Abstract
Most of the hereditary breast cancers are attributed to constitutive alterations of either BRCA1 or BRCA2 genes; nonetheless, germline mutations of these genes in `high risk' families are found less frequently than expected from linkage data. Recent findings suggest that major genomic rearrangements of the BRCA1 gene might account for at least some of the apparently mutation negative cases. We studied 60 affected probands belonging to families with a strong history of breast and/or ovarian cancer who scored negative for BRCA1 gene mutations by PTT and SSCP analysis. DNA was analysed by the Southern blotting procedure using three different restriction enzymes, and two probes obtained by RT – PCR of the 5′ and 3′ BRCA1 coding sequence. A 3 kb deletion encompassing exon 17 and causing a frameshift mutation was identified in two independently ascertained families. RT – PCR and long-range DNA PCR were employed to characterize the rearrangement that was finally shown to be the result of a recombination between two very similar Alu repeats. This type of mutation is not identified by the conventional methods of mutation detection which are based on PCR amplification of single exons. Therefore, further search for gene rearrangements is needed to better define the proportion of `high risk' families that might be explained by gross genomic alterations of the BRCA1 gene.
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Acknowledgements
We thank the family members and the physicians (S Aversa, A Bononi, C Di Maggio, E Ferrazzi, A Fornasiero, V Fosser, O Nascimben, O Nicoletto, A Rosa-Bian, G Zavagno) who contributed to this study; M Quaggio for her expert technical assistance; P Gallo for artwork and P Segato for help in preparing the manuscript. M Montagna and M Santacatterina are fellows of the Associazione and Fondazione Italiana per la Ricerca sul Cancro (AIRC/FIRC), respectively. This study was supported by grants from Ministero della Ricerca Scientifica e Tecnologica (MURST), Italian Hereditary Breast/Ovarian Cancer Consortium/AIRC-Coordinated Project, Regione Veneto/Ricerca Sanitaria Finalizzata, and Fondazione Cassa di Risparmio di Padova e Rovigo, Italy.
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Montagna, M., Santacatterina, M., Torri, A. et al. Identification of a 3 kb Alu-mediated BRCA1 gene rearrangement in two breast/ovarian cancer families. Oncogene 18, 4160–4165 (1999). https://doi.org/10.1038/sj.onc.1202754
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DOI: https://doi.org/10.1038/sj.onc.1202754