109–1114

    Google Scholar 

  68. Ito K, Watanabe K, Nasim S, Sasano H, Sato S, Yajima A, Silverberg SG, Garrett CT (1994) Prognostic significance of p53 overexpression in endometrial cancer. Cancer Res 54:4667–4670

    Google Scholar 

  69. Iwaya K, Tsuda H, Hiraide H, Tamaki K, Tamakuma S, Fukutomi T, Mukai K, Hirohashi S (1991) Nuclear p53 immunoreaction associated with poor prognosis of breast cancer. Jpn J Cancer Res 82:835–840

    Google Scholar 

  70. Jaros E, Perry R, Adams L (1992) Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours. Br J Cancer 66:373–385

    Google Scholar 

  71. Jenkins JR, Rudge K, Currie GA (1984) Cellular immortalization by cDNA clone encoding the transformation-associated phosphoprotein p53. Nature 312:651–653

    Google Scholar 

  72. 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 tumour-suppressor gene protein in gastric adenocarcinoma. Br J Cancer 69:943–946

    Google Scholar 

  73. 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 

  74. Kaur J, Srivastava A, Ralhan R (1994) Overexpression of p53 protein in betel- and tobacco-related human oral dysplasia and squamous-cell carcinoma in India. Int J Cancer 58:340–345

    Google Scholar 

  75. Kern SE, Fearon ER, Tersmette KWF, Enterline JP, Leppert M, Nakamura Y, White R, Vogelstein B, Hamilton SR (1989) Clinical and pathologic associations with allelic loss in colorectal carcinomas. JAMA 261:3099–3103

    Google Scholar 

  76. Kerns B-J M, Jordan PA, Moore M-B H, Humphrey PA, Berchuk A, Kohler MF, Bast RC, Iglehart JD, Marks JR (1992) p53 overexpression in formalin-fixed, paraffin-embedded tissue detected by immunohistochemistry. J Histochem Cytochem 40:1047–1051

    Google Scholar 

  77. Kerr JFR, Winterford CM, Harmon BV (1994) Apoptosis. Its significance in cancer and cancer therapy. Cancer 73:2013–2026

    Google Scholar 

  78. Kessis TD, Slebos RJ, Nelson WG (1992) Human papillomavirus 16 E6 expression disrupts the p53-mediated response to DNA damage. Proc Natl Acad Sci USA 90:3988–3992

    Google Scholar 

  79. Khalifa MA, Mannel RS, Haraway SD, Walker J, Min K-W (1994) Expression of EGFR, HER-2/neu, P53, and PCNA in endometrioid, serous papillary, and clear cell endometrial adenocarcinomas. Gynecol Oncol 53:84–92

    Google Scholar 

  80. Kieser A, Weich HA, Brandner G, Marme' D, Kolch W (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:964–969

    Google Scholar 

  81. Kros JM, Godschalk JJCJ, Krishnadath KK, Eden CG van (1993) Expression of p53 in oligodendrogliomas. J Pathol 171:285–290

    Google Scholar 

  82. Lambkin HA, Mothersill CM, Kelehan P (1994) Variations in immunohistochemical detection of p53 protein overexpression in cervical carcinomas with different antibodies and methods of detection. J Pathol 172:13–18

    Google Scholar 

  83. Lane DP, Crawford LV (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263

    Google Scholar 

  84. Lechner MS, Laimins LA (1994) Inhibition of p53 DNA binding of human papillomavirus E6 proteins. J Virol 68:4262–4273

    Google Scholar 

  85. Levesque MA, Katsaros D, Yu H, Zola P, Sismondi P, Giardina G, Diamandis EP (1995) Mutant p53 protein overexpression is associated with poor outcome in patients with well or moderately differentiated ovarian carcinoma. Cancer 75:1327–1338

    Google Scholar 

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

    Google Scholar 

  87. Levine AJ, Perry ME, Chang A, Silver A, Dittmer D, Wu M, Welsh D (1994) Role of the p53 tumour-suppressor gene in tumorigenesis. Br J Cancer 69:409–416

    Google Scholar 

  88. Linzer DIH, Levine AJ (1979) Characterization of a 54K dalton cellular SV40 tumor antigen in SV40 transformed cells. Cell 17:43–52

    Google Scholar 

  89. Lipponen PK (1993) Over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. Int J Cancer 53:365–370

    Google Scholar 

  90. Lipponen P, Aaltomaa S, Syrjanen S, Syrjanen K (1993) p53 protein expression in breast cancer as related to histopathological characteristics and prognosis. Int J Cancer 55:51–56

    Google Scholar 

  91. Lipponen P, Eskelinen M, Hietala K, Syrjanen K, Gambetta RA (1994) Expression of proliferating cell nuclear antigen (PC10), p53 protein and c-erbB-2 in renal adenocarcinoma. Int J Cancer 57:275–280

    Google Scholar 

  92. Loda M (1994) Polymerase chain reaction-based methods for the detection of mutations in oncogenes and tumor supressor genes. Hum Pathol 25:564–571

    Google Scholar 

  93. Lowe SW, Ruley HE, Jacks T, Housman DE (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967

    Google Scholar 

  94. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362:847–849

    Google Scholar 

  95. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T (1994) p53 status and the efficacy of cancer therapy in vivo. Science 266:807–810

    CAS  PubMed  Google Scholar 

  96. Lukes AS, Kohler MF, Pieper CF, Kerns BJ, Bentley R, Rodriguez GC, Soper JT, Clarke-Pearson DL, Bast RC Jr, Berchuck A (1994) Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer. Cancer 73:2380–2385

    Google Scholar 

  97. Marchetti A, Buttitta F, Merlo G, Diella F, Pellegrini S, Pepe S, Macchiarini P, Chella A, Angeletti CA, Callahan R, Bistocchi M, Squartini F (1993) p53 alterations in non-small cell lung cancer correlate with metastic involvement of hilar and mediastinal lymph nodes. Cancer Res 53:2846–2851

    Google Scholar 

  98. Marks JR, Davidoff AM, Kerns BJ, Humphrey PA, Pence JC, Dodge RK, Clarke Pearson DL, Iglehart JD, Bast RC Jr, Berchuk A (1991) Overexpression and mutation of p53 in epithelial ovarian cancer. Cancer Res 51:2979–2984

    Google Scholar 

  99. Marks JR, Humphrey PA, Wu K, Berry D, Bandarenko N, Kerns B-JM, Iglehart JD (1994) Overexpression of p53 and HER-2/neu proteins as prognostic markers in early stage breast cancer. Ann Surg 219:332–341

    Google Scholar 

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

    Google Scholar 

  101. Masood S, Barnes R, Villas B, Wilson W, Shi S, Clark G, Tandon A (1993) p53 oncosuppressor protein in carcinoma of the breast. Lab Inves 68:17A

    Google Scholar 

  102. McLaren R, Kuzu I, dunnill M, Harris A, Lane D, Gatter KC (1992) The relationship of p53 immunostaining to survival in carcinoma of the lung. Br J Cancer 566:735–738

    Google Scholar 

  103. Mitsudomi T, Oyama T, Kusano T, Osaki T, Nakanishi R, Shirakusa T (1993) Mutations of the p53 gene as a predcictor of poor prognosis in patients with non-small-cell lung cancer. J Natl Cancer Inst 85:2018–2023

    Google Scholar 

  104. Momand J, Zambett GP, Olson DC, George DL, 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 

  105. Montine TJ, Bruner JM, Vandersteenhoven JJ, Dodge RK, Burger PC (1994) Prognostic significance of p53 immunoreactivity in adult patients with supratentorial fibrillary astrocytic neoplasms. Diagn Mol Pathol 3:240–245

    Google Scholar 

  106. Morkve O, Halvorsen OJ, Skjaerven R, Stangeland L, Gulsvik A, Laerum OD (1993) Prognostic significance of p53 protein expression and DNA ploidy in surgically treated non-small cell lung carcinomas. Anticancer Res 13:571–578

    Google Scholar 

  107. Moyret C, Theillet C, Laurent-Puig P, Moles J-P, Thomas G, Hamelin R (1994) Relative efficiency of denaturing gel electrophoresis and single-strand conformation polymorphism in the detection of mutation in exon 5 to 8 of the p53 gene. Oncogene 9:1739–1743

    Google Scholar 

  108. Murakami Y, Hayashi K, Sekiya T (1991) Detection of aberrations of the p53 alleles and the gene transcript in human tumor cell lines by single-stranded conformation polymorphism analysis of polymerase chain reaction products. Cancer Res 51:3356–3361

    Google Scholar 

  109. Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, Henderson IC (1994) c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330:1260–1266

    Google Scholar 

  110. Myers RM, Maniatis T, Lerman LS (1987) Detection and localization of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol 155:501–527

    Google Scholar 

  111. Nathanson SD, Linden MD, Tender P, Zarbo RJ, Jacobsen G, Nelson LT (1994) Relationship among p53, stage, and prognosis of large bowel cancer. Dis Colon Rectum 37:527–534

    Google Scholar 

  112. Nielsen AL, Nyholm HC (1994) p53 protein and c-erbB-2 protein (p185) expression in endometrial adenocarcinoma of endometrial type. Ann immunohistochemical examination on paraffin sections. Am J Clin Pathol 102:76–79

    Google Scholar 

  113. Nigro JM, Baker SJ, Preisinger AC, Milburn Jessup J, 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 tumour type. Nature 342:705–708

    Google Scholar 

  114. Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) A rapid and sensitive detection of point mutations and genetic polymorphisms using polymerase chain reaction. Genomics 5:874–879

    CAS  PubMed  Google Scholar 

  115. Ostrowski JL, Sawan A, Henry L, Wright C, Henry JA, Hennessy C, Lennard TJW, Angus B, Horne CHW (1991) p53 expression in human breast cancer related to survival and prognostic factors: an immunohistochemical study. J Pathol 164:75–81

    Google Scholar 

  116. Parada LF, Land H, Weinberg RA, Wolf D, Rotter V (1984) Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation. Nature 312:649–651

    Google Scholar 

  117. Pezzella F, Micklem K, Turley H, Pulford K, Kocialkowski S, Delia D, Aiello A, Bicknell R, Smity K, Harris AL, Gatter KC, Mason DY (1994) Antibody for detecting p53 protein in immunohistochemistry in normal tissues. J Clin Pathol 47:592–596

    Google Scholar 

  118. Picksley SM, Vojtesek B, Sparsk A, Lane DP (1994) Immunochemical analysis of the interaction of p53 with MDM-2. Fine mapping of the MDM-2 binding site on p53 using synthetic peptides. Oncogene 9:2523–2529

    Google Scholar 

  119. Poller DN, Hutchings CE, Galea M, Bell JA, Nicholson RA, Elston CW, Blamey RW, Ellis IO (1992) p53 protein expression in human breast carcinoma: relationship to expression of epidermal growth factor receptor, c-erbB-2 protein overexpression, and oestrogen receptor. Br J Cancer 66:583–588

    Google Scholar 

  120. Quinlan DC, Davidson AG, Summers CL, Warden HE, Doshi HM (1992) Accumulation of p53 protein correlates with a poor prognosis in human lung cancer. Cancer Res 52:4828–4831

    Google Scholar 

  121. Reinartz JJ, George E, Lindgren BR, Niehans GA (1994) Expression of p53, transforming growth factor alpha, epidermal growth factor receptor, and c-erbB-2 in endometrial carcinoma and correlation with survival and known predictors of survival. Hum Pathol 25:1075–1083

    Google Scholar 

  122. Remvikos Y, Tominaga O, Hammel P, Laurent-Puig P, Salmon RJ, Dutrillaux B, Thomas G (1992) Increased p53 protein content of colorectal tumors correlates with poor survival. Br J Cancer 66:758–764

    Google Scholar 

  123. Rosen PP, Lesser ML, Arroyo CD, Cranor M, Borgen P, Norton L (1995) p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis. J Clin Oncol 13:821–830

    Google Scholar 

  124. Rubio M-P, Deimling A von, Yandell DW, Wiestler OD, Gusella JF, Louis DN (1993) Accumulation of wild type p53 protein in human astrocytomas. Cancer Res 53:3465–3467

    Google Scholar 

  125. Sang B-C, Chen J-Y, Minna J, Barbosa MS (1994) Distinct domains of p53 have a differential role in transcriptional activation and repression functions. Oncogene 9:853–859

    Google Scholar 

  126. Sarbia M, Porschen R, Borchard F, Horstmann O, Willers R, Gabbert HE (1994) p53 protein expression and prognosis in squamous cell carcinoma of the esophagus. Cancer 74:2218–2223

    Google Scholar 

  127. Sarkis AS, Dalbagni G, Cordon-Cardo C, Zhang ZF, Sheinfeld J, Fair WR, Herr HW, Reuter VE (1993) Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 85:53–59

    CAS  PubMed  Google Scholar 

  128. Sarkis AS, Dalbagni G, Cordon-Cardo C, Melamed J, Zhang ZF, Sheinfeld J, Fair WR, Herr HW, Reuter VE (1994) Association of P53 nuclear overexpression and tumor progression in carcinoma in situ of the bladder. J Urol 152:388–392

    Google Scholar 

  129. Sawan A, Randall B, Angus B, Wright C, Henry JA, Ostrowski J, Hennessy C, Lennard TWJ, Corbett I, Horne CHW (1992) Retinoblastoma and p53 gene expression related to relapse and survival in human breast cancer: an immunohistochemical study. J Pathol 168:23–28

    Google Scholar 

  130. Scott NP, Sagar P, Stewart J, Blair GE, Dixon MF, Quirke P (1991) p53 in colorectal cancer: clinicopathological correlations and prognostic significance. Br J Cancer 63:317–319

    Google Scholar 

  131. Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J (1992) Induction of apoptosis by wild-type p53 in a human colon-derived cell line. Proc Natl Acad Sci USA 89:4495–4499

    Google Scholar 

  132. Sheffield VC, Cox DR, Lerman LS, Myers RM (1989) Attachment of a 40-base-pair G+C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase reaction results in improved detection of single-base changes. Proc Natl Acad Sci USA 86:232–236

    Google Scholar 

  133. Shiao Y-H, Rugge M, Correa P, Lehmann HP, Scheer WD (1994) p53 alteration in gastric precancerous lesions. Am J Pathol 144:511–517

    Google Scholar 

  134. 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 

  135. Shin DM, Kim J, Ro JY Hittelman J, Roth JA, Hong WK, Hittelman WN (1994) Activation of p53 gene expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 54:321–326

    Google Scholar 

  136. Shurbaji MS, Kalbfleisch JH, Thurmond TS (1995) Immunohistochemical detection of p53 protein as a prognostic indicator in prostate cancer. Hum Pathol 26:106–109

    Google Scholar 

  137. Silvestrini R, Benini E, Daidone MG, Veneroni S, Boracchi P, Cappelletti V, DiFronzo G, Veronesi U (1993) p53 as an independent prognostic marker in lymph node-negative breast cacer patients. J Natl Cancer Inst 85:965–970

    Google Scholar 

  138. Smith ML, Chen IT, Zhan Q, O'Connor PM, Fornace AJ Jr (1995) Involvement of the p53 tumor suppressor in repair of u.v.-type DNA damage. Oncogene 10:1053–1059

    Google Scholar 

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

    Google Scholar 

  140. Sun X-F, Carstensen JM, Zhang H, Stal O, Wingren S, Hatschek T, Nordenskjold B (1992) Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma. Lancet 340:1369–1373

    Google Scholar 

  141. Tanaka M, Omura K, Watanabe Y, Oda Y, Nakanishi I (1994) Prognostic factors of colorectal cancer: K-ras mutation, overexpression of the p53 protein, and cell proliferative activity. J Surg Oncol 57:57–64

    Google Scholar 

  142. Tanaka N, Ishihara M, Kitagawa M, Harada H, Kimura T, Matsuyama T, Lamphier MS, Aizawa S, Mak TW, Taniguchi T (1994) Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1. Cell 77:829–839

    Google Scholar 

  143. Terada T, Shimizu K, Izumi R, Nakanuma Y (1994) p53 expression in formalin-fixed, paraffin-embedded archival specimens of intrahepatic cholangiocarcinoma: retrieval of p53 antigenicity by microwave oven heating of tissue sections. Mod Pathol 7:249–252

    Google Scholar 

  144. Tetu B, Plante V, Brisson J, Bernard P (1995) Prognostic significance of p53 expression in node-positive breast carcinoma. Lab Invest 72:27A

    Google Scholar 

  145. Thor AD, Moore DH, Edgerton SM, Kawasaki ES, Reishaus E, Lynch HT, Marcus JN, Schwartz L, Chen L-C, 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 

  146. Thorlacius S, Borresen A-L, Eyfjord JE (1993) Somatic p53 mutations in human breast carcinomas in an Icelandic population: a prognostic factor. Cancer Res 53:1637–1641

    Google Scholar 

  147. Uhlman DL, Nguyen PL, Manivel JC, Aeppli D, Resnick JM, Fraley EE, Zhang G, Niehans GA (1994) Association of immunohistochemical staining for p53 with metastatic progression and poor survival in patients with renal cell carcinoma. J Natl Cancer Inst 86:1470–1475

    Google Scholar 

  148. Vesalainen SL, Lipponen PK, Talja MT, Alhava EM, Syrjanen KJ (1994) Proliferating cell nuclear antigen and p53 expression as prognostic factors in T1−2M0 prostatic adenocarcinoma. Int J Cancer 58:303–308

    Google Scholar 

  149. Vet JA, Bringuier PP, Poddighe PJ, Karthaus HF, Debruyne FM, Schalken JA (1994) p53 mutations have no additional prognostic value over stage in bladder cancer. Br J Cancer 70:496–500

    Google Scholar 

  150. Visakorpi T, Kallioniemi O-P, Heikkinen A, Koivula T, Isola J (1992) Small subgroup of aggressive, highly proliferative prostatic carcinomas defined by p53 accumulation. J Natl Cancer Inst 84:883–887

    Google Scholar 

  151. Visscher DW, Sarkar FH, Wykes S, Kothari K, Macoska J, Crissman J (1993) Clinicopathologic significance of p53 immunostaining in adenocarcinoma of the breast. Arch Pathol Lab Med 117:973–976

    Google Scholar 

  152. Vogelstein B, Kinzler KW (1992) p53 function and dysfunction. Cell 70:523–526

    Google Scholar 

  153. Wang D-Y, Xiang Y-Y, Tanaka M, Li X-R, Li J-L, Shen Q, Sugimura H, Kino I (1994) High prevalence of p53 protein overexpression in patients with esophageal cancer in Linxian, China and its relationship to progression and prognosis. Cancer 74:3089–3096

    Google Scholar 

  154. Wartell RM, Hosseini SH, Moran CP Jr (1990) Detecting base pair substitutions in DNA fragments by temperature-gradient gel electrophoresis. Nucleic Acids Res 18:2699–2705

    Google Scholar 

  155. Yamaguchi A, Kurosaka Y, Fushida S, Kanno M, Yonemura Y, Miwa K, Miyazaki I (1992) Expression of p53 protein in colorectal cancer and its relationship to short-term prognosis. Cancer 70:2778–2784

    Google Scholar 

  156. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352:345–347

    Google Scholar 

  157. Zee AGJ van der, Hollema H, Suurmeijer AJH, Krans M, Sluiter WJ, Willemse PHB, Aalders JG, Vries EGE de (1995) Value of P-glycoprotein, glutathione-S-transferase pi, c-erbB-2, and p53 as prognostic factors in ovarian carcinomas. J Clin Oncol 13:70–78

    Google Scholar 

  158. Zeng Z-S, Sarkis AS, Zhang Z-F, Klimstra DS, Charytonowicz E, Guillem JG, Cordon-Cardo C, Cohen AM (1994) p53 nuclear overexpression: an independent predictor of survival in lymph node-positive colorectal cancer patients. J Clin Oncol 12:2043–2050

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA

    S. Bosari

  2. Department of Pathology, University of Milan School of Medicine, European Institute of Oncology, Via Ripamonti 435, I-20141, Milan, Italy

    G. Viale

Authors
  1. S. Bosari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Viale
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bosari, S., Viale, G. The clinical significance of p53 aberrations in human tumours. Vichows Archiv A Pathol Anat 427, 229–241 (1995). https://doi.org/10.1007/BF00203389

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00203389

Key words

Search

Navigation