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Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin

  • Epidemiology
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Abstract

Large genomic rearrangements (LGRs) at the BRCA2 locus explain a non-negligible proportion of hereditary breast and ovarian cancer (HBOC) syndromes. The multiplex ligation and probe amplification (MLPA) assay has permitted in recent years to identify several families carrying LGRs at this locus, but very few such alterations have been fully characterized at the molecular level. Yet, molecular characterization is essential to identify recurrent alterations, to analyze the genetic mechanisms underlying such alterations, or to investigate potential genotype/phenotype relationships. We have used MLPA to identify BRCA2 LGRs in 7 out of 813 Spanish HBOC families previously tested negative for BRCA1 and BRCA2 small genomic alterations (substitutions and indels) and BRCA1 LGRs. We used a combination of long-range PCR, restriction mapping, and cDNA analysis to characterize the alterations at the molecular level. We found that Del Exon1-Exon2, Del Exon12-Exon16 and Del Exon22-Exon24 explain one family each, while Del Exon2 appears to be a Spanish founder mutation explaining four independent families. Finally, we have combined our data with a comprehensive review of the literature to reevaluate the genetic mechanisms underlying LGRs at the BRCA2 locus. Our study substantially increases the spectrum of BRCA2 LGRs fully characterized at the molecular level. Further on, we provide data to suggest that non-allelic homologous recombination has been overestimated as a mechanism underlying these alterations, while the opposite might be true for microhomology-mediated events.

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Acknowledgments

We thank the individuals whose participation made this project possible. We thank Paula Diaque, Anna Tenés, Miriam Masas, and Alicia Barroso for technical assistance. This study was supported by Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS) Research Grants 09/00859 and 08/1120 to MdH and JB, respectively. Fundación Canaria de Investigación y Salud (FUNCIS) Research Grant 08/08 to ASdA. Fundación Mutua Madrileña (FMM) Research Grant FMM-08 to MdH. Asociación Española contra el Cáncer (AECC) Research Grant (2009) to JB. Red Temática de Investigación Cooperativa en Cáncer; Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (RETICC 06/0020/0021) supported PG, AR, PPS, EDR, TC, and MdH. Centro de Investigación en Red de Enfermedades Raras (CIBERER) supported JB. SGE is supported by a Miguel Servet contract of the Instituto de Salud Carlos III.

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Authors and Affiliations

  1. Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, C/Martín Lagos s/n, 28040, Madrid, Spain

    Gorka Ruiz de Garibay, Pilar Garre, Atocha Romero, Eduardo Díaz-Rubio, Trinidad Caldés & Miguel de la Hoya

  2. Laboratori d’Oncogenètica, Institut d’Oncologia Vall d’Hebron (VHIO), Barcelona, Spain

    Sara Gutiérrez-Enríquez & Orland Díez

  3. Laboratori d’Oncogenètica, Institut de Recerca Vall d’Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelone, Spain

    Sandra Bonache & Laura Palomo

  4. Servicio de Bioquímica Clínica, Hospitalario Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain

    Ana Sánchez de Abajo

  5. Grupo de Genética Humana, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    Javier Benítez

  6. Servei d’Oncologia Mèdica, Hospital Universitari Vall d’Hebron, Barcelone, Spain

    Judith Balmaña

  7. Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain

    Pedro Pérez-Segura & Eduardo Díaz-Rubio

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  1. Gorka Ruiz de Garibay
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  2. Sara Gutiérrez-Enríquez
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Correspondence to Miguel de la Hoya.

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Ruiz de Garibay, G., Gutiérrez-Enríquez, S., Garre, P. et al. Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin. Breast Cancer Res Treat 133, 273–283 (2012). https://doi.org/10.1007/s10549-011-1909-0

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