Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Assessing TP53 status in human tumours to evaluate clinical outcome

Abstract

TP53 is probably the most extensively studied tumour-suppressor gene, and patients with TP53 mutations are known to have a poor outcome. However, inconsistencies in the analysis of TP53 status, and failure to realize that different mutations behave in different ways, prevent us from effectively applying our vast knowledge of this protein in clinical practice. What simple steps can be taken to ensure that patients benefit from our understanding of TP53?

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Literature survey of strategies used for mutation analysis of TP53.
Figure 2: Distribution (%) of TP53 mutations along its exons.
Figure 3: Distribution of mutational events in each exon of the TP53 gene.
Figure 4: Schematic representation of the p53 protein.

References

  1. Vousden, K. H. p53. Death star. Cell 103, 691–694 (2000).

    CAS  PubMed  Google Scholar 

  2. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).

    CAS  Article  PubMed  Google Scholar 

  3. Soussi, T., Dehouche, K. & Béroud, C. p53 website and analysis of p53 gene mutations in human cancer: forging a link between epidemiology and carcinogenesis. Hum. Mutat. 15, 105–113 (2000).

    CAS  PubMed  Google Scholar 

  4. Moll, U. M., Laquaglia, M., Benard, J. & Riou, G. Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. Proc. Natl Acad. Sci. USA 92, 4407–4411 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Oliner, J. D., Kinzler, K. W., Meltzer, P. S., Georges, D. L. & Vogelstein, B. Amplification of a gene encoding a p53 associated protein in human sarcomas. Nature 358, 80–83 (1992).

    CAS  PubMed  Google Scholar 

  6. Crook, T. et al. Clonal p53 mutation in primary cervical cancer- association with human-papillomavirus-negative tumours. Lancet 339, 1070–1073 (1992).

    CAS  PubMed  Google Scholar 

  7. Soengas, M. S. et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409, 207–211 (2001).

    CAS  PubMed  Google Scholar 

  8. Bell, D. W. et al. Heterozygous germ line hCHK2 mutations in Li–Fraumeni syndrome. Science 286, 2528–2531 (1999).

    CAS  PubMed  Google Scholar 

  9. Rotman, G. & Shiloh, Y. ATM: a mediator of multiple responses to genotoxic stress. Oncogene 18, 6135–6144 (1999).

    CAS  PubMed  Google Scholar 

  10. Baker, S. J. et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244, 217–221 (1989).

    CAS  PubMed  Google Scholar 

  11. Takahashi, T. et al. p53- a frequent target for genetic abnormalities in lung cancer. Science 246, 491–494 (1989).

    CAS  PubMed  Google Scholar 

  12. Nigro, J. M. et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 342, 705–708 (1989).

    CAS  PubMed  Google Scholar 

  13. Dowell, S. P., Wilson, P. O. G., Derias, N. W., Lane, D. P. & Hall, P. A. Clinical utility of the immunocytochemical detection of p53 protein in cytological specimens. Cancer Res. 54, 2914–2918 (1994).

    CAS  PubMed  Google Scholar 

  14. Varley, J. M. et al. Characterization of germline TP53 splicing mutations and their genetic and functional analysis. Oncogene 20, 2647–2654 (1999).

    Google Scholar 

  15. Gu, J., Kawai, H., Wiederschain, D. & Yuan, Z. M. Mechanism of functional inactivation of a Li–Fraumeni syndrome p53 that has a mutation outside of the DNA-binding domain. Cancer Res. 61, 1741–1746 (2001).

    CAS  PubMed  Google Scholar 

  16. Hashimoto, T. et al. p53 null mutations undetected by immunohistochemical staining predict a poor outcome with early-stage non-small cell lung carcinomas. Cancer Res. 59, 5572–5577 (1999).

    CAS  PubMed  Google Scholar 

  17. Skaug, V. et al. p53 mutations in defined structural and functional domains are related to poor clinical outcome in non-small cell lung cancer patients. Clin. Cancer Res. 6, 1031–1037 (2000).

    CAS  PubMed  Google Scholar 

  18. Tomizawa, Y. et al. Correlation between the status of the p53 gene and survival in patients with stage I non-small cell lung carcinoma. Oncogene 18, 1007–1014 (1999).

    CAS  PubMed  Google Scholar 

  19. Schiller, J. H. et al. Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: a Laboratory Ancillary Study on an Eastern Cooperative Oncology Group Prospective Randomized Trial of Postoperative Adjuvant Therapy. J. Clin. Oncol. 19, 448–457 (2001).

    CAS  PubMed  Google Scholar 

  20. Hartmann, A., Blaszyk, H., Kovach, J. S. & Sommer, S. S. The molecular epidemiology of p53 gene mutations in human breast cancer. Trends Genet. 13, 27–33 (1997).

    CAS  PubMed  Google Scholar 

  21. Kern, S. E. et al. Mutant p53 proteins bind DNA abnormally in vitro. Oncogene 6, 131–136 (1991).

    CAS  PubMed  Google Scholar 

  22. El-Deiry, W. S., Kern, S. E., Pientenpol, J. A., Kinzler, K. W. & Vogelstein, B. Definition of a consensus binding site for p53. Nature Genet. 1, 45–49 (1992).

    CAS  PubMed  Google Scholar 

  23. Kern, S. E. et al. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256, 827–830 (1992).

    CAS  PubMed  Google Scholar 

  24. Milner, J. & Medcalf, E. A. Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell 65, 765–774 (1991).

    CAS  PubMed  Google Scholar 

  25. Dittmer, D. et al. Gain of function mutations in p53. Nature Genet. 4, 42–46 (1993).

    CAS  PubMed  Google Scholar 

  26. Halevy, O., Michalovitz, D. & Oren, M. Different tumor-derived p53 mutants exhibit distinct biological activities. Science 250, 113–116 (1990).

    CAS  PubMed  Google Scholar 

  27. Harvey, M. et al. A mutant p53 transgene accelerates tumour development in heterozygous but not nullizygous p53 deficient mice. Nature Genet. 9, 305–311 (1995).

    CAS  PubMed  Google Scholar 

  28. Blandino, G., Levine, A. J. & Oren, M. Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene 18, 477–485 (1999).

    CAS  PubMed  Google Scholar 

  29. Rowan, S. et al. Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J. 15, 827–838 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Forrester, K. et al. Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent. Oncogene 10, 2103–2111 (1995).

    CAS  PubMed  Google Scholar 

  31. Cho, Y. J., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. Crystal structure of a p53 tumor suppressor DNA complex: understanding tumorigenic mutations. Science 265, 346–355 (1994).

    CAS  PubMed  Google Scholar 

  32. Ory, K., Legros, Y., Auguin, C. & Soussi, T. Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. EMBO J. 13, 3496–3504 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hinds, P. W. et al. Mutant p53 DNA clones from human colon carcinomas cooperate with Ras in transforming primary rat cells: a comparison of the 'Hot Spot' mutant phenotypes. Cell Growth Differ. 1, 571–580 (1990).

    CAS  PubMed  Google Scholar 

  34. Selivanova, G. et al. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nature Med. 3, 632–638 (1997).

    CAS  PubMed  Google Scholar 

  35. Bullock, A. N., Henckel, J. & Fersht, A. R. Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy. Oncogene 19, 1245–1256 (2000).

    CAS  PubMed  Google Scholar 

  36. Wong, K. B. et al. Hot-spot mutants of p53 core domain evince characteristic local structural changes. Proc. Natl Acad. Sci. USA 96, 8438–8442 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Berns, E. et al. Mutations in residues of TP53 that directly contact DNA predict poor outcome in human primary breast cancer. Br. J. Cancer 77, 1130–1136 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kucera, E. et al. Prognostic significance of mutations in the p53 gene, particularly in the zinc-binding domains, in lymph node- and steroid receptor positive breast cancer patients. Eur. J. Cancer 35, 398–405 (1999).

    CAS  PubMed  Google Scholar 

  39. Borresen, A. L. et al. TP53 mutations and breast cancer prognosis: particularly poor survival rates for cases with mutations in the zinc-binding domains. Gene Chromosom. Cancer 14, 71–75 (1995).

    CAS  Google Scholar 

  40. Borresen Dale, A. L. et al. TP53 and long-term prognosis in colorectal cancer: mutations in the L3 zinc-binding domain predict poor survival. Clin. Cancer Res. 4, 203–210 (1998).

    CAS  PubMed  Google Scholar 

  41. Goh, H. S., Yao, J. & Smith, D. R. p53 point mutation and survival in colorectal cancer patients. Cancer Res. 55, 5217–5221 (1995).

    CAS  PubMed  Google Scholar 

  42. Liu, G. et al. High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc. Natl Acad. Sci. USA 97, 4174–4179 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chappuis, P. O. et al. Prognostic significance of p53 mutation in breast cancer: frequent detection of non-missense mutations by yeast functional assay. Int. J. Cancer 84, 587–593 (1999).

    CAS  PubMed  Google Scholar 

  44. Smith, P. D. et al. Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions. Oncogene 18, 2451–2459 (1999).

    CAS  PubMed  Google Scholar 

  45. de Cremoux, P. et al. p53 mutation as a genetic trait of typical medullary breast carcinoma. J. Natl Cancer Inst. 91, 641–643 (1999).

    CAS  PubMed  Google Scholar 

  46. Yang, A. & McKeon, F. p63 and p73: p53 mimics, menaces and more. Nature Rev. Mol. Cell Biol. 1, 199–207 (2000).

    CAS  Google Scholar 

  47. Ikawa, S., Nakagawara, A. & Ikawa, Y. p53 family genes: structural comparison, expression and mutation. Cell Death Differ. 6, 1154–1161 (1999).

    CAS  PubMed  Google Scholar 

  48. Levrero, M. et al. Structure, function and regulation of p63 and p73. Cell Death Differ. 6, 1146–1153 (1999).

    CAS  PubMed  Google Scholar 

  49. Hibi, K. et al. AIS is an oncogene amplified in squamous cell carcinoma. Proc. Natl Acad. Sci. USA 97, 5462–5467 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Strano, S. et al. Physical and functional interaction between p53 mutants and different isoforms of p73. J. Biol. Chem. 275, 29503–29512 (2000).

    CAS  PubMed  Google Scholar 

  51. Marin, M. C. et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nature Genet. 25, 47–54 (2000).

    CAS  PubMed  Google Scholar 

  52. Gaiddon, C., Lokshin, M., Ahn, J., Zhang, T. & Prives, C. A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol. Cell Biol. 21, 1874–1887 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Agami, R., Blandino, G., Oren, M. & Shaul, Y. The tyrosine kinase c-ABL regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399, 806–809 (1999).

    Google Scholar 

  54. Ratovitski, E. A. et al. p53 associates with and targets ΔNp63 into a protein degradation pathway. Proc. Natl Acad. Sci. USA 98, 1817–1822 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Storey, A. et al. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 393, 229–234 (1998).

    CAS  PubMed  Google Scholar 

  56. Rosenthal, A. N. et al. p53 codon 72 polymorphism and risk of cervical cancer in UK. Lancet 352, 871–872 (1998).

    CAS  PubMed  Google Scholar 

  57. Storey, A. et al. p53 polymorphism and risk of cervical cancer: reply. Nature 396, 532 (1998).

    CAS  Google Scholar 

  58. Lanham, S., Campbell, I., Watt, P. & Gornall, R. p53 polymorphism and risk of cervical cancer. Lancet 352, 1631–1631 (1998).

    CAS  PubMed  Google Scholar 

  59. Helland, A. et al. p53 polymorphism and risk of cervical cancer. Nature 396, 530–531 (1998).

    CAS  PubMed  Google Scholar 

  60. Zehbe, I. et al. p53 codon 72 polymorphism and various human papillomavirus 16 E6 genotypes are risk factors for cervical cancer development. Cancer Res. 61, 608–611 (2001).

    CAS  PubMed  Google Scholar 

  61. Beckman, G. et al. Is p53 polymorphism maintained by natural selection? Hum. Hered. 44, 266–270 (1994).

    CAS  PubMed  Google Scholar 

  62. Stolzenberg, M. C. et al. Germ-line exclusion of a single p53 allele by premature termination of translation in a Li–Fraumeni syndrome family. Oncogene 9, 2799–2804 (1994).

    CAS  PubMed  Google Scholar 

  63. Ahrendt, S. A. et al. Rapid p53 sequence analysis in primary lung cancer using an oligonucleotide probe array. Proc. Natl Acad. Sci. USA 96, 7382–7387 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Bullock, A. N. & Fersht, A. R. Rescuing the function of mutant p53. Nature Reviews Cancer 1, 68–76 (2001).

    CAS  PubMed  Google Scholar 

  65. Zhao, R. et al. Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14, 981–993 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Yu, J. et al. Identification and classification of p53-regulated genes. Proc. Natl Acad. Sci. USA 96, 14517–14522 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kostic, C. & Shaw, P. H. Isolation and characterization of sixteen novel p53 response genes. Oncogene 19, 3978–3987 (2000).

    CAS  PubMed  Google Scholar 

  68. Kannan, K. et al. DNA microarrays identification of primary and secondary target genes regulated by p53. Oncogene 20, 2225–2234 (2001).

    CAS  PubMed  Google Scholar 

  69. Tokino, T. & Nakamura, Y. The role of p53-target genes in human cancer. Crit. Rev. Oncol. Hematol. 33, 1–6 (2000).

    CAS  PubMed  Google Scholar 

  70. Hansen, R. & Oren, M. p53: from inductive signal to cellular effect. Curr. Opin. Genet. Dev. 7, 46–51 (1997).

    CAS  PubMed  Google Scholar 

  71. May, P. & May, E. Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene 18, 7621–7636 (1999).

    CAS  PubMed  Google Scholar 

  72. Aas, T. et al. Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nature Med. 2, 811–814 (1996).

    CAS  PubMed  Google Scholar 

  73. Geisler, S. et al. Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res. 61, 2505–2512 (2001).

    CAS  PubMed  Google Scholar 

  74. Takahashi, M. et al. Distinct prognostic values of p53 mutations and loss of estrogen receptor and their cumulative effect in primary breast cancers. Int. J. Cancer 89, 92–99 (2000).

    CAS  PubMed  Google Scholar 

  75. Powell, B., Soong, R., Iacopetta, B., Seshadri, R. & Smith, D. R. Prognostic significance of mutations to different structural and functional regions of the p53 gene in breast cancer. Clin. Cancer Res. 6, 443–451 (2000).

    CAS  PubMed  Google Scholar 

  76. Gentile, M., Jungestrom, M. B., Olsen, K. E., Soderkvist, P. & Wingren, S. p53 and survival in early onset breast cancer: analysis of gene mutations, loss of heterozygosity and protein accumulation. Eur. J. Cancer 35, 1202–1207 (1999).

    CAS  PubMed  Google Scholar 

  77. Berns, E. M. et al. Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer. Cancer Res. 60, 2155–2162 (2000).

    CAS  PubMed  Google Scholar 

  78. Clausen, O. P. F. et al. Association of p53 accumulation with TP53 mutations, loss of heterozygosity at 17p13, and DNA ploidy status in 273 colorectal carcinomas. Diagn. Mol. Pathol. 7, 215–223 (1998).

    CAS  PubMed  Google Scholar 

  79. Huang, C. et al. Mutations in exon 7 and 8 of p53 as poor prognostic factors in patients with non-small cell lung cancer. Oncogene 16, 2469–2477 (1998).

    CAS  PubMed  Google Scholar 

  80. Vega, F. J. et al. p53 exon 5 mutations as a prognostic indicator of shortened survival in non-small-cell lung cancer. Br. J. Cancer 76, 44–51 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Erber, R. et al. TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer. Oncogene 16, 1671–1679 (1998).

    CAS  PubMed  Google Scholar 

  82. Kihara, C. et al. Mutations in zinc-binding domains of p53 as a prognostic marker of esophageal–cancer patients. Jpn J. Cancer Res. 91, 190–198 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to D. Barnes, N. Basset-Seguin, E. M. J. J. Berns, A. L. Borresen, D. Brash, R. Camplejohn, R. Iggo, U. Moll, D. Sidransky and B. Vogelstein for critical reading of this manuscript. T.S. is grateful to B. Asselain and P. Viehl for helpful discussions. Our work is supported by grants from Association de Recherche contre le Cancer, Institut Curie, Ligue contre le Cancer (Comité de Paris) and Fondation de France.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thierry Soussi.

Supplementary information

Related links

Related links

DATABASES

CancerNet:

breast cancer

cervical cancer

colon tumours

head and neck cancer

melanoma

neuroblastoma

non-Hodgkin's lymphomas

non-small-cell lung carcinoma

testicular cancer

 GenBank:

E6 protein

 InterPro:

SAM

 LocusLink:

APAF

APC

ATM

BRCA1

MDM2

p19ARF

RET

TP53

TP63

TP73

Trp53

Trp63

 Medscape DrugInfo:

cisplatin

etoposide

tamoxifen

 OMIM:

ataxia telangiectasia

Li–Fraumeni syndrome

FURTHER INFORMATION

The APC database at the Institut Curie

The City of Hope Database of MDM2 Mutations in Human Tumors

The IARC TP53 Mutation Database

The NIH p53 Resources Page

The OncoLink p53 Information Center

The p53 mutation database

The TP53 site at the Institut Curie

The Universal Mutation Database site

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Soussi, T., Béroud, C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer 1, 233–239 (2001). https://doi.org/10.1038/35106009

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35106009

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing