title: BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients.
abstract: To date, more than 300 distinct small deletions, insertions and point mutations, mostly leading to premature termination of translation, have been reported in the breast/ovarian-cancer susceptibility gene BRCA1. The elevated frequencies of some mutations in certain ethnic subpopulations are caused by founder effects, rather than by mutation hotspots. Here we report that the currently available mutation spectrum of BRCA1 has been biased by PCR-based mutation-screening methods, such as SSCP, the protein truncation test (PTT) and direct sequencing, using genomic DNA as template. Three large genomic deletions that are not detected by these approaches comprise 36% of all BRCA1 mutations found in Dutch breast-cancer families to date. A 510-bp Alu-mediated deletion comprising exon 22 was found in 8 of 170 breast-cancer families recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counselling. In addition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detected in 4 of 170 research families, while an deletion of approximately 14 kb was detected in a single family [corrected]. Haplotype analyses indicated that each recurrent deletion had a single common ancestor.
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Petrij-Bosch
authors.forename: T
authors.initials: T
authors.lastname: Peelen
authors.forename: M
authors.initials: M
authors.lastname: van Vliet
authors.forename: R
authors.initials: R
authors.lastname: van Eijk
authors.forename: R
authors.initials: R
authors.lastname: Olmer
authors.forename: M
authors.initials: M
authors.lastname: Drüsedau
authors.forename: F B
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: S
authors.initials: S
authors.lastname: Hageman
authors.forename: P J
authors.initials: PJ
authors.lastname: Arts
authors.forename: M J
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: H
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.forename: J G
authors.initials: JG
authors.lastname: Klijn
authors.forename: H F
authors.initials: HF
authors.lastname: Vasen
authors.forename: C J
authors.initials: CJ
authors.lastname: Cornelisse
authors.forename: L J
authors.initials: LJ
authors.lastname: van 't Veer
authors.forename: E
authors.initials: E
authors.lastname: Bakker
authors.forename: G J
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: P
authors.initials: P
authors.lastname: Devilee
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D001483:Base Sequence; D015139:Blotting, Southern; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D015247:Deoxyribonuclease HindIII / Q000235:genetics / Q000378:metabolism; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009426:Netherlands; D010051:Ovarian Neoplasms / Q000235:genetics; D016133:Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid; D017384:Sequence Deletion
chemical_list: D019313:BRCA1 Protein; D015247:Deoxyribonuclease HindIII