Breast Cancer Research and Treatment

, Volume 103, Issue 1, pp 103–107 | Cite as

Screening for large rearrangements of the BRCA2 gene in Spanish families with breast/ovarian cancer

  • Sara Gutiérrez-Enríquez
  • Miguel de La Hoya
  • Cristina Martínez-Bouzas
  • Ana Sanchez de Abajo
  • Teresa Ramón y Cajal
  • Gemma Llort
  • Ignacio Blanco
  • Elena Beristain
  • Eduardo Díaz-Rubio
  • Carmen Alonso
  • María-Isabel Tejada
  • Trinidad Caldés
  • Orland Diez
Article

Abstract

Germ-line mutations in BRCA1 and BRCA2 are responsible for about 30–60% of the hereditary breast and ovarian cancer (HBOC). A large number of point mutations have been described in both genes. However, large deletions and duplications that disrupt one or more exons are overlooked by point mutation detection approaches. Over the past years several rearrangements have been identified in BRCA1, while few studies have been designed to screen this type of mutations in BRCA2. Our aim was to estimate the prevalence of large genomic rearrangements in the BRCA2 gene in Spanish breast/ovarian cancer families. The multiplex ligation-dependent probe amplification (MLPA) was employed to search gross deletions or duplications of BRCA2 in 335 Spanish moderate to high-risk breast/ovarian cancer families previously screened negative for point mutations by conventional methods. Four different and novel large genomic alterations were consistently identified by MLPA in five families, respectively: deletions of exon 2, exons 10–12 and exons 15–16 and duplication of exon 20 (in two families). RT-PCR experiments confirmed the deletion of exons 15–16. All patients harbouring a genomic rearrangement were members of high-risk families, with three or more breast/ovarian cancer cases or the presence of breast cancer in males. We provide evidence that the BRCA2 rearrangements seem to account for a relatively small proportion of familial breast cancer cases in Spanish population. The screening for these alterations as part of the comprehensive genetic testing can be recommended, especially in multiple case breast/ovarian families and families with male breast cancer cases.

Keywords

BRCA1 BRCA2 Hereditary breast cancer Genomic rearrangements 

References

  1. 1.
    Diez O, Osorio A, Duran M, Martinez-Ferrandis JI, de la Hoya M, Salazar R, Vega A, Campos B, Rodriguez-Lopez R, Velasco E et al (2003) Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat 22:301–312PubMedCrossRefGoogle Scholar
  2. 2.
    Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acid Res 30:e57PubMedCrossRefGoogle Scholar
  3. 3.
    Gad S, Caux-Moncoutier V, Pages-Berhouet S, Gauthier-Villars M, Coupier I, Pujol P, Frenay M, Gilbert B, Maugard C, Bignon YJ et al (2002) Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families. Oncogene 21:6841–6847PubMedCrossRefGoogle Scholar
  4. 4.
    Petrij-Bosch A, Peelen T, van Vliet M, van Eijk, Olmer R, Drusedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ et al (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17:341–355PubMedCrossRefGoogle Scholar
  5. 5.
    Montagna M, Dalla Palma M, Menin C, Agata S, De Nicolo A, Chieco-Bianchi L, D’Andrea E (2003) Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet 12:1055–1061PubMedCrossRefGoogle Scholar
  6. 6.
    Mazoyer S (2005) Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat 25:415–422PubMedCrossRefGoogle Scholar
  7. 7.
    Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S et al (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379–1388PubMedCrossRefGoogle Scholar
  8. 8.
    de la Hoya M, Gutiérrez-Enríquez S, Velasco E, Osorio A, Sánchez de Abajo A, Vega A, Salazar R, Esteban E, Llort G, Gonzalez-Sarmiento R et al (2006) Genomic rearrangements at the BRCA1 locus in Spanish families with breast/ovarian cancer. Clin Chem 52:1480–1485CrossRefGoogle Scholar
  9. 9.
    Nordling M, Karlsson P, Wahlstrom J, Engwall Y, Wallgren A, Marrtinsson T (1998) A large deletion disrupts the exon 3 transcription activation domain of the BRCA2 gene in a breast/ovarian cancer family. Cancer Res 58:1372–1375PubMedGoogle Scholar
  10. 10.
    Peelen T, van Vliet M, Bosch A, Bignell G, Vasen HF, Klijn JG, Meijers-Heijboer H, Stratton M, van Ommen GJ, Cornelisse CJ et al (2000) Screening for BRCA2 mutations in 81 Dutch breast-ovarian cancer families. Br J Cancer 82:151–156PubMedCrossRefGoogle Scholar
  11. 11.
    Lahti-Domenici J, Rapakko K, Paakkonen K, Allinen M, Nevanlinna H, Kujala M, Huusko P, Winqvist R (2001) Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2 in Finnish breast and ovarian cancer families. Cancer Genet Cytogenet 129:120–123PubMedCrossRefGoogle Scholar
  12. 12.
    Gad S, Klinger M, Caux-Moncoutier V, Pages-Berhouet S, Gauthier-Villars M, Coupier I, Bensimon A, Aurias A, Stoppa-Lyonnet D (2002) Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2 genes in French breast cancer families. J Med Genet 39:817–821PubMedCrossRefGoogle Scholar
  13. 13.
    Tournier I, Paillerets BB, Sobol H, Stoppa-Lyonnet D, Lidereau R, Barrois M, Mazoyer S, Coulet F, Hardouin A, Chompret A et al (2004) Significant contribution of germline BRCA2 rearrangements in male breast cancer families. Cancer Res 64:8143–8147PubMedCrossRefGoogle Scholar
  14. 14.
    Agata S, Dalla Palma M, Callegaro M, Scaini MC, Menin C, Ghiotto C, Nicoletto O, Zavagno G, Chieco-Bianchi L, D’Andrea E et al (2005) Large genomic deletions inactivate the BRCA2 gene in breast cancer families. J Med Genet 42:e64PubMedCrossRefGoogle Scholar
  15. 15.
    Wagner T, Stoppa-Lyonnet D, Fleuschmann E, Muhr D, Pages S, Sandberg T, Caux V, Moeslinger R, Langbauer G, Borg A et al (1999) Denaturing high-performance liquid chromatography detects reliably BRCA1 and BRCA2 mutations. Genomics 62:369–376PubMedCrossRefGoogle Scholar
  16. 16.
    Campos B, Díez O, Domènech M, Baena M, Pericay C, del Río E, Balmaña J, Alonso C, Baiget M (2001) BRCA2 mutation analysis of 87 Spanish breast/ovarian cancer families. Ann Oncol 12:1699–1703PubMedCrossRefGoogle Scholar
  17. 17.
    Durán M, Esteban-Cardeñosa E, Velasco E, Infante M, Miner C (2003) Mutational analysis of BRCA2 in Spanish breast cancer patients from Castilla-Leon: identification of four novel truncating mutations. Hum Mutat 21:448PubMedCrossRefGoogle Scholar
  18. 18.
    Woodward AM, Davis TA, Silva AG, Kirk JA, Leary JA, kConFab Investigators (2005) Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families. J Med Genet 42:e31PubMedCrossRefGoogle Scholar
  19. 19.
    Moisan AM, Fortin J, Dumont M, Samson C, Bessette P, Chiquette J, Laframboise R, Lepine J, Lesperance B, Pichette R et al (2006) No evidence of BRCA1/2 genomic rearrangements in high-risk French-Canadian breast/ovarian cancer families. Genet Test 10:104–115PubMedCrossRefGoogle Scholar
  20. 20.
    Preisler-Adams S, Schonbuchner I, Fiebig B, Welling B, Dworniczak B, Weber BH (2006) Gross rearrangements in BRCA1 but not BRCA2 play a notable role in predisposition to breast and ovarian cancer in high-risk families of German origin. Cancer Genet Cytogenet 168:44–49PubMedCrossRefGoogle Scholar
  21. 21.
    Bunyan DJ, Eccles DM, Sillibourne J, Wilkins E, Thomas NS, She-Simonds J, Duncan PJ, Curtis CE, Robinson DO, Harvey JF et al (2004) Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification. Br J Cancer 91:1155–1159PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Sara Gutiérrez-Enríquez
    • 1
  • Miguel de La Hoya
    • 2
  • Cristina Martínez-Bouzas
    • 3
  • Ana Sanchez de Abajo
    • 2
  • Teresa Ramón y Cajal
    • 4
  • Gemma Llort
    • 5
  • Ignacio Blanco
    • 5
  • Elena Beristain
    • 3
  • Eduardo Díaz-Rubio
    • 2
  • Carmen Alonso
    • 4
  • María-Isabel Tejada
    • 3
  • Trinidad Caldés
    • 2
  • Orland Diez
    • 1
  1. 1.Servei de GenèticaHospital de la Santa Creu i Sant PauBarcelonaSpain
  2. 2.Laboratorio de Oncología Molecular y Servicio de Oncología MédicaHospital Clínico San CarlosMadridSpain
  3. 3.Laboratorio de Genética MolecularHospital de CrucesBarakaldoSpain
  4. 4.Servicio de Oncología MédicaHospital de la Santa Creu i Sant PauBarcelonaSpain
  5. 5.Unidad de Consejo Genético, Servicio de Prevención y Control del CáncerInstitut Català d’OncologiaBarcelonaSpain

Personalised recommendations