Breast Cancer Research and Treatment

, Volume 124, Issue 1, pp 251–258 | Cite as

Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics

  • Monica ZuradelliEmail author
  • Bernard Peissel
  • Siranoush Manoukian
  • Daniela Zaffaroni
  • Monica Barile
  • Valeria Pensotti
  • Ugo Cavallari
  • Giovanna Masci
  • Frederique Mariette
  • Anne Caroline Benski
  • Armando Santoro
  • Paolo Radice
Brief Report


Double heterozygosity (DH) for BRCA1 and BRCA2 mutations is a very rare finding, particularly in non-Ashkenazi individuals, and only a few cases have been reported to date. In addition, little is known on the pathological features of the tumors that occur in DH cases and on their family history of cancer. Four carriers of pathogenic mutations in both BRCA1 and BRCA2 were identified among women who underwent genetic counseling for hereditary susceptibility to breast and ovarian carcinoma at three different Italian institutions. Clinical, pathological, and family history data were collected from medical records and during genetic counseling sessions. All identified DH cases developed breast carcinoma and three of them were also diagnosed with ovarian carcinoma. Mean ages of breast and ovarian cancer diagnosis were 42.7 and 48.6 years, respectively. The majority of breast cancers showed a BRCA1-related phenotype, being negative for hormone receptors and HER2. Two cases reported different gastrointestinal tumors among relatives. Although the individuals described in this study show more severe clinical features in comparison to previously reported BRCA1 and BRCA2 DH cases, our observations support the hypothesis of a non specific phenotype of DH cases in terms of age of disease onset. In addition, our observations indicate that in DH patients breast carcinogenesis appears to be driven mainly by the mutations in BRCA1. The possible association of DH for BRCA gene mutations with gastrointestinal tumors is in keeping with previous reports, but needs to be confirmed by further analyses.


Cancer susceptibility Genetic counseling BRCA1 BRCA2 Double heterozygosity 



Double heterozygosity


Estrogen receptor


Progesterone receptor



This study was supported by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors”), Ministero della Salute (“Progetto Tumori Femminili”), and by funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori (INT), according to Italian laws (INT-Institutional strategic projects “5 × 1000”).


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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Monica Zuradelli
    • 1
    Email author
  • Bernard Peissel
    • 2
  • Siranoush Manoukian
    • 2
  • Daniela Zaffaroni
    • 2
  • Monica Barile
    • 3
  • Valeria Pensotti
    • 4
  • Ugo Cavallari
    • 1
  • Giovanna Masci
    • 1
  • Frederique Mariette
    • 4
  • Anne Caroline Benski
    • 1
  • Armando Santoro
    • 1
  • Paolo Radice
    • 5
    • 6
  1. 1.Unit of Medical Oncology and HematologyIstituto Clinico HumanitasRozzanoItaly
  2. 2.Unit of Medical Genetics, Department of Preventive and Predictive MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  3. 3.Division of Cancer Prevention and GeneticsIstituto Europeo di OncologiaMilanItaly
  4. 4.Consortium for Genomics Technology (Cogentech)MilanItaly
  5. 5.Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  6. 6.IFOM, Fondazione FIRC di Oncologia MolecolareMilanItaly

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