Skip to main content

Advertisement

SpringerLink
Log in

Clinical impact of TP53 alterations in adrenocortical carcinomas

  • Original Article
  • Published:
Langenbeck's Archives of Surgery Aims and scope Submit manuscript

Abstract

Background

To evaluate the role of somatic TP53 mutations and to correlate somatic and germline mutations with results of immunostaining, a large cohort of ACC patients was analyzed.

Patients and methods

Patients with ACC who underwent potential curative surgery at the authors’ department were screened for TP53 somatic and germline mutations in exons 5, 6, 7, 8, and 10 by DHPLC analysis. Aberrant samples were further analyzed by direct sequencing. Immunostaining was performed on corresponding paraffin sections in all patients. Complete clinical and follow-up data were correlated with the status of TP53.

Results

Thirty ACC patients were included. Four of 30 patients showed aberrant DHPLC configuration and direct sequencing confirmed 2 (7%) germline mutations (R337H, R248W), 1 (3%) somatic mutation (R213X), and 1 (3%) noncoding polymorphism (g.17708 A>T). The only patient with a positive family history harbored a TP53 mutation. Tumors of the three patients with mutations showed aberrant p53 expression in more than 10% of cells by immunostaining, compared to only 3 of 27 patients without mutations (p = 0.009). Aberrant p53 expression (>5%) was detected in 12/30 (40%) ACCs. The latter was associated with an increased Ki67 and van Slooten index (p ≤ 0.001; p = 0.020). Disease-free survival decreased significantly in patients with aberrant p53 IHC of more than 5% of cells (65.7 ± 12.4 vs. 26.6 ± 8.7 months; p = 0.043 log rank test).

Conclusions

Patients with ACC revealed aberrant expression of p53 in 40%, and mutations were identified in 25% of these patients. Therefore aberrant p53 expression should be considered an indicator for genetic testing. A subgroup of apparently sporadic ACC is caused by TP53 germline mutations, and family history is a strong indicator for p53 germline mutations.

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. 1
Fig. 2

Similar content being viewed by others

References

  1. Wajchenberg BL, Albergaria Pereira MA, Medonca BB, Latronico AC, Campos Carneiro P, Alves VA, Zerbini MC, Liberman B, Carlos Gomes G, Kirschner MA (2000) Adrenocortical carcinoma: clinical and laboratory observations. Cancer 88(4):711–736

    Article  PubMed  CAS  Google Scholar 

  2. Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, Cougard P, Henry JF, Proye C (2001) Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 25(7):891–897

    Article  PubMed  CAS  Google Scholar 

  3. Vassilopoulou-Sellin R, Schultz PN (2001) Adrenocortical carcinoma. Clinical outcome at the end of the 20th century. Cancer 92(5):1113–1121

    Article  PubMed  CAS  Google Scholar 

  4. Velazquez-Fernandez D, Laurell C, Geli J, Hoog A, Odeberg J, Kjellman M, Lundeberg J, Hamberger B, Nilsson P, Backdahl M (2005) Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. Surgery 138(6):1087–1094

    Article  PubMed  Google Scholar 

  5. Slater EP, Diehl SM, Langer P, Samans B, Ramaswamy A, Zielke A, Bartsch DK (2006) Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors. Eur J Endocrinol 154(4):587–598

    Article  PubMed  CAS  Google Scholar 

  6. Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL, Sanders D, Aljundi RT, Gauger PG, Thompson NW, Taylor JM, Hanash SM (2003) Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 162(2):521–531

    Article  PubMed  CAS  Google Scholar 

  7. Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, Komoto Y, Okada A, Ohishi S, Nabetani A, Morisaki H, Nakayama M, Niikawa N, Mukai T (1996) An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet 14(2):171–173

    Article  PubMed  CAS  Google Scholar 

  8. Birch JM, Alston RD, McNally RJ, Evans DG, Kelsey AM, Harris M, Eden OB, Varley JM (2001) Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20(34):4621–4628

    Article  PubMed  CAS  Google Scholar 

  9. Hisada M, Garber J, Fung CY, Fraumeni JF Jr, Li FP (1998) Multiple primary cancers in families with Li–Fraumeni Syndrome. J Natl Cancer Inst 90:7622–7627

    Google Scholar 

  10. Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, Bertherat J, Chapuis Y, Duclos JM, Schlumberger M, Plouin PF, Luton JP, Le Bouc Y (2001) Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 61(18):6762–6767

    PubMed  CAS  Google Scholar 

  11. Libe R, Groussin L, Tissier F, Elie C, Rene-Corail F, Fratticci A, Jullian E, Beck-Peccoz P, Bertagna X, Gicquel C, Bertherat J (2007) Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. Clin Cancer Res 13(3):844–850

    Article  PubMed  CAS  Google Scholar 

  12. Reincke M, Karl M, Travis WH, Mastorakos G, Allolio B, Linehan HM, Chrousos GP (1994) p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 78(3):790–794

    Article  PubMed  CAS  Google Scholar 

  13. Sidhu S, Martin E, Gicquel C, Melki J, Clark SJ, Campbell P, Magarey CJ, Schulte KM, Roher HD, Delbridge L, Robinson BG (2005) Mutation and methylation analysis of TP53 in adrenal carcinogenesis. Eur J Surg Oncol 31(5):549–554

    Article  PubMed  CAS  Google Scholar 

  14. van Slooten H, Schaberg A, Smeenk D, Moolenaar AJ (1985) Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55:766–773

    Article  PubMed  Google Scholar 

  15. Weiss LM, Medeiros LJ, Vickery AL Jr (1989) Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13(3):202–206

    Article  PubMed  CAS  Google Scholar 

  16. Waldmann J, Feldmann G, Slater EP, Langer P, Buccholz M, Ramaswamy A, Saeger W, Rothmund M, Fendrich V (2008) Expression of the zinc-finger transcription factor Snail in adrenocortical carcinoma is associated with decreased survival. Br J Cancer 99:1900–1907

    Article  PubMed  CAS  Google Scholar 

  17. Barzon L, Chilosi M, Fallo F, Martignoni G, Montagna L, Palu G, Boscaro M (2001) Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors. Eur J Endocrinol 145(2):207–212

    Article  PubMed  CAS  Google Scholar 

  18. Sidhu S, Marsh DJ, Theodosopoulos G, Philips J, Bambach CP, Campbell P, Magarey CJ, Russell CF, Schulte KM, Roher HD, Delbridge L, Robinson BG (2002) Comparative genomic hybridization analysis of adrenocortical tumors. J Clin Endocrinol Metab 87(7):3467–3474

    Article  PubMed  CAS  Google Scholar 

  19. Ohgaki H, Kleihues P, Heitz PU (1993) p53 mutations in sporadic adrenocortical tumors. Int J Cancer 54(3):408–410

    Article  PubMed  CAS  Google Scholar 

  20. Libe R, Bertherat J (2005) Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol 153(4):477–487

    Article  PubMed  CAS  Google Scholar 

  21. Arola J, Salmenkivi K, Liu J, Kahri AI, Heikkila P (2000) p53 and Ki67 in adrenocortical tumors. Endocr Res 26(4):861–865

    Article  PubMed  CAS  Google Scholar 

  22. McNicol AM, Nolan CE, Struthers AJ, Farquharson MA, Hermans J, Haak HR (1997) Expression of p53 in adrenocortical tumours: clinicopathological correlations. J Pathol 181(2):146–152

    Article  PubMed  CAS  Google Scholar 

  23. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28(6):622–629

    Article  PubMed  CAS  Google Scholar 

  24. Bourdon JC, D’Errico A, Paterlini P, Grigioni W, May E, Debuire B (1995) p53 protein accumulation in European hepatocellular carcinoma is not always dependent on p53 gene mutation. Gastroenterology 108(4):1176–1182

    Article  PubMed  CAS  Google Scholar 

  25. Moll UM, Riou G, Levine AJ (1992) Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci U S A 89(15):7262–7266

    Article  PubMed  CAS  Google Scholar 

  26. Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, Allred DC (1993) p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res 53:3369–3373

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Prof. Domann, PD, Dr. Imirzalioglu, and Prof. Chakraborty for the technical support with the WAVE analysis and the use of the WAVE DHPLC system.

Conflicts of interest

The authors hereby declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

The present research did not receive any specific grant from any funding agency in the public, commercial, or nonprofit sector.

Author information

Authors and Affiliations

  1. Department of Visceral, Thoracic and Vascular Surgery, University Hospital Giessen and Marburg, Baldingerstraße, 35043, Marburg, Germany

    Jens Waldmann, Nikolaos Patsalis, Volker Fendrich, Peter Langer, Brunhilde Chaloupka, Detlef K. Bartsch & Emily P. Slater

  2. Department of Surgery, University of Cologne, Cologne, Germany

    Nikolaos Patsalis

  3. Department of Pathology, Marienkrankenhaus, Hamburg, Germany

    Wolfgang Saeger

  4. Department of Pathology, University Hospital Giessen and Marburg, Marburg, Germany

    Annette Ramaswamy

  5. Department of Internal Medicine, Division of Diabetology and Endocrinology, University Hospital Wuerzburg, Wuerzburg, Germany

    Martin Fassnacht

Authors
  1. Jens Waldmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nikolaos Patsalis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Volker Fendrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Langer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wolfgang Saeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Brunhilde Chaloupka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Annette Ramaswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martin Fassnacht
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Detlef K. Bartsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Emily P. Slater
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jens Waldmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waldmann, J., Patsalis, N., Fendrich, V. et al. Clinical impact of TP53 alterations in adrenocortical carcinomas. Langenbecks Arch Surg 397, 209–216 (2012). https://doi.org/10.1007/s00423-011-0868-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00423-011-0868-6

Keywords

Search

Navigation