Familial Cancer

, Volume 18, Issue 2, pp 273–280 | Cite as

TP53 germline mutation testing in early-onset breast cancer: findings from a nationwide cohort

  • J. J. BakhuizenEmail author
  • F. B. Hogervorst
  • M. E. Velthuizen
  • M. W. Ruijs
  • K. van Engelen
  • T. A. van Os
  • J. J. Gille
  • M. Collée
  • A. M. van den Ouweland
  • C. J. van Asperen
  • C. M. Kets
  • A. R. Mensenkamp
  • E. M. Leter
  • M. J. Blok
  • M. M. de Jong
  • M. G. Ausems
Original Article


Early-onset breast cancer may be due to Li–Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31 years. However, large studies investigating TP53 mutation prevalence in this population are scarce. We collected nationwide laboratory records for all young breast cancer patients tested for TP53 mutations in the Netherlands. Between 2005 and 2016, 370 women diagnosed with breast cancer younger than 30 years of age were tested for TP53 germline mutations, and eight (2.2%) were found to carry a (likely) pathogenic TP53 sequence variant. Among BRCA1/BRCA2 mutation negative women without a family history suggestive of LFS or a personal history of multiple LFS-related tumours, the TP53 mutation frequency was < 1% (2/233). Taking into consideration that TP53 mutation prevalence was comparable or even higher in some studies selecting patients with breast cancer onset at older ages or HER2-positive breast cancers, raises the question of whether a very early age of onset is an appropriate single TP53 genetic testing criterion.


Genetic testing Li–Fraumeni syndrome TP53 Breast cancer Hereditary 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The Medical Research Ethical Committee concluded that the Medical Research Human Subject Acts (WMO) does not apply.


  1. 1.
    Netherlands Comprehensive Cancer Organisation (IKNL) (2016) Dutch cancer Figs. 2016 [Internet]. Accessed May 21 2018
  2. 2.
    Turnbull C, Rahman N (2008) Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet 9:321–345CrossRefGoogle Scholar
  3. 3.
    Tung N, Lin NU, Kidd J et al (2016) Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 34(13):1460–1468CrossRefGoogle Scholar
  4. 4.
    Claus EB, Risch NJ, Thompson D (1990) Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol 131(6):961–972CrossRefGoogle Scholar
  5. 5.
    NABON (2017) Breast Cancer, Dutch Guideline [Internet]. Accessed May 25 2018
  6. 6.
    National Comprehensive Cancer Network (2018) NCCN Clinical Practice Guidelines in Oncology: genetic/familial high risk assessment: breast and ovarian (Version 2.2019) [internet]. (registration required). Accessed 7 Nov 2018
  7. 7.
    Adank MA, Hes FJ, van Zelst-Stams WAG et al (2015) CHEK2-mutation in Dutch breast cancer families: expanding genetic testing for breast cancer (in Dutch). Ned Tijdschr Geneeskd 159:A8910Google Scholar
  8. 8.
    Schneider K, Zelley K, Nichols KE et al (1999) Li–Fraumeni syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al (eds) GeneReviews [Internet]. University of Washington, Seattle, WAGoogle Scholar
  9. 9.
    Gonzalez KD, Noltner KA, Buzin CH et al (2009) Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 27(8):1250–1256CrossRefGoogle Scholar
  10. 10.
    Mai PL, Best AF, Peters JA et al (2016) Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li–Fraumeni syndrome cohort. Cancer 122(23):3673–3681CrossRefGoogle Scholar
  11. 11.
    Bougeard G, Renaux-Petel M, Flaman JM et al (2015) Revisiting Li–Fraumeni Syndrome from TP53 mutation carriers. J Clin Oncol 33(21):2345–2352CrossRefGoogle Scholar
  12. 12.
    Li FP, Fraumeni JF Jr, Mulvihill JJ et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362Google Scholar
  13. 13.
    Birch JM, Hartley AL, Tricker KJ et al (1994) Prevalence and diversity of constitutional mutations in the P53 gene among 21 Li–Fraumeni families. Cancer Res 54(5):1298–1304Google Scholar
  14. 14.
    Eeles RA (1995) Germline mutations in the TP53 gene. Cancer Surv 25:101–124Google Scholar
  15. 15.
    Chompret A, Abel A, Stoppa-Lyonnet D et al (2001) Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38(1):43–47CrossRefGoogle Scholar
  16. 16.
    Tinat J, Bougeard G, Baert-Desurmont S et al (2009) 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27(26):e108-9CrossRefGoogle Scholar
  17. 17.
    Renaux-Petel M, Charbonnier F, Thery JC et al (2018) Contribution of de novo and mosaic TP53 mutations to Li–Fraumeni syndrome. J Med Genet 55(3):173–180Google Scholar
  18. 18.
    Rana HQ, Gelman R, LaDuca H et al (2018) Differences in TP53 mutation carrier phenotypes emerge from panel-based testing. J Natl Cancer Inst 110(8):863–870CrossRefGoogle Scholar
  19. 19.
    Amadou A, Waddington Achatz MI, Hainaut P (2018) Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li–Fraumeni syndrome. Curr Opin Oncol 30(1):23–29CrossRefGoogle Scholar
  20. 20.
    Fortuno C, James PA, Spurdle AB (2018) Current review of TP53 pathogenic germline variants in breast cancer patients outside Li–Fraumeni syndrome. Hum Mutat 39:1764–1773CrossRefGoogle Scholar
  21. 21.
    Bouaoun L, Sonkin D, Ardin M et al (2016) TP53 variations in human cancers: new lessons from the IARC TP53 database and genomics data. Hum Mutat 37(9):865–876CrossRefGoogle Scholar
  22. 22.
    Lalloo F, Varley J, Moran A et al (2006) BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 42(8):1143–1150CrossRefGoogle Scholar
  23. 23.
    Mouchawar J, Korch C, Byers T et al (2010) Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res 70(12):4795–4800CrossRefGoogle Scholar
  24. 24.
    McCuaig JM, Armel SR, Novokmet A et al (2012) Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer 11(4):607–613CrossRefGoogle Scholar
  25. 25.
    Ginsburg OM, Akbari MR, Aziz Z et al (2009) The prevalence of germline TP53 mutations in women diagnosed with breast cancer before age 30. Fam Cancer 8(4):563–567CrossRefGoogle Scholar
  26. 26.
    Eccles DM, Li N, Handwerker R et al (2016) Genetic testing in a cohort of young patients with HER2-amplified breast cancer. Ann Oncol 27(3):467–473CrossRefGoogle Scholar
  27. 27.
    Wilson JR, Bateman AC, Hanson H et al (2010) A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet 47(11):771–774CrossRefGoogle Scholar
  28. 28.
    Masciari S, Dillon DA, Rath M et al (2012) Breast cancer phenotype in women with TP53 germline mutations: a Li–Fraumeni syndrome consortium effort. Breast Cancer Res Treat 133(3):1125–1130CrossRefGoogle Scholar
  29. 29.
    Melhem-Bertrandt A, Bojadzieva J, Ready KJ et al (2012) Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 118(4):908–913CrossRefGoogle Scholar
  30. 30.
    Netherlands Foundation for the Detection of Hereditary Tumours (STOET) and the Dutch Society of Clinical Genetics (VKGN) (2005) Guidelines for the diagnosis and prevention of hereditary cancer predisposition syndromes (in Dutch). Edition 2005Google Scholar
  31. 31.
    Netherlands Foundation for the Detection of Hereditary Tumours (STOET) and the Dutch Society of Clinical Genetics (VKGN) (2010) Guidelines for the diagnosis and prevention of hereditary cancer predisposition syndromes (in Dutch). Edition 2010Google Scholar
  32. 32.
    Netherlands Foundation for the Detection of Hereditary Tumours (STOET) and the Dutch Society of Clinical Genetics (VKGN) (2017) Guidelines for the diagnosis and prevention of hereditary cancer predisposition syndromes (in Dutch). Edition 2017Google Scholar
  33. 33.
    Bakhuizen JJ, Velthuizen ME, Stehouwer S et al (2018) Genetic counselling of young women with breast cancer for Li–Fraumeni syndrome: a nationwide survey on the experiences and attitudes of genetics professionals. Fam Cancer. Google Scholar
  34. 34.
    Wevers MR, Aaronson NK, Verhoef S et al (2014) Impact of rapid genetic counselling and testing on the decision to undergo immediate or delayed prophylactic mastectomy in newly diagnosed breast cancer patients: findings from a randomised controlled trial. Br J Cancer 110(4):1081–1087CrossRefGoogle Scholar
  35. 35.
    Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424CrossRefGoogle Scholar
  36. 36.
    Lee DS, Yoon SY, Looi LM et al (2012) Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res 14(2):R66. CrossRefGoogle Scholar
  37. 37.
    Ang P, Lim IH, Yong RY, Lee AS (2009) A molecular approach for identifying individuals with Li–Fraumeni syndrome who have a limited family history. Clin Genet 75(3):294–297CrossRefGoogle Scholar
  38. 38.
    Carraro DM, Koike Folgueira MA, Garcia Lisboa BC et al (2013) Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil. PLoS ONE 8(3):e57581CrossRefGoogle Scholar
  39. 39.
    Rath MG, Masciari S, Gelman R et al (2013) Prevalence of germline TP53 mutations in HER2+ breast cancer patients. Breast Cancer Res Treat 139(1):193–198CrossRefGoogle Scholar
  40. 40.
    O’Shea R, Clarke R, Berkley E et al (2017) Next generation sequencing is informing phenotype: a TP53 example. Fam Cancer 17(1):123–128CrossRefGoogle Scholar
  41. 41.
    Schon K, Tischkowitz M (2018) Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat 167(2):417–423CrossRefGoogle Scholar
  42. 42.
    Heymann S, Delaloge S, Rahal A et al (2010) Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li–Fraumeni syndrome. Radiat Oncol 5:104CrossRefGoogle Scholar
  43. 43.
    Lammens C, Bleiker E, Aaronson N et al (2009) Attitude towards pre-implantation genetic diagnosis for hereditary cancer. Fam Cancer 8(4):457–464CrossRefGoogle Scholar
  44. 44.
    PGD Netherlands (2017) Annual report 2017 [Internet]. Accessed 7 Nov 2018
  45. 45.
    Ballinger ML, Best A, Mai PL et al (2017) Baseline surveillance in Li–Fraumeni Syndrome using whole-body magnetic sesonance imaging: a meta-analysis. JAMA Oncol 3(12):1634–1639CrossRefGoogle Scholar
  46. 46.
    Villani A, Tabori U, Schiffman J et al (2011) Biochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: a prospective observational study. Lancet Oncol 12(6):559–567CrossRefGoogle Scholar
  47. 47.
    Villani A, Shore A, Wasserman JD et al (2016) Biochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol 17(9):1295–1305CrossRefGoogle Scholar
  48. 48.
    McBride KA, Ballinger ML, Killick E et al (2014) Li–Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol 11(5):260–271CrossRefGoogle Scholar
  49. 49.
    Ruijs MWG, Loo CE, van Buchem CAJM, Bleiker EMA, Sonke GS (2017) Surveillance of Dutch patients with Li–Fraumeni syndrome: the LiFe-Guard Study. JAMA Oncol 3(12):1733–1734CrossRefGoogle Scholar
  50. 50.
    Peterson SK, Pentz RD, Marani SK et al (2008) Psychological functioning in persons considering genetic counseling and testing for Li–Fraumeni syndrome. Psychooncology 17(8):783–789CrossRefGoogle Scholar
  51. 51.
    Lammens CR, Aaronson NK, Wagner A et al (2010) Genetic testing in Li–Fraumeni syndrome: uptake and psychosocial consequences. J Clin Oncol 28(18):3008–3014CrossRefGoogle Scholar
  52. 52.
    Lammens CR, Bleiker EM, Verhoef S et al (2011) Distress in partners of individuals diagnosed with or at high risk of developing tumors due to rare hereditary cancer syndromes. Psychooncology 20(6):631–638CrossRefGoogle Scholar
  53. 53.
    Azzollini J, Mariani M, Peissel B, Manoukian S (2018) Increased access to TP53 analysis through breast cancer multi-gene panels: clinical considerations. Fam Cancer 17(3):317–319CrossRefGoogle Scholar
  54. 54.
    MacFarland SP, Maxwell KN (2018) The differential diagnosis of a TP53 genetic testing result. Genet Med 20(8):806–808CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • J. J. Bakhuizen
    • 1
    Email author
  • F. B. Hogervorst
    • 2
  • M. E. Velthuizen
    • 1
  • M. W. Ruijs
    • 2
  • K. van Engelen
    • 3
  • T. A. van Os
    • 3
  • J. J. Gille
    • 3
  • M. Collée
    • 4
  • A. M. van den Ouweland
    • 4
  • C. J. van Asperen
    • 5
  • C. M. Kets
    • 6
  • A. R. Mensenkamp
    • 6
  • E. M. Leter
    • 7
  • M. J. Blok
    • 7
  • M. M. de Jong
    • 8
  • M. G. Ausems
    • 1
  1. 1.Department of GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Family Cancer ClinicNetherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Department of Clinical GeneticsAmsterdam University Medical CentersAmsterdamThe Netherlands
  4. 4.Department of Clinical GeneticsErasmus University Medical CenterRotterdamThe Netherlands
  5. 5.Department of Clinical GeneticsLeiden University Medical CenterLeidenThe Netherlands
  6. 6.Department of Human GeneticsRadboud University Nijmegen Medical CenterNijmegenThe Netherlands
  7. 7.Department of Clinical GeneticsMaastricht University Medical CenterMaastrichtThe Netherlands
  8. 8.Department of Clinical Genetics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands

Personalised recommendations