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TP53 germline mutation testing in 180 families suspected of Li–Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes
  1. Marielle W G Ruijs1,2,
  2. Senno Verhoef1,
  3. Matti A Rookus3,
  4. Roelof Pruntel1,
  5. Annemarie H van der Hout4,
  6. Frans B L Hogervorst1,
  7. I Kluijt1,
  8. Rolf H Sijmons4,
  9. Cora M Aalfs5,
  10. Anja Wagner6,
  11. Margreet G E M Ausems7,
  12. Nicoline Hoogerbrugge8,
  13. Christi J van Asperen9,
  14. Encarna B Gomez Garcia10,
  15. Hanne Meijers-Heijboer2,
  16. Leo P ten Kate2,
  17. Fred H Menko2,
  18. Laura J van 't Veer1
  1. 1Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  2. 2Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
  3. 3Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  4. 4Department of Genetics, University Medical Centre, Groningen, The Netherlands
  5. 5Department of Clinical Genetics, Amsterdam Medical Centre, Amsterdam, The Netherlands
  6. 6Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
  7. 7Department of Clinical Genetics, University Medical Centre, Utrecht, The Netherlands
  8. 8Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands
  9. 9Department of Clinical Genetics, Leiden University Medical Centre, The Netherlands
  10. 10Department of Clinical Genetics, University Medical Centre, Maastricht, The Netherlands
  1. Correspondence to Dr Laura J van 't Veer, The Netherlands Cancer Institute, Department of Pathology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; l.vt.veer{at}


Background Li–Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria are in use to decide which patients qualify for TP53 mutation analysis, including the LFS, Li–Fraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest mutation detection rate and sensitivity in Dutch families. We describe the tumour spectrum in TP53-positive families and calculated tumour type specific relative risks.

Method A total of 180 Dutch families referred for TP53 mutation analysis were evaluated. Tumour phenotypes were verified by pathology reports or clinical records.

Results A TP53 germline mutation was identified in 24 families. When the Chompret criteria were used 22/24 mutations were detected (sensitivity 92%, mutation detection rate 21%). In LFS and LFL families 18/24 mutations were found (sensitivity 75%). The two mutations detected outside the ‘Chompret group’ were found in a child with rhabdomyosarcoma and a young woman with breast cancer. In the mutation carriers, in addition to the classical LFS tumour types, colon and pancreatic cancer were also found significantly more often than in the general population.

Conclusion We suggest TP53 mutation testing for all families fulfilling the Chompret criteria. In addition, TP53 mutation testing can be considered in the event of childhood sarcoma and breast cancer before 30 years. In addition to the risk for established LFS tumour types, TP53-positive individuals may also have an elevated risk for pancreatic and colon cancer.

  • Li-Fraumeni syndrome
  • TP53 germline mutations
  • mutation detection rate
  • tumour types
  • relative risks
  • clinical genetics
  • genetic screening/counselling
  • molecular genetics
  • oncology

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  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.