Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families.
BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0-36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian cancer patients in whom a deleterious mutation in BRCA1 and BRCA2 was not detected by sequencing using the multiplex ligation-dependent probe amplification (MLPA) assay. We identified 15 patients with 7 different genomic rearrangements, including a BRCA1 exon 5-7 deletion with a novel breakpoint, a BRCA1 exon 13 duplication, a BRCA1 exon 17-19 deletion, a BRCA1 exon 3-16 deletion, and a BRCA2 exon 20 deletion with a novel breakpoint as well as two novel BRCA1 exon 17-18 and BRCA1 exon 19 deletions. The large rearrangements in BRCA1 and BRCA2 accounted for 9.2% (15/163) of all BRCA1 and BRCA2 mutations in East Denmark. Nine patients had the exon 3-16 deletion in BRCA1. By SNP analysis we find that the patients share a 5 Mb fragment of chromosome 17, including BRCA1, indicating that the exon 3-16 deletion represents a Danish founder mutation.
Department of Clinical Biochemistry 4111, Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark. tvoh@rh.dk
Thomas v O
Tv
Hansen
Lars
L
Jønson
Anders
A
Albrechtsen
Mette K
MK
Andersen
Bent
B
Ejlertsen
Finn C
FC
Nielsen
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D003718:Denmark; D005260:Female; D018703:Founder Effect; D015321:Gene Rearrangement; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors