Breast Cancer Research and Treatment

, Volume 133, Issue 1, pp 273–283 | Cite as

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

  • Gorka Ruiz de Garibay
  • Sara Gutiérrez-Enríquez
  • Pilar Garre
  • Sandra Bonache
  • Atocha Romero
  • Laura Palomo
  • Ana Sánchez de Abajo
  • Javier Benítez
  • Judith Balmaña
  • Pedro Pérez-Segura
  • Eduardo Díaz-Rubio
  • Orland Díez
  • Trinidad Caldés
  • Miguel de la HoyaEmail author


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.


Familial breast cancer BRCA2 MLPA Genomic rearrangements Non-allelic homologous recombination Microhomology 



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.

Conflicts of interest


Supplementary material

10549_2011_1909_MOESM1_ESM.doc (78 kb)
Supplementary material 1 (DOC 77 kb)
10549_2011_1909_MOESM2_ESM.ppt (162 kb)
Supplementary material 2 (PPT 162 kb)


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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Gorka Ruiz de Garibay
    • 1
  • Sara Gutiérrez-Enríquez
    • 2
  • Pilar Garre
    • 1
  • Sandra Bonache
    • 3
  • Atocha Romero
    • 1
  • Laura Palomo
    • 3
  • Ana Sánchez de Abajo
    • 4
  • Javier Benítez
    • 5
  • Judith Balmaña
    • 6
  • Pedro Pérez-Segura
    • 7
  • Eduardo Díaz-Rubio
    • 1
    • 7
  • Orland Díez
    • 2
  • Trinidad Caldés
    • 1
  • Miguel de la Hoya
    • 1
    Email author
  1. 1.Laboratorio de Oncología MolecularInstituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San CarlosMadridSpain
  2. 2.Laboratori d’OncogenèticaInstitut d’Oncologia Vall d’Hebron (VHIO)BarcelonaSpain
  3. 3.Laboratori d’OncogenèticaInstitut de Recerca Vall d’Hebron (VHIR), Universitat Autònoma de BarcelonaBarceloneSpain
  4. 4.Servicio de Bioquímica ClínicaHospitalario Universitario Insular de Gran CanariaLas Palmas de Gran CanariaSpain
  5. 5.Grupo de Genética HumanaCentro Nacional de Investigaciones Oncológicas (CNIO)MadridSpain
  6. 6.Servei d’Oncologia MèdicaHospital Universitari Vall d’HebronBarceloneSpain
  7. 7.Servicio de Oncología MédicaHospital Clínico San CarlosMadridSpain

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