A founder mutation in Sardinian brest cancer families detected by identity-by-descent method

Genetically homogeneous populations, such as Sardinian, could be useful to identify disease-causing mutations in cancer families using the identity-descent method. We selected seven Sardinian breast cancer families with multiple affected members in different generations, without ovarian cancer associated. One hundred and six members of seven and 20 control families were genotyped with markers flanking the BRCA2 locus at 13q12-q13.A common haplotype, shared by four out of seven families, but not presnt in 80 control chromosomes , indicated the presence of a specific disease-causing mutation. Direct sequencing of BRCA2 exons of patients carrying this haplotype, allowed the identification of a novel 'frameshift' mutation in exon 20, causing a premature termination-codon, indicating a founder effect. Thi mutation was present in all breast cancer patients carrying the identity-by-descent haplotype. We then investigated the frequency of this mutation in Sardinian breast cancer population by analyzing 270 paraffin-embedded tissue samples from breast cancer patients. Only five patients were found to be positive but they came from families presenting with multiple cases of breast cancer as well as other tumors in firt-and second-degree relatives confirming the high penetrance of this mutation.