Abstract
Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast-ovarian cancers. However, BRCA1 germline mutations are found much less frequently than expected, especially as standard PCR-based mutation detection approaches focus on point and small gene alterations. In order to estimate the contribution of large gene rearrangements to the BRCA1 mutation spectrum, we have extensively analysed a series of 120 French breast-ovarian cancer cases. Thirty-eight were previously found carrier of a BRCA1 point mutation, 14 of a BRCA2 point mutation and one case has previously been reported as carrier of a large BRCA1 deletion. The remaining 67 cases were studied using the BRCA1 bar code approach on combed DNA which allows a panoramic view of the BRCA1 region. Three additional rearrangements were detected: a recurrent 23.8 kb deletion of exons 8–13, a 17.2 kb duplication of exons 3–8 and a 8.6 kb duplication of exons 18–20. Thus, in our series, BRCA1 large rearrangements accounted for 3.3% (4/120) of breast-ovarian cancer cases and 9.5% (4/42) of the BRCA1 gene mutation spectrum, suggesting that their screening is an important step that should be now systematically included in genetic testing surveys.
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Acknowledgements
We wish to thank the patients and their families for their cooperation. We gratefully acknowledge Isabelle Eugene and Sandrine Miglierina for their daily and efficient support in the organization of the genetic clinic. We wish to thank also Isabelle Lambert and Isabelle Bezier for the lymphoblastoid cell line establishment (Généthon, Evry). Thanks also to Stanislas Lyonnet and Mario Tosi for critical reading of the manuscript. This work was supported by the Institut Curie ‘Programme Incitatif et Coopératif: Génétique et Biologie des Cancers du Sein’ and the Ligue Nationale Contre le Cancer (A Aurias). S Gad is supported by a fellowship from the Association pour la Recherche contre le Cancer.
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Gad, S., Caux-Moncoutier, V., Pagès-Berhouet, S. et al. Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families. Oncogene 21, 6841–6847 (2002). https://doi.org/10.1038/sj.onc.1205685
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DOI: https://doi.org/10.1038/sj.onc.1205685
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