title: Genomic rearrangements at the BRCA1 locus in Spanish families with breast/ovarian cancer.
abstract: BACKGROUND
  Large genomic rearrangements (LGRs) account for a substantial proportion of the BRCA1 disease-causing changes, or variations, identified in families with hereditary breast/ovarian cancer [HB(O)C]. Great differences in the spectrum and prevalence of BRCA1 LGR have been observed among populations. Here we report the first comprehensive analysis of BRCA1 LGRs conducted in Spain.
  
  
  METHODS
  We used multiplex ligation-dependent probe amplification (MLPA) to screen for BRCA1 LGRs in the index case individuals of 384 HB(O)C families who previously tested negative for BRCA1 and BRCA2 point variations, small insertions, and deletions. An alternative set of MLPA probes, long-range PCR, and real-time PCR were used to confirm positive results.
  
  
  RESULTS
  We have identified 8 different BRCA1 rearrangements (del exon 1-24, del exon 8-13, del exon 11-15, del exon 14, dup exon 19-20, dup exon 20, exon 21-22 amplification, and del exon 23-24). With the exception of del exon 8-13, they are novel alterations. Overall, BRCA1 LGRs explain 1.4% of the Spanish HB(O)C families, and they account for 8.2% of all BRCA1 pathogenic variations identified in our study population. BRCA1 genetic variants affecting hybridization of commercially available MLPA probes are very rare in our population.
  
  
  CONCLUSIONS
  Screening for BRCA1 LGRs should be mandatory in Spanish HB(O)C families. A high proportion of country-specific rearrangements are scattered along the gene. MLPA is a robust method to screen for LGRs in our population. MLPA analysis of positive samples with an alternative set of probes, together with long-range PCR and real-time PCR, is a feasible approach to confirm results in cases in which LGR breakpoints have not been characterized.
authors.affiliation: Laboratorio de Oncología Molecular y Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, and Instituto de Biología y Genética Molecular, Facultad de Medicina, Universidad de Valladolid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.forename: Sara
authors.initials: S
authors.lastname: Gutiérrez-Enríquez
authors.forename: Eladio
authors.initials: E
authors.lastname: Velasco
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Ana
authors.initials: A
authors.lastname: Sanchez de Abajo
authors.forename: Ana
authors.initials: A
authors.lastname: Vega
authors.forename: Raquel
authors.initials: R
authors.lastname: Salazar
authors.forename: Eva
authors.initials: E
authors.lastname: Esteban
authors.forename: Gemma
authors.initials: G
authors.lastname: Llort
authors.forename: Rogelio
authors.initials: R
authors.lastname: Gonzalez-Sarmiento
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Cristina
authors.initials: C
authors.lastname: Miner
authors.forename: Orland
authors.initials: O
authors.lastname: Díez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Díaz-Rubio
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldes
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D005240:Feasibility Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D021141:Nucleic Acid Amplification Techniques; D010051:Ovarian Neoplasms / Q000235:genetics*; D013030:Spain
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein