BRCA1:185delAG found in the San Luis Valley probably originated in a Jewish founder.

T hree BRCA1/2 mutations (185delAG and 5382insC in BRCA1, and 617delT in BRCA2) are present in about 2.5% of the Ashkenazi Jewish population, and in 10– 12% of Ashkenazi Jewish women with breast cancer. Mutations that become common in a population are often explained by the presence of a ‘‘founder effect’’. This effect tends to exist when a population is established by a small group of ancestors. The members of the group are called founders and become isolated from the original population from which they are derived on account of geographical, cultural, or linguistic barriers. If this isolation persists, genetic drift can cause disease producing alleles present in the founders to become more frequent in subsequent generations. The San Luis Valley (SLV) is a large, isolated valley situated on the border between New Mexico and Colorado. The first settlers were Spaniards of the de Oñate expedition in 1598, but today it has an admixed population descended from Native Americans, West Africans, and Europeans. A previous study in Colorado of breast cancer patients with SLV ancestry revealed the presence of a hereditary breast cancer mutation, BRCA1:185delAG. Many of these individuals came from areas of Spanish settlement in what is now northern New Mexico, an area known to have had a number of Spanish settlers with Jewish heritage. This population remained fairly coherent until the mid-1900s, which would have allowed the fixation of certain mutations in the population through the founder effect. The 185delAG mutation (c.68_69del2) is a founder mutation in the Ashkenazi Jewish population and is the most common BRCA1 mutation in this population, with a frequency of 1%. 3 Markers flanking this mutation have conserved alleles among Ashkenazi carriers, allowing for the construction of a distinct, linked haplotype. In this study, we followed up on our original finding and set out to determine whether the BRCA1:185delAG mutation found in patients from the SLV is the same mutation found in Jewish patients, by testing seven nearby markers known to be conserved on the 185delAG Jewish haplotype. All participants of this study identified themselves as Spanish/Latin American and denied any Jewish ancestry. Subjects 1–8 of the study were included in our previous study, where details of the family history can be found, and subjects 9–11 are new subjects who were seen at the same genetic counselling centres and underwent the same clinical testing as the rest of the subjects (table 1). All subjects have a strong family history of breast or ovarian cancer. Patients with breast or ovarian cancer satisfied the American Society of Clinical Oncologists genetic testing for cancer predisposition inclusion criteria before genetic mutation analysis. Myriad Genetics Laboratories Inc carried out the mutation analysis by direct genomic sequencing, and showed that all patients except patient 7 are carriers of the 185delAG mutation. We amplified DNA from these patients by radioactive polymerase chain reaction (PCR) and visualised the genotypes on a 6% polyacrylamide sizing gel. Table 1 shows the genotypes of the subjects for each marker in reference to the conserved Jewish haplotype. We found that all 185delAG mutation carriers share a conserved allele at each of the seven loci tested. Moreover, subject 7, a non-carrier, does not have the conserved alleles at any of the loci. These results are consistent with the hypothesis that individuals in the SLV who carry the 185delAGmutation share a common ancestor with Jews who also carry this mutation. This finding suggests that individuals in this population have at least one ancestor of Jewish origin.