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The most commonly detected mutations in BRCA1 are 185delAG in exon 2, and 5382insC in exon 20, which have a frequency in the Ashkenazi Jewish population of 0.9% and 0.1%, respectively (Struewing et al, 1995;Roa et al, 1996). The 185delAG mutation has been frequently identified in women with breast cancer who are of Jewish ancestry (Bar-sade et al, 1998), almost always sharing the same haplotype described in Ashkenazim, and in different populations, including the Spanish population (Osorio et al, 1998). The 6174delT BRCA2 mutation, in exon 11, occurs very frequently (1.5%) among Ashkenazi Jews, but also appears in nonJewish individuals (Berman et al, 1996a).Nowadays, about 80% of Jews are of Ashkenazim origin. They originated in present day Israel, and migrated to Eastern Europe. From the 3rd century until the end of the 15th century, Spain was one of the main areas of settlement for Sephardic Jews (Keller, 1969). After this period, they were expelled and migrated, but some of them remained in the Peninsula after forced conversion to Christianity. We evaluated the prevalence of 185delAG, 5382insC and 6174delT mutations in Spanish breast cancer patients, bearing in mind the possible presence of Sephardic Jewish ancestors among this population. PATIENTS AND METHODSWe studied the 185delAG and 5382insC mutations in the BRCA1 gene in 108 families of women with breast/ovarian cancer, and 190 women regarded as sporadic cases of breast cancer, 90% of them diagnosed between the ages of 16 and 40 years. The BRCA2 6174delT mutation was analysed in 77 of these families, and in 171 women with sporadic breast cancer.Families were selected if they met the following criteria: three or more close relatives with breast and/or ovarian cancer (highrisk families), two affected relatives (moderate-risk), and one or two second-degree affected relatives or late age of onset (lowrisk). All patients gave informed consent for testing before providing blood samples to obtain genomic DNA.Mutation detection was accomplished by polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and direct sequencing. RESULTSOnly two patients with a moderate-and high-risk family history of breast cancer showed the 185delAG BRCA1 mutation. No other variations were detected. One patient had early-onset breast and ovarian cancer (diagnosed at 34 years) and the other had breast and ovarian cancer (at 51 and 55 years, respectively). In both cases the probandÕs mother was affected with breast cancer.Four microsatellite markers (D17S855, D17S1322, D17S1323 and D17S327) were analysed to obtain the haplotype of the members from the two families with the mutation. In both families, the carriers of the mutation showed the same haplotype as reported in Ashkenazim with the 185delAG mutation (Tonin et al, 1995;Neuhausen et al, 1996). In one family, the Sephardic Jewish origin could be confirmed by the known ancestors. We extended this study to 20 control chromosomes and this haplotype was absent in all of them (Table 1). DISCUSSIONGiven the prese...

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The 185delAG BRCA1 deletion occurs with a high frequency in Ashkenazi Jews. We detected this mutation in two Spanish Gypsy women (the only Gypsy participants) in an extensive study of 90 high-risk families and 160 women with early-onset breast cancer. One of these Gypsy women belonged to a high-risk family and the other had had early-onset breast cancer. The mutation was also detected in 1 out of 25 Gypsy samples unrelated to breast cancer. All the samples with the mutation shared the marker alleles present in Jewish samples with 185delAG. This is the first report of this mutation in a non-Jewish well-defined ethnic population. According to these findings the carrier frequency of this mutation in Gypsy individuals could be several times higher than that of the general population, and this should be taken into consideration in genetic screening for cancer in Gypsy populations.

There is an association between BRCA2 mutations and male breast cancer, especially in those with a family history of BC. The high prevalence of BRCA2 mutations among males should be considered when estimating risk for female relatives. All new male cases of BC should be regarded as being possibly inherited and should be fully investigated.