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

Monica Zuradelli (1) , 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 Unit of Medical Oncology and Hematology
2 Unit of Medical Genetics, Department of Preventive and Predictive Medicine
3 Division of Cancer Prevention and Genetics
4 Consortium for Genomics Technology (Cogentech)
5 Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medicine
6 IFOM - IFOM, Istituto FIRC di Oncologia Molecolare

Double heterozygosity (DH) for and 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 and 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 -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 and 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 . 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.

Mots clés: Cancer susceptibility; Genetic counseling; Double heterozygosity

Monica Zuradelli, Bernard Peissel, Siranoush Manoukian, Daniela Zaffaroni, Monica Barile, et al.. Four new cases of double heterozygosity for and gene mutations: clinical, pathological, and family characteristics. Breast Cancer Research and Treatment, 2010, 124 (1), pp.251-258. ⟨10.1007/s10549-010-0853-8⟩. ⟨hal-00526204⟩