title: Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain).
abstract: BACKGROUND
  The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain).
  
  
  METHODS
  In the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA).
  
  
  RESULTS
  A total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family.
  
  
  CONCLUSIONS
  In this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area.
authors.affiliation: Unidad de Cáncer Familiar, Servicio de Oncología Médica, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Hospital Universitario Central de Asturias (HUCA), Calle de Celestino Villamil, Oviedo 33006, Spain. pilarblayalbors@gmail.com
authors.forename: Pilar
authors.initials: P
authors.lastname: Blay
authors.forename: Iñigo
authors.initials: I
authors.lastname: Santamaría
authors.forename: Ana S
authors.initials: AS
authors.lastname: Pitiot
authors.forename: María
authors.initials: M
authors.lastname: Luque
authors.forename: Marta G
authors.initials: MG
authors.lastname: Alvarado
authors.forename: Ana
authors.initials: A
authors.lastname: Lastra
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Fernández
authors.forename: Angeles
authors.initials: A
authors.lastname: Paredes
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
authors.forename: Milagros
authors.initials: M
authors.lastname: Balbín
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D013030:Spain