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Prevalence of germline TP53 mutations in HER2+ breast cancer patients

  • Epidemiology
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Abstract

Breast cancer is the most frequent tumor in Li–Fraumeni syndrome (LFS), a rare inherited cancer syndrome associated with germline mutations in the TP53 gene. Recent data show that breast cancer in germline TP53 mutation carriers is commonly HER2+ (63–83 %). We assessed the prevalence of germline TP53 mutations in a cohort of women with HER2+ breast cancer diagnosed age ≤50 years. We identified blood specimens from 213 women with primary invasive HER2+ breast cancer age ≤50 years from a single center. Exon grouping analysis sequencing and multiplex ligation-dependent probe amplification techniques were used to screen for germline TP53 mutations. Among 213 women with HER2+ breast cancer age ≤50 years, 3 (ages at diagnosis 23, 32, 44 years) were found to carry a TP53 mutation (1.4 %, 95 % CI 0.3–4.1 %). ER/PR status was not uniform. Two TP53 carriers met Chompret criteria for LFS; none met classic LFS criteria. Although two-thirds of breast cancers in women with TP53 mutations are HER2+, we observed a low prevalence of germline TP53 mutations among unselected young women with HER2+ breast cancer. Given the potential clinical impact, consideration of germline TP53 testing should be given to young women with HER2+ breast cancer, especially if family cancer history is notable.

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References

  1. Chompret A, Abel A, Stoppa-Lyonnet D, Brugieres L, Pages S, Feunteun J, Bonaiti-Pellie C (2001) Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38:43–47

    Article  PubMed  CAS  Google Scholar 

  2. Davies H, Dicks E, Stephens P, Cox C, Teague J, Greenman C, Bignell G, O’Meara S, Edkins S, Parker A, Stevens C, Menzies A, Blow M, Bottomley B, Dronsfield M, Futreal PA, Stratton MR, Wooster R (2006) High throughput DNA sequence variant detection by conformation sensitive capillary electrophoresis and automated peak comparison. Genomics 87:427–432. doi:10.1016/j.ygeno.2005.11.008

    Article  PubMed  CAS  Google Scholar 

  3. Ganguly A, Rock MJ, Prockop DJ (1993) Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc Natl Acad Sci U S A 90:10325–10329

    Article  PubMed  CAS  Google Scholar 

  4. Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni JF Jr, Li FP (1991) Follow-up study of twenty-four families with Li–Fraumeni syndrome. Cancer Res 51:6094–6097

    PubMed  CAS  Google Scholar 

  5. 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 8:563–567. doi:10.1007/s10689-009-9287-z

    Article  PubMed  CAS  Google Scholar 

  6. Gonzalez KD, Buzin CH, Noltner KA, Gu D, Li W, Malkin D, Sommer SS (2009) High frequency of de novo mutations in Li–Fraumeni syndrome. J Med Genet 46:689–693. doi:10.1136/jmg.2008.058958

    Article  PubMed  CAS  Google Scholar 

  7. Hernandez-Boussard T, Rodriguez-Tome P, Montesano R, Hainaut P (1999) IARC p53 mutation database: a relational database to compile and analyze p53 mutations in human tumors and cell lines. International Agency for Research on Cancer. Hum Mutat 14:1–8

    Article  PubMed  CAS  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 90:606–611

    Article  PubMed  CAS  Google Scholar 

  9. Hwang SJ, Lozano G, Amos CI, Strong LC (2003) Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet 72:975–983. doi:10.1086/374567

    Article  PubMed  CAS  Google Scholar 

  10. 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 150:1–13

    PubMed  CAS  Google Scholar 

  11. Korkko J, Annunen S, Pihlajamaa T, Prockop DJ, Ala-Kokko L (1998) Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: comparison with denaturing gradient gel electrophoresis and nucleotide sequencing. Proc Natl Acad Sci U S A 95:1681–1685

    Article  PubMed  CAS  Google Scholar 

  12. Lalloo F, Varley J, Ellis D, Moran A, O’Dair L, Pharoah P, Evans DG (2003) Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet 361:1101–1102. doi:10.1016/S0140-6736(03)12856-5

    Article  PubMed  CAS  Google Scholar 

  13. Lalloo F, Varley J, Moran A, Ellis D, O’Dair L, Pharoah P, Antoniou A, Hartley R, Shenton A, Seal S, Bulman B, Howell A, Evans DG (2006) BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 42:1143–1150. doi:10.1016/j.ejca.2005.11.032

    Article  PubMed  CAS  Google Scholar 

  14. Langerod A, Zhao H, Borgan O, Nesland JM, Bukholm IR, Ikdahl T, Karesen R, Borresen-Dale AL, Jeffrey SS (2007) TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res 9:R30. doi:10.1186/bcr1675

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. 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 48:5358–5362

    PubMed  CAS  Google Scholar 

  17. 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 96:238–242

    Article  PubMed  CAS  Google Scholar 

  18. Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Balmana J, Gruber SB, Ford JM, Euhus D, Lebensohn A, Telli M, Pochebit SM, Lypas G, Garber JE (2012) Breast cancer phenotype in women with TP53 germline mutations: a Li–Fraumeni syndrome consortium effort. Breast Cancer Res Treat 133:1125–1130

    Article  PubMed  CAS  Google Scholar 

  19. Masciari SD, Dick MG, Robson ME, Weitzel JN, Ford JM, Balmaña J, Gruber SB, Euhus D, Garber JE (2011) Breast cancer phenotype in women with TP53 germ-line mutations: an LFS consortium effort. In: ASCO 2011, Chicago, USA

  20. Melhem-Bertrandt A, Bojadzieva J, Ready KJ, Obeid E, Liu DD, Gutierrez-Barrera AM, Litton JK, Olopade OI, Hortobagyi GN, Strong LC, Arun BK (2012) Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 118:908–913. doi:10.1002/cncr.26377

    Article  PubMed  CAS  Google Scholar 

  21. NCCN (2011) National Comprehensive Cancer Network: practice guidelines in oncology-v1.2010: genetic/familial high-risk assessment: breast and ovarian: Li–Fraumeni syndrome. http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf

  22. Nichols KE, Malkin D, Garber JE, Fraumeni JF Jr, Li FP (2001) Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 10:83–87

    PubMed  CAS  Google Scholar 

  23. Schneider KA, DiGianni LM, Patenaude AF, Klar N, Stopfer JE, Calzone KA, Li FP, Weber BL, Garber JE (2004) Accuracy of cancer family histories: comparison of two breast cancer syndromes. Genet Test 8:222–228

    Article  PubMed  Google Scholar 

  24. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, Bonaiti-Pellie C, Stoppa-Lyonnet D, Frebourg T (2009) 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27:e108–e109. doi:10.1200/JCO.2009.22.7967

    Article  PubMed  Google Scholar 

  25. Velasco E, Infante M, Duran M, Perez-Cabornero L, Sanz DJ, Esteban-Cardenosa E, Miner C (2007) Heteroduplex analysis by capillary array electrophoresis for rapid mutation detection in large multiexon genes. Nat Protoc 2:237–246. doi:10.1038/nprot.2006.482

    Article  PubMed  CAS  Google Scholar 

  26. Wilson JR, Bateman AC, Hanson H, An Q, Evans G, Rahman N, Jones JL, Eccles DM (2010) A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet 47:771–774. doi:10.1136/jmg.2010.078113

    Article  PubMed  CAS  Google Scholar 

  27. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145. doi:10.1200/JCO.2006.09.2775

    Article  PubMed  CAS  Google Scholar 

  28. Wong P, Verselis SJ, Garber JE, Schneider K, DiGianni L, Stockwell DH, Li FP, Syngal S (2006) Prevalence of early onset colorectal cancer in 397 patients with classic Li–Fraumeni syndrome. Gastroenterology 130:73–79. doi:10.1053/j.gastro.2005.10.014

    Article  PubMed  Google Scholar 

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Acknowledgments

Dr. Elgene Lim for helpful comments on the manuscript. The work was supported by the Breast Cancer Research Foundation and the Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer Grant (No. P50 CA89393). Michelle Rath received funding from the German Research Foundation.

Conflict of interest

The authors have declared no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Michelle G. Rath, Serena Masciari, Ian E. Krop & Judy E. Garber

  2. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Rebecca Gelman

  3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Alexander Miron, Penelope Miron & Kathleen Foley

  4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Andrea L. Richardson & Deborah A. Dillon

  5. Molecular Diagnostics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA

    Sigitas J. Verselis

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  1. Michelle G. Rath
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  2. Serena Masciari
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  3. Rebecca Gelman
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  11. Judy E. Garber
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Correspondence to Judy E. Garber.

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Rath, M.G., Masciari, S., Gelman, R. et al. Prevalence of germline TP53 mutations in HER2+ breast cancer patients. Breast Cancer Res Treat 139, 193–198 (2013). https://doi.org/10.1007/s10549-012-2375-z

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  • DOI: https://doi.org/10.1007/s10549-012-2375-z

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