Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics
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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.
KeywordsCancer susceptibility Genetic counseling BRCA1 BRCA2 Double heterozygosity
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”).
- 6.Friedman E, Bar-Sade Bruchim R, Kruglikova A, Risel S, Levy-Lahad E, Halle D, Bar-On E, Gershoni-Baruch R, Dagan E, Kepten I, Peretz T, Lerer I, Wienberg N, Shushan A, Abeliovich AD (1998) Double heterozygotes from the Ashkenazi founder mutations in BRCA1 and BRCA2 genes. Am J Hum Genet 63:1224–1227CrossRefPubMedGoogle Scholar
- 17.Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10.000 individuals. J Clin Oncol 20:1480–1490CrossRefPubMedGoogle Scholar
- 18.Leegte B, van der Hout AH, Deffenbaugh AM, Bakker MK, Mulder IM, ten Berge A, Leenders EP, Wesseling J, de Hullu J, Hoogerbrugge N, Ligtenberg MJ, Ardern-Jones A, Bancroft E, Salmon A, Barwell J, Eeles R, Oosterwijk JC (2005) Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations. J Med Genet 42:e20CrossRefPubMedGoogle Scholar
- 23.Caligo MA, Ghimenti C, Cipollini G, Ricci S, Brunetti I, Marchetti V, Olsen R, Neuhausen S, Shattuck-Eidens D, Conte PF, Skolnick MH, Bevilacqua G (1996) BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations. Oncogene 13:1483–1488PubMedGoogle Scholar
- 24.Baudi F, Quaresima B, Grandinetti C, Cuda G, Faniello C, Tassone P, Barbieri V, Bisegna R, Ricevuto E, Conforti S, Viel A, Marchetti P, Ficorella C, Radice P, Costanzo F, Venuta S (2001) Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer. Hum Mutat 18:163–164CrossRefPubMedGoogle Scholar
- 25.Papi L, Putignano AL, Congregati C, Zanna I, Sera F, Morrone D, Falchetti M, Turco MR, Ottini L, Palli D, Genuardi M (2009) Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. Breast Cancer Res Treat. doi: 10.1007/s10549-008-0190-3
- 26.Phillips KA (2000) Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancers. J Clin Oncol 18:107–112Google Scholar