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Identification and comprehensive characterization of large genomic rearrangements in the BRCA1 and BRCA2 genes

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Abstract

Large genomic rearrangements are estimated to account for approximately 5–10% of all disease-causing mutations in BRCA1 and BRCA2 genes in patients with hereditary breast and ovarian cancer syndrome (HBOC). We use MRC-Holland Multiplex Ligation-dependent Probe Amplification (MLPA) to screen for such rearrangements in patients with HBOC and as a first step in our genetic testing workflow. The technique was applied to a set of 310 independent patients and detected eight different copy number alterations, corresponding to 2.6% of the studied samples. MLPA was also found to identify point mutations located in probe sequences. As commercial MLPA tests are not suitable for determining the specific breakpoints or for defining the exact extent of rearrangements, we applied a set of different complementary techniques to characterize these genetic alterations with greater precision. Long-range PCR amplification, RNA analysis, SNP-array chips, non-commercial MLPA probes, and FISH analysis were used to fully define the extent and mechanism of each alteration. In BRCA1, six rearrangements were characterized: deletion of E22, duplication of E9–E24, deletion of E16–E23, deletion of E1–E13, deletion of E1–E2 and duplication of E1–E2. In BRCA2, we studied a deletion of E15–E16 and a deletion of E1–E24. To the best of our knowledge, this is the most comprehensive study of the nature and underlying molecular causes of these mutational events in the BRCA1/2 genes.

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Acknowledgments

We thank all patients and relatives who participated in this study. We also thank the Fundació Roses Contra el Càncer for financial support. Contract grant sponsor: Spanish Health Research Fund; Carlos III Health Institute; Spanish Ministry of Education and Science; Catalan Health Institute; and the Autonomous Government of Catalonia. Contract grant numbers: SAF2006-05399; ISCIIIRETIC: RD06/0020/0028, RD06/0020/1020, RD06/0020/1050, RD06/0020/1051, and 2009SGR290.

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Authors and Affiliations

  1. Programa de Diagnòstic Molecular de Càncer Hereditari, Laboratori de Recerca Translacional, Institut Català d’Oncologia-IDIBELL, Hospital Duran i Reynals, Hospitalet de Llobregat, Gran Via s/n, km 2.7, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Jesús del Valle, Lídia Feliubadaló, Marga Nadal, Raquel Cuesta, Eva Tornero, Mireia Menéndez, Gabriel Capellà & Conxi Lázaro

  2. Programa de Consell Genètic en Càncer, Institut Català d’Oncologia, Hospitalet de Llobregat-IDIBELL, Barcelona, Spain

    Alex Teulé & Ignacio Blanco

  3. Institut de Biotecnologia i Biomedicina, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain

    Rosa Miró

  4. Programa de Consell Genètic en Càncer, Institut Català d’Oncologia, Girona-IdIBGi, Girona, Spain

    Esther Darder & Joan Brunet

Authors
  1. Jesús del Valle
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  2. Lídia Feliubadaló
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  3. Marga Nadal
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  4. Alex Teulé
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  5. Rosa Miró
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  6. Raquel Cuesta
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  7. Eva Tornero
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  8. Mireia Menéndez
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  9. Esther Darder
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  10. Joan Brunet
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  11. Gabriel Capellà
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  12. Ignacio Blanco
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  13. Conxi Lázaro
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Correspondence to Conxi Lázaro.

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del Valle, J., Feliubadaló, L., Nadal, M. et al. Identification and comprehensive characterization of large genomic rearrangements in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 122, 733–743 (2010). https://doi.org/10.1007/s10549-009-0613-9

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  • DOI: https://doi.org/10.1007/s10549-009-0613-9

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