Analysis ofBRCA1andBRCA2genes in Spanish breast/ovarian cancer patients: A high proportion of mutations unique to Spain and evidence of founder effects

Abstract

We screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germ-line mutations in the BRCA1 and BRCA2 genes, using SSCP, PTT, CSGE, DGGE, and direct sequencing. We identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 are novel and 12 have been reported only in Spanish families (41.5%). The prevalence of mutations in this set of families was 26.3%, but the percentage was higher in the families with breast and ovarian cancer (52.1%). The lowest proportion of mutations was found in the site-specific female breast cancer families (15.4%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. We found a higher frequency of ovarian cancer associated with mutations localized in the 5' end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the ovarian cancer cluster region (OCCR) region of exon 11 of the BRCA2 gene. The mutations 187_188delAG, 330A>G, 5236G>A, 5242C>A, and 589_590del (numbered after GenBank U14680) account for 46.6% of BRCA1 detected mutations whereas 3036_3039del, 6857_6858del, 9254_9258del, and 9538_9539del (numbered after GenBank U43746) account for 56.6% of the BRCA2 mutations. The BRCA1 330A>G has a Galician origin (northwest Spain), and BRCA2 6857_6858del and 9254_9258del probably originated in Catalonia (northeast Spain). Knowledge of the spectrum of mutations and their geographical distribution in Spain will allow a more effective detection strategy in countries with large Spanish populations.

Gene expression profiling integrated into network modelling reveals heterogeneity in the mechanisms of BRCA1 tumorigenesis

“…Samples proceeded from CNIO (Madrid), Istituto Tumori (Milan), Hospital Clínico San Carlos (Madrid) and ICO (Barcelona). Patient selection and mutational analysis are described elsewhere (Diez et al, 2003;Manoukian et al, 2007). A tissue microarray containing an independent series of 15 BRCA1 tumours previously classified as basal or luminal-like phenotype (Palacios et al, 2005) was used to analyse the CD133 (Prominin 1) and MMP7 (Matrix Metalloproteinase 7) proteins.…”

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

“…These breast cancer samples were selected from families with at least three women affected with breast and/or ovarian cancer and at least one of them diagnosed before 50 years of age, or from families with female breast and/or ovarian cancer and at least one case of male breast cancer. All cases were studied for mutations and large rearrangements in the BRCA genes using standard procedures (Osorio et al, 2000;Diez et al, 2003). A total of 18 cases had mutations in the BRCA1 gene, 16 patients presented mutations in the BRCA2 gene and 28 cases were negative for germ-line mutations in the BRCA genes (non-BRCA1/2 or BRCAX).…”

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

“…[26][27][28] Alternatively, specific mutation risks may be attributed to the type and location of the variants. 12 Considering the mutations described in previously published articles and in this article, we did not observe any association between the BC or OC risk and location of the mutations along RAD51D (data not shown).…”