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Routine TP53 testing for breast cancer under age 30: ready for prime time?

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Abstract

It is well known that early-onset breast cancer may be due to an inherited predisposition. When evaluating women diagnosed with breast cancer under age 30, two important syndromes are typically considered: Hereditary Breast and Ovarian Cancer Syndrome and Li-Fraumeni syndrome. Many women are offered genetic testing for mutations in the BRCA1 and BRCA2 genes; however, few are offered genetic testing for mutations in the TP53 gene. There is a concern that overly restrictive testing of TP53 may fail to recognize families with Li-Fraumeni syndrome. We reviewed the genetic test results and family histories of all women with early-onset breast cancer who had genetic testing of the TP53 gene at the Toronto Hospital for Sick Children. Of the 28 women tested, six (33.3 %) had a mutation in the TP53 gene; a mutation was found in 7.7 % of women who did not meet current criteria for Li-Fraumeni syndrome. By reviewing similar data published between 2000 and 2011, we estimate that 5–8 % of women diagnosed with early-onset breast cancer, and who have a negative family history, may have a mutation in the TP53 gene. Given the potential benefits versus harms of this testing, we discuss the option of simultaneous testing of all three genes (BRCA1, BRCA2, and TP53) for women diagnosed with breast cancer before age 30.

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References

  1. Collaborative Group on Hormonal Factors in Breast Cancer (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358(9291):1389–1399

    Article  Google Scholar 

  2. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjäkoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130

    Article  PubMed  CAS  Google Scholar 

  3. U.S. Preventive Services Task Force (2005) Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 143(5):355–361

    Google Scholar 

  4. Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, Lanchbury S, Stemke-Hale K, Hennessy BT, Arun BK, Hortobagyi GN, Do KA, Mills GB, Meric-Bernstam F (2011) Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17(5):1082–1089

    Article  PubMed  CAS  Google Scholar 

  5. Wu CC, Shete S, Amos CI, Strong LC (2006) Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res 66(16):8287–8292

    Article  PubMed  CAS  Google Scholar 

  6. Wilson JRF, Bateman AC, Hanson H, An Q, Evans G, Rahman N et al (2010) A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet 47:771–774

    Article  PubMed  CAS  Google Scholar 

  7. Amal Melhem-Bertrandt A, Bojadzieva J, Ready KJ, Obeid E, Liu DD, Gutierrez-Barrera AM et al (2011) Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 118(4):908–913

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  10. Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, Harris M, Jones PH, Binchy A, Crowther D, Craft AW, Eden OB, Evans DGR, Thompson E, Mann JR, Martin J, Mitchell ELD, Santibanez-Koref MF (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 54(5):1298–1304

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  12. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, Bonaïti-Pillié C, Stoppa-Lyonnet D, Frébourg T (2009) 2009 version of the Chompret criteria for Li-Fraumeni syndrome. J Clin Onco 27(26):e108–e109

    Article  Google Scholar 

  13. Toronto Hospital for Sick Children (n.d.) Li-Fraumeni syndrome. In: Molecular genetics laboratory: test services available. 2011. [http://www.sickkids.ca/PaediatricLaboratoryMedicine/Laboratories-Services/Molecular-Genetics-Laboratory/Test-Services-Available/Li-Fraumeni-Syndrome.html#3]

  14. Lalloo F, Varley J, Ellis D, Moran A, O’Dair L, Pharoah P, Evans DG, Early Onset Breast Cancer Study Group (2003) Prediction of pathogenic mutations in patients with early-onset family history. Lancet 361(9363):1101–1102

    Article  PubMed  CAS  Google Scholar 

  15. Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, Foretova L, Soucek P, King MC (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295(12):1379–1388

    Article  PubMed  CAS  Google Scholar 

  16. Bougeard G, Sesboüé R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, Brugières L, Compret A, de Paillerets BB, Stoppa-Lyonnet D, Bonaïti-Pillié C, Frébourg T, 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

    Article  PubMed  CAS  Google Scholar 

  17. Ruijs MW, Verhoef S, Rookus MA, Pruntel R, van der Hout AH, Hogervorst FB, Kluijt I, Siimons RH, Aalfs CW, Wagner A, Ausems MG, Hoogerbrugge N, van Asperen CJ, Gomez Garcia EB, Meihers-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

    Article  PubMed  CAS  Google Scholar 

  18. Ginsburg OM, Akbari MR, Aziz Z, Young R, Lynch H, Ghadirian P, Robidoux A, Londono J, Vasquez G, Gomes M, Costa MM, Dimitrakakis C, Gutierrez G, Pilarski R, Royer R, Narod SA (2009) The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. Fam Cancer 8(4):563–567

    Article  PubMed  CAS  Google Scholar 

  19. Gonzalez KD, Noltner KA, Buszin CH, Gu D, Wen-Fong CY, Nguyen VQ, Han JH, Lowstuter K, Longmate J, Sommer SS, Weitzel JN (2009) Beyond Li-Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 27(8):1250–1256

    Article  PubMed  CAS  Google Scholar 

  20. Mouchawar J, Korch C, Byers T, Pitts TM, Li E, McCredie MR, Gilies GG, Hopper JL, Southey MC (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):4795–4800

    Article  PubMed  CAS  Google Scholar 

  21. Malone KE, Daling JR, Neal C, Suter NM, O’Brien C, Cushing-Haugen K, Jonasdottir TJ, Thompson JD, Ostrander EA (2000) Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer 88(6):1393–1402

    Article  PubMed  CAS  Google Scholar 

  22. Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, Easton DF (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318

    Article  PubMed  CAS  Google Scholar 

  23. Hansen TV, Bisgaard ML, Jønson L, Albrechtsen A, Filtenborg-Barnkob B, Eiberg H, Ejlertsen B, Nielsen FC (2008) Novel de novo BRCA2 mutation in a patient with a family history of breast cancer. BMC Med Genet 9:58

    Article  PubMed  Google Scholar 

  24. Marshall M, Solomon S, Lawrence Wickerham D (2009) Case report: de novo BRCA2 gene mutation in a 35-year-old woman with breast cancer. Clin Genet 76(5):427–430

    Article  PubMed  CAS  Google Scholar 

  25. Robson M, Scheuer L, Nafa K, Ellis N, Offit K (2002) Unique de novo mutation of BRCA2 in a woman with early onset breast cancer. J Med Genet 39(2):126–128

    Article  PubMed  CAS  Google Scholar 

  26. Tesoriero A, Andersen C, Southey M, Somers F, McKay M, Armes J, McCredie M, Giles G, Hopper JL, Venter D (1999) De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 65(2):567–569

    Article  PubMed  CAS  Google Scholar 

  27. van der Luijt RB, van Zon PH, Jansen RP, van der Sijs-Bos CJ, Warlam-Rodenhuis CC, Ausems MG (2001) De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer. J Med Genet 38(2):102–105

    Article  PubMed  Google Scholar 

  28. Edwards E, Yearwood C, Sillibourne J, Baralle D, Eccles D (2009) Identification of a de novo BRCA1 mutation in a woman with early onset bilateral breast cancer. Fam Cancer 8(4):479–482

    Google Scholar 

  29. Gonzalez KD, Buzin CH, Noltner KAGuD, Li W, Malkin D, Sommer SS (2009) High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet 46(10):689–693

    Article  PubMed  CAS  Google Scholar 

  30. 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  PubMed  CAS  Google Scholar 

  31. Villani A, Tabori U, Schiffman J, Shlien A, Bevene J, Druker H, Novokmet A, Finlay J, Malkin D (2011) Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 12(6):559–567

    Article  PubMed  CAS  Google Scholar 

  32. Lee DSC, Yoon S, Looi LM, Kang P, Kang IN, Sivanandan K 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:R66

    Article  PubMed  CAS  Google Scholar 

  33. Canadian Cancer Society’s Steering Committee on Cancer Statistics (2011) Canadian cancer statistics 2011. Canadian Cancer Society, Toronto

    Google Scholar 

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Acknowledgments

No funding was received for this study.

Conflict of interest

The authors have no financial/ethical conflict of interests to declare. All authors have reviewed the content of the article.

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Authors and Affiliations

  1. Division of Gynecologic Oncology, Princess Margaret Hospital, University Health Network, M-704 610 University Avenue, Toronto, ON, M5G 2M9, Canada

    Jeanna M. McCuaig, Susan R. Armel & Rochelle Demsky

  2. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Susan R. Armel & Rochelle Demsky

  3. Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Ana Novokmet & David Malkin

  4. Women’s College Research Institute and the Department of Medicine, University of Toronto, Toronto, ON, Canada

    Ophira M. Ginsburg

  5. Women’s College Research Institute, University of Toronto, Toronto, ON, Canada

    Steven A. Narod

Authors
  1. Jeanna M. McCuaig
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  2. Susan R. Armel
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  3. Ana Novokmet
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Correspondence to Jeanna M. McCuaig.

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McCuaig, J.M., Armel, S.R., Novokmet, A. et al. Routine TP53 testing for breast cancer under age 30: ready for prime time?. Familial Cancer 11, 607–613 (2012). https://doi.org/10.1007/s10689-012-9557-z

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  • DOI: https://doi.org/10.1007/s10689-012-9557-z

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