© 2007 European Society for Medical Oncology
breast and ovarian cancer |
High prevalence of BRCA1 deletions in BRCAPRO-positive patients with high carrier probability
1 Department of Oncology and Neurosciences, University ‘G. d'Annunzio’, Chieti, Pescara
2 Center of Excellence on Aging, ‘G. d'Annunzio’ University Foundation, Chieti, Pescara
3 Department of Human Movement Sciences
4 Department of Clinical Sciences and Bioimages
5 Department of Biomedical Sciences, University ‘‘G. d'Annunzio’’, Chieti, Pescara
6 Service of Human Genetics, Pescara Hospital, Pescara
7 Department of Surgical and Oncology; Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, Università di Palermo, Palermo
8 Molecular Genetic Institute - Research National Center, Bologna
9 Leonardo da Vinci Telematic University, Torrevecchia Teatina, Chieti, Italy
* Correspondence to: Dr L. Stuppia, Department of Biomedical Sciences, University ‘G. d'Annunzio’, Via dei Vestini 35, 66013 Chieti, Italy. Tel: +39-0871-3554137; Fax: +39-0871-3554133; E-mail: stuppia{at}unich.it
Mutation screening of the BRCA1 and BRCA2 genes in probands with familial breast/ovarian cancer has been greatly improved by the multiplex ligation-dependent probe amplification (MLPA) assay able to evidence gene rearrangements not detectable by standard screening methods. However, no criteria for selection of cases to be submitted to the MLPA test have been reported yet. We used the BRCAPro software for the selection of familial breast/ovarian cancer probands investigated with the MLPA approach after negative BRCA1/2 conventional mutation screening. One hundred and seventy-seven probands were investigated for germline BRCA1/2 mutations after assessment of genetic risk using BRCAPro. Probands were classified as BRCAPro positive (n = 67) when the carrier probability (CP) was >10% and as BRCAPro negative (n = 110), when the CP was <10%. Conventional mutational analyses of the BRCA1/2 genes and, in one case, of p53 identified 22 pathogenetic germline mutations, 12 in BRCA1, 9 in BRCA2 and 1 in p53, in 22/177 (12.4%) probands. All the mutations except one were detected in BRCAPro-positive patients. In the 46 BRCAPro-positive cases that resulted negative by BRCA1/2 mutation, screening analysis of rearrangements within BRCA1/2 by MLPA was carried out. Three patients with a very high CP showed BRCA1 deletions, consisting of deletions of exons 1–2 in two probands and of exon 24 in the third proband. In one case, the exons 1–2 deletion was shown to cosegregate with disease in the family. No BRCA2 rearrangements were detected, but one patient showed the 1100delC of the CHEK2 gene, whose probe is present in the BRCA2 kit. In our series, the highest carrier detection rate of mutation screening plus MLPA analysis (52.3%) was in patients with a BRCAPro CP >50%.
Key words: BRCA1, BRCA2, BRCAPro, breast cancer, MLPA, ovarian cancer