title: Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics.
abstract: 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.
authors.affiliation: Unit of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy. monica.zuradelli@humanitas.it
authors.forename: Monica
authors.initials: M
authors.lastname: Zuradelli
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Daniela
authors.initials: D
authors.lastname: Zaffaroni
authors.forename: Monica
authors.initials: M
authors.lastname: Barile
authors.forename: Valeria
authors.initials: V
authors.lastname: Pensotti
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallari
authors.forename: Giovanna
authors.initials: G
authors.lastname: Masci
authors.forename: Frederique
authors.initials: F
authors.lastname: Mariette
authors.forename: Anne Caroline
authors.initials: AC
authors.lastname: Benski
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D005260:Female; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D010375:Pedigree; D010641:Phenotype; D016896:Treatment Outcome
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human