Familial Cancer

, Volume 14, Issue 2, pp 333–336 | Cite as

The breast cancer immunophenotype of TP53-p.R337H carriers is different from that observed among other pathogenic TP53 mutation carriers

  • Mariana Fitarelli-Kiehl
  • Juliana Giacomazzi
  • Patricia Santos-Silva
  • Marcia Silveira Graudenz
  • Edenir Inez Palmero
  • Rodrigo Augusto Depieri Michelli
  • Maria Isabel Achatz
  • Cynthia Aparecida Bueno de Toledo Osório
  • Victor Evangelista de Faria Ferraz
  • Clarissa Gondim Picanço
  • Patricia Ashton-Prolla
Short Communication


Germline TP53 mutations are associated with Li–Fraumeni syndrome, an autosomal dominant disorder characterized by a predisposition to multiple early-onset cancers including breast cancer (BC), the most prevalent tumor among women. The majority of germline TP53 mutations are clustered within the DNA-binding domain of the gene, disrupting the structure and function of the protein. A specific germline mutation in the tetramerization domain of p53, p.R337H, was reported at a high frequency in Southern and Southeastern Brazil. This mutation appears to result in a more subtle defect in the protein, which becomes functionally deficient only under particular conditions. Recent studies show that the BC phenotype in TP53 mutation carriers is often HER2 positive (63–83 %). Considering that the immunophenotype of BC among p.R337H carriers has not been reported, we reviewed immunohistochemistry data of 66 p.R337H carriers in comparison with 12 patients with other non-functional TP53 germline mutation. Although 75 % of carriers of these mutations showed significant HER2 overexpression (3+), corroborating previous studies, only 22.7 % of p.R337H patients had BC overexpressing HER2. These results reinforce the notion that different germline mutations in TP53 may predispose to BC via different mechanisms.


Breast cancer HER2 Li–Fraumeni syndrome TP53 p.R337H 


Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

In all cases, patients underwent pre- and post-test genetic counseling and signed an informed consent for genetic testing. Information on mutation status and clinical data necessary for this study were obtained only after approval by the institutional ethics committees.


  1. 1.
    Malkin D, Li FP, Strong LC et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(80):1233–1238CrossRefPubMedGoogle Scholar
  2. 2.
    Li FP, Fraumeni JF, Mulvihill JJ et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358–5362PubMedGoogle Scholar
  3. 3.
    Kleihues P, Schauble B, zur Hausen A et al (1997) Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 150:1–13PubMedCentralPubMedGoogle Scholar
  4. 4.
    Olivier M, Goldgar DE, Sodha N et al (2003) Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63:6643–6650PubMedGoogle Scholar
  5. 5.
    Petitjean A, Mathe E, Kato S et al (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 28:622–629. doi: 10.1002/humu.20495 CrossRefPubMedGoogle Scholar
  6. 6.
    Custodio G, Parise GA, Kiesel Filho N et al (2013) Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol. doi: 10.1200/JCO.2012.46.3711 PubMedCentralPubMedGoogle Scholar
  7. 7.
    Palmero EI, Schüler-Faccini L, Caleffi M et al (2008) Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil. Cancer Lett 261:21–25. doi: 10.1016/j.canlet.2007.10.044 CrossRefPubMedGoogle Scholar
  8. 8.
    Giacomazzi J, Graudenz MS, Osorio CABT et al (2014) Prevalence of the TP53 p.R337H mutation in breast cancer patients in Brazil. PLoS One. doi: 10.1371/journal.pone.0099893 Google Scholar
  9. 9.
    Giacomazzi J, Koehler-Santos P, Palmero EI et al (2013) A TP53 founder mutation, p.R337H, is associated with phyllodes breast tumors in Brazil. Virchows Arch 463:17–22. doi: 10.1007/s00428-013-1439-8 CrossRefPubMedGoogle Scholar
  10. 10.
    Ribeiro RC, Sandrini F, Figueiredo B et al (2001) An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98:9330–9335. doi: 10.1073/pnas.161479898 CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Achatz MI, Olivier M, Le Calvez F et al (2007) The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 245:96–102. doi: 10.1016/j.canlet.2005.12.039 CrossRefPubMedGoogle Scholar
  12. 12.
    Seidinger AL, Mastellaro MJ, Paschoal Fortes F et al (2011) Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in Southeast Brazil. Cancer 117:2228–2235. doi: 10.1002/cncr.25826 CrossRefPubMedGoogle Scholar
  13. 13.
    DiGiammarino EL, Lee AS, Cadwell C et al (2002) A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9:12–16. doi: 10.1038/nsb730 CrossRefPubMedGoogle Scholar
  14. 14.
    Wilson JR, Bateman AC, Hanson H et al (2010) A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet 47:771–774. doi: 10.1136/jmg.2010.078113 CrossRefPubMedGoogle Scholar
  15. 15.
    Melhem-Bertrandt A, Bojadzieva J, Ready KJ et al (2012) Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 118:908–913. doi: 10.1002/cncr.26377 CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    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 133:1125–1130. doi: 10.1007/s10549-012-1993-9 CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Kato S, Han S-Y, Liu W et al (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 100:8424–8429. doi: 10.1073/pnas.1431692100 CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Hammond MEH, Hayes DF, Wolff AC et al (2010) American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract 6:195–197. doi: 10.1200/JOP.777003 CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Wolff AC, Hammond MEH, Hicks DG et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013. doi: 10.1200/JCO.2013.50.9984 CrossRefPubMedGoogle Scholar
  20. 20.
    Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(80):707–712CrossRefPubMedGoogle Scholar
  21. 21.
    Collins LC, Marotti JD, Gelber S et al (2012) Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat 131:1061–1066. doi: 10.1007/s10549-011-1872-9 CrossRefPubMedGoogle Scholar
  22. 22.
    de Carvalho LV, Pereira EM, Frappart L et al (2010) Molecular characterization of breast cancer in young Brazilian women. Rev Assoc Med Bras 56:278–287. doi: 10.1590/S0104-42302010000300010 PubMedGoogle Scholar
  23. 23.
    Brosh R, Rotter V (2009) When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9:701–713. doi: 10.1038/nrc2693 PubMedGoogle Scholar
  24. 24.
    Muller PAJ, Vousden KH (2013) P53 Mutations in Cancer. Nat Cell Biol 15:2–8. doi: 10.1038/ncb2641 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Mariana Fitarelli-Kiehl
    • 1
    • 2
  • Juliana Giacomazzi
    • 3
  • Patricia Santos-Silva
    • 2
    • 4
  • Marcia Silveira Graudenz
    • 5
    • 6
  • Edenir Inez Palmero
    • 7
  • Rodrigo Augusto Depieri Michelli
    • 7
  • Maria Isabel Achatz
    • 8
  • Cynthia Aparecida Bueno de Toledo Osório
    • 9
  • Victor Evangelista de Faria Ferraz
    • 10
    • 11
  • Clarissa Gondim Picanço
    • 10
  • Patricia Ashton-Prolla
    • 1
    • 2
    • 3
    • 4
  1. 1.Post-Graduate Program in Genetics and Molecular BiologyUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  2. 2.Genomic Medicine Laboratory, Experimental Research CenterHospital de Clínicas de Porto Alegre (HCPA)Porto AlegreBrazil
  3. 3.Department of GeneticsUFRGSPorto AlegreBrazil
  4. 4.Post-Graduate Program in Medicine, Medical SciencesUFRGSPorto AlegreBrazil
  5. 5.Department of PathologyUFRGSPorto AlegreBrazil
  6. 6.Instituto de PatologiaPorto AlegreBrazil
  7. 7.Molecular Oncology Research CenterHospital de Câncer de BarretosBarretos, São PauloBrazil
  8. 8.Department of Oncogenetics, International Research CenterHospital do Câncer A.C. Camargo (HCACC)São PauloBrazil
  9. 9.Pathology ServiceHCACCSão PauloBrazil
  10. 10.Department of Genetics, Faculdade de Medicina de Ribeirão PretoUniversidade de São Paulo (FMRP-USP)Ribeirão Preto, São PauloBrazil
  11. 11.Center for Medical Genomics, Hospital das Clínicas da Faculdade de Medicina de Ribeirão PretoUniversidade de São Paulo (HCFMRP-USP)Ribeirão Preto, São PauloBrazil

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