BRCA1 GENOMIC DELETIONS ARE MAJOR FOUNDER MUTATIONS IN DUTCH BREAST-CANCER PATIENTS

To date, more than 300 distinct small deletions, insertions and point mutations, mostly leading to premature termination of translation(1), have been reported in the breast/ovarian-cancer susceptibility gene BR CA1. The elevated frequencies of some mutations in certain ethnic subp opulations(2-4) are caused by founder effects(5,6), rather than by mut ation hotspots. Here we report that the currently available mutation s pectrum of BRCA1 has been biased by PCR-based mutation-screening metho ds, such as SSCP, the protein truncation test (PTT) and direct sequenc ing, using genomic DNA as template. Three large genomic deletions that are not detected by these approaches comprise 36% of all BRCA1 mutati ons found in Dutch breast-cancer families to date. A 510-bp Alu-mediat ed deletion comprising exon 22 was found in 8 of 170 breast-cancer fam ilies recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counselling. In add ition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detec ted in 6 of the 170 research families, while an deletion of approximat ely 14 kb was detected in a single family. Haplotype analyses indicate d that each recurrent deletion had a single common ancestor.