POSTER NO: 164

Haplotype analyses and age estimation of a west Swedish founder mutation of the BRCA1 gene

¹Annika Bergman, ²Ulrica Olofsson, ³Zakaria Einbeigi, ²Ziad Taib, ³Arne Wallgren, ³Per Karlsson, ¹Jan Wahlström, ¹Tommy Martinsson, ¹Margareta Nordling
¹Dept. of Clinical Genetics, Sahlgrenska University hospital/East, Gothenburg, Sweden, ²Dept. of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden, ³Dept. of Oncology, Sahlgrenska University hospital, Gothenburg, Sweden

The cloning of BRCA1 and BRCA2 genes has led to the identification of several hundreds germline mutations in families with a history of hereditary breast cancer. Some of the mutations in BRCA1 and BRCA2 are recurrently identified in distinct geographic and ethnic populations and are believed to have spread from a single ancestor. It is important to characterize these founder mutations and determine their geographic distribution in order to be able to design efficient mutation screening. The most recurrent mutation in Sweden is the 3171ins5 mutation in BRCA1. In the western part of Sweden this mutation accounts for as much as 77% of all identified mutations in this region. Our aim was to in detail analyze the haplotype and founder effects of the 3171ins5 mutation and furthermore attempt to estimate the time since the first appearance of the mutation.

In the study we included eighteen families with hereditary breast and/or ovarian cancer. At least one individual in each family had previously tested positive for the 3171ins5 mutation. We used polymorphic microsatellite markers for the haplotype analyses. The markers were located within or flanking the BRCA1 gene spanning a region of 17,3 cM.

We found several different haplotypes as well on the disease allele as on the normal allele. We observed however a conserved haplotype in the 3171ins5 carriers for three markers within or very close to the BRCA1 gene. As this haplotype only was found once in the normal alleles it is highly likely that this is a mutation identical by descent, i.e. a true founder. The results from the haplotype analyses were used to estimate the age of the mutation. Using the method of moments, based on the theory of Galton-Watson branching processes we estimate that the mutation first appeared sometime around the 11th century, approximately 50 generations ago.