Skip to main content

Advertisement

SpringerLink
Log in

TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li–Fraumeni family

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Li–Fraumeni syndrome (LFS) is a rare autosomal dominant inherited disorder associated with the occurrence of a wide spectrum of early-onset malignancies, the most prevalent being breast cancer and sarcoma. The presence of TP53 germline mutations in the majority of LFS patients suggests a genetic basis for the cancer predisposition. No special recommendations for the treatment of LFS patients have been made to date, except that of minimizing radiation. We hypothesized that TP53 germline mutations may be associated not only with cancer predisposition, but also with lack of response to chemo- and radiotherapy. Here, we present an Austrian LFS family whose members were intensively treated with chemo- and radiotherapy due to cancers that occurred at a predominantly young age, including eight breast cancers in six patients. Material from seven family members was screened for p53 mutation by Sanger sequencing and immunohistochemistry. A rare missense mutation in the tetramerization domain of exon 10 of the TP53 gene was found to segregate with malignant disease in this family. Lack of response to various chemotherapies and radiotherapy could be ascertained by histopathology of surgical specimens after neoadjuvant treatment, by cancer relapse occurring while receiving adjuvant systemic treatment and by the occurrence of second primaries in areas of adjuvant radiation. Our observations suggest that current standards of cancer treatment may not be valid for patients with LFS. In patients with TP53 germline mutation, cytotoxic treatment may bear not only the risk of tumor induction but also the risk of treatment failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Abbreviations

CMF:

Cyclophosphamide, methotrexate and 5-fluorouracil

FFPE:

Formalin-fixed paraffin-embedded tissue

IHC:

Immunohistochemistry

LFS:

Li–Fraumeni syndrome

PBMC:

Peripheral blood mononuclear cells

PCR:

Polymerase chain reaction

References

  1. Li FP, Fraumeni JF Jr (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71(4):747–752

    Article  CAS  PubMed  Google Scholar 

  2. Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362

    CAS  PubMed  Google Scholar 

  3. Kleihues P, Schauble B, zur Hausen A, Esteve J, Ohgaki H (1997) Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 150(1):1–13

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Varley JM (2003) Germline TP53 mutations and Li–Fraumeni syndrome. Hum Mutat 21(3):313–320

    Article  CAS  PubMed  Google Scholar 

  5. Ruijs MW, Verhoef S, Rookus MA, Pruntel R, van der Hout AH, Hogervorst FB, Kluijt I, Sijmons RH, Aalfs CM, Wagner A, Ausems MG, Hoogerbrugge N, van Asperen CJ, Gomez Garcia EB, Meijers-Heijboer H, Ten Kate LP, Menko FH, van ‘t Veer LJ (2010) TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet 47(6):421–428. doi:10.1136/jmg.2009.073429

    Article  CAS  PubMed  Google Scholar 

  6. NCCN (2014) National comprehensive cancer network. Genetic/familial high-risk assessment: breast and ovarian. Version 1. Available at: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf

  7. McBride KA, Ballinger ML, Killick E, Kirk J, Tattersall MH, Eeles RA, Thomas DM, Mitchell G (2014) Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol 11(5):260–271. doi:10.1038/nrclinonc.2014.41

    Article  CAS  PubMed  Google Scholar 

  8. Hisada M, Garber JE, Fung CY, Fraumeni JF Jr, Li FP (1998) Multiple primary cancers in families with Li–Fraumeni syndrome. J Natl Cancer Inst 90(8):606–611

    Article  CAS  PubMed  Google Scholar 

  9. Nutting C, Camplejohn RS, Gilchrist R, Tait D, Blake P, Knee G, Yao WQ, Ross G, Fisher C, Eeles R (2000) A patient with 17 primary tumours and a germ line mutation in TP53: tumour induction by adjuvant therapy? Clin Oncol (R Coll Radiol) 12(5):300–304

    CAS  Google Scholar 

  10. Heymann S, Delaloge S, Rahal A, Caron O, Frebourg T, Barreau L, Pachet C, Mathieu MC, Marsiglia H, Bourgier C (2010) Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li–Fraumeni syndrome. Radiat Oncol 5:104. doi:10.1186/1748-717X-5-104

    Article  PubMed Central  PubMed  Google Scholar 

  11. Limacher JM, Frebourg T, Natarajan-Ame S, Bergerat JP (2001) Two metachronous tumors in the radiotherapy fields of a patient with Li–Fraumeni syndrome. Int J Cancer 96(4):238–242

    Article  CAS  PubMed  Google Scholar 

  12. Kamihara J, Rana HQ, Garber JE (2014) Germline TP53 mutations and the changing landscape of Li–Fraumeni syndrome. Hum Mutat 35(6):654–662. doi:10.1002/humu.22559

    Article  CAS  PubMed  Google Scholar 

  13. Wallace-Brodeur RR, Lowe SW (1999) Clinical implications of p53 mutations. Cell Mol Life Sci 55(1):64–75

    Article  CAS  PubMed  Google Scholar 

  14. Hematulin A, Sagan D, Sawanyawisuth K, Seubwai W, Wongkham S (2014) Association between cellular radiosensitivity and G1/G2 checkpoint proficiencies in human cholangiocarcinoma cell lines. Int J Oncol 45(3):1159–1166. doi:10.3892/ijo.2014.2520

    CAS  PubMed  Google Scholar 

  15. Kandioler D, Zwrtek R, Ludwig C, Janschek E, Ploner M, Hofbauer F, Kuhrer I, Kappel S, Wrba F, Horvath M, Karner J, Renner K, Bergmann M, Karner-Hanusch J, Potter R, Jakesz R, Teleky B, Herbst F (2002) TP53 genotype but not p53 immunohistochemical result predicts response to preoperative short-term radiotherapy in rectal cancer. Ann Surg 235(4):493–498

    Article  PubMed Central  PubMed  Google Scholar 

  16. McIlwrath AJ, Vasey PA, Ross GM, Brown R (1994) Cell cycle arrests and radiosensitivity of human tumor cell lines: dependence on wild-type p53 for radiosensitivity. Cancer Res 54(14):3718–3722

    CAS  PubMed  Google Scholar 

  17. Kandioler D, Stamatis G, Eberhardt W, Kappel S, Zochbauer-Muller S, Kuhrer I, Mittlbock M, Zwrtek R, Aigner C, Bichler C, Tichy V, Hudec M, Bachleitner T, End A, Muller MR, Roth E, Klepetko W (2008) Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non-small cell lung cancer. J Thorac Cardiovasc Surg 135(5):1036–1041. doi:10.1016/j.jtcvs.2007.10.072

    Article  CAS  PubMed  Google Scholar 

  18. Kandioler D, Schoppmann SF, Zwrtek R, Kappel S, Wolf B, Mittlbock M, Kuhrer I, Hejna M, Pluschnig U, Ba-Ssalamah A, Wrba F, Zacherl J, Zacherl J (2014) The biomarker TP53 divides patients with neoadjuvantly treated esophageal cancer into 2 subgroups with markedly different outcomes. A p53 research group study. J Thorac Cardiovasc Surg. doi:10.1016/j.jtcvs.2014.1006.1079

    PubMed  Google Scholar 

  19. Sclafani F, Gonzalez D, Cunningham D, Hulkki Wilson S, Peckitt C, Tabernero J, Glimelius B, Cervantes A, Dewdney A, Wotherspoon A, Brown G, Tait D, Oates J, Chau I (2014) TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial. J Natl Cancer Inst. doi:10.1093/jnci/dju121

    PubMed  Google Scholar 

  20. Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C (2003) Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA 100(14):8424–8429. doi:10.1073/pnas.1431692100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. 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. doi:10.1002/humu.20495

    Article  CAS  PubMed  Google Scholar 

  22. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(4985):1233–1238

    Article  CAS  PubMed  Google Scholar 

  23. Achatz MI, Olivier M, Le Calvez F, Martel-Planche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, Da Rocha JC, Vettore AL, Hainaut P (2007) The TP53 mutation, R337H, is associated with Li–Fraumeni and Li–Fraumeni-like syndromes in Brazilian families. Cancer Lett 245(1–2):96–102

    Article  CAS  PubMed  Google Scholar 

  24. Fiszer-Maliszewska L, Kazanowska B, Padzik J (2009) p53 Tetramerization domain mutations: germline R342X and R342P, and somatic R337G identified in pediatric patients with Li–Fraumeni syndrome and a child with adrenocortical carcinoma. Fam Cancer 8(4):541–546

    Article  CAS  PubMed  Google Scholar 

  25. Bougeard G, Sesboue R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, Brugieres L, Chompret A, de Paillerets BB, Stoppa-Lyonnet D, Bonaiti-Pellie C, Frebourg T, The French LFS working group (2008) Molecular basis of the Li–Fraumeni syndrome: an update from the French LFS families. J Med Genet 45(8):535–538. doi:10.1136/jmg.2008.057570

  26. Chene P (2001) The role of tetramerization in p53 function. Oncogene 20(21):2611–2617

    Article  CAS  PubMed  Google Scholar 

  27. Eeles RA (1995) Germline mutations in the TP53 gene. Cancer Surv 25:101–124

    CAS  PubMed  Google Scholar 

  28. Etzold A, Schroder JC, Bartsch O, Zechner U, Galetzka D (2014) Further evidence for pathogenicity of the TP53 tetramerization domain mutation p.Arg342Pro in Li–Fraumeni syndrome. Fam cancer. doi:10.1007/s10689-014-9754-z

    Google Scholar 

  29. Rollenhagen C, Chene P (1998) Characterization of p53 mutants identified in human tumors with a missense mutation in the tetramerization domain. Int J Cancer 78(3):372–376

    Article  CAS  PubMed  Google Scholar 

  30. Camplejohn RS, Rutherford J (2001) p53 functional assays: detecting p53 mutations in both the germline and in sporadic tumours. Cell Prolif 34(1):1–14

    Article  CAS  PubMed  Google Scholar 

  31. Meinhold-Heerlein I, Ninci E, Ikenberg H, Brandstetter T, Ihling C, Schwenk I, Straub A, Schmitt B, Bettendorf H, Iggo R, Bauknecht T (2001) Evaluation of methods to detect p53 mutations in ovarian cancer. Oncology 60(2):176–188

    Article  CAS  PubMed  Google Scholar 

  32. Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bieche I, Varley J, Bignon Y, Uhrhammer N, Winqvist R, Jukkola-Vuorinen A, Niederacher D, Kato S, Ishioka C, Hainaut P, Borresen-Dale AL (2006) The clinical value of somatic TP53 gene mutations in 1794 patients with breast cancer. Clin Cancer Res 12(4):1157–1167. doi:10.1158/1078-0432.CCR-05-1029

    Article  CAS  PubMed  Google Scholar 

  33. Faille A, De Cremoux P, Extra JM, Linares G, Espie M, Bourstyn E, De Rocquancourt A, Giacchetti S, Marty M, Calvo F (1994) p53 mutations and overexpression in locally advanced breast cancers. Br J Cancer 69(6):1145–1150

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Izawa N, Matsumoto S, Manabe J, Tanizawa T, Hoshi M, Shigemitsu T, Machinami R, Kanda H, Takeuchi K, Miki Y, Arai M, Shirahama S, Kawaguchi N (2008) A Japanese patient with Li–Fraumeni syndrome who had nine primary malignancies associated with a germline mutation of the p53 tumor-suppressor gene. Int J Clin Oncol 13(1):78–82

    Article  PubMed  Google Scholar 

  35. Salmon A, Amikam D, Sodha N, Davidson S, Basel-Vanagaite L, Eeles RA, Abeliovich D, Peretz T (2007) Rapid development of post-radiotherapy sarcoma and breast cancer in a patient with a novel germline ‘de-novo’ TP53 mutation. Clin Oncol (R Coll Radiol) 19(7):490–493

    Article  CAS  Google Scholar 

  36. Warren S, Sommer GN (1936) Fibrosarcoma of the soft parts with special reference to recurrence and metastasis. Arch Surg 33:425–450

    Article  Google Scholar 

  37. Sheppard DG, Libshitz HI (2001) Post-radiation sarcomas: a review of the clinical and imaging features in 63 cases. Clin Radiol 56(1):22–29. doi:10.1053/crad.2000.0599

    Article  CAS  PubMed  Google Scholar 

  38. Zhang SS, Huang QY, Yang H, Xie X, Luo KJ, Wen J, Cai XL, Yang F, Hu Y, Fu JH (2013) Correlation of p53 status with the response to chemotherapy-based treatment in esophageal cancer: a meta-analysis. Ann Surg Oncol 20(7):2419–2427. doi:10.1245/s10434-012-2859-4

    Article  PubMed  Google Scholar 

  39. Kandioler-Eckersberger D, Ludwig C, Rudas M, Kappel S, Janschek E, Wenzel C, Schlagbauer-Wadl H, Mittlbock M, Gnant M, Steger G, Jakesz R (2000) TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res 6(1):50–56

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the LFS family members for support in data collection and for assistance in completing the pedigree.

Conflict of interest

Sonja Kappel is a part-time employee of MARK53 LTD Vienna. Daniela Kandioler is an uncompensated consultant and holds a leadership position at MARK53 LTD Vienna. Other authors have no conflicts of interest to declare.

Ethical standards

The Medical University of Vienna commits to the principles of the Declaration of Helsinki, and thus ethical guidelines were observed in all procedures concerning the LFS family. The p53 Research Group (Medical University of Vienna) received approval for TP53 germline testing from the Austrian Federal Ministry of Health and Women.

Author information

Authors and Affiliations

  1. Department of Surgery, Surgical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Sonja Kappel & Brigitte Wolf

  2. Department of Gynecology and Obstetrics, Hospital Villach, Nikolaigasse 43, 9500, Villach, Austria

    Elisabeth Janschek

  3. Department of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Margaretha Rudas

  4. Department of General Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Bela Teleky, Raimund Jakesz & Daniela Kandioler

Authors
  1. Sonja Kappel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabeth Janschek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brigitte Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margaretha Rudas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bela Teleky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Raimund Jakesz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniela Kandioler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sonja Kappel.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kappel, S., Janschek, E., Wolf, B. et al. TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li–Fraumeni family. Breast Cancer Res Treat 151, 671–678 (2015). https://doi.org/10.1007/s10549-015-3424-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-015-3424-1

Keywords

Search

Navigation