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Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

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Abstract

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.

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Acknowledgements

Lis Krüger and Lis Nielsen are acknowledged for excellent technical assistance. This study was supported by the Neye Foundation.

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Authors and Affiliations

  1. Department of Clinical Biochemistry 4111, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Thomas v. O. Hansen, Lars Jønson & Finn C. Nielsen

  2. Department of Biostatistics, University of Copenhagen, Øster Farimagsgade 5, 1014, Copenhagen, Denmark

    Anders Albrechtsen

  3. Department of Clinical Genetics, The Juliane Marie Center, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark

    Mette K. Andersen

  4. Department of Oncology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Bent Ejlertsen

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  1. Thomas v. O. Hansen
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Correspondence to Thomas v. O. Hansen.

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10549_2008_88_MOESM1_ESM.pdf

Supplementary Fig. 1. SNP array analsis of genomic DNA from patients with BRCA1 exon 3-16 deletion. For each chromosome the length of the possible shared haplotypes are shown as lines above the SNP density of the same chromsome. The SNP density is not completely uniform across the genome and some regions, like centromeric regions, have little of no SNPs on the chip. The largest possible shared haplotype at postion 34,179,358-39,461,220 on chromosome 17 around the BRCA1 region that consists of 301 SNPs. The possible shared haplotype with the second largest number of SNP is on chromosome 12 at position 86,691,951 to 88,423,908 and contains 68 SNPs and is 1.26 Mb long. (PDF 448 kb)

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Hansen, T.v.O., Jønson, L., Albrechtsen, A. et al. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families. Breast Cancer Res Treat 115, 315–323 (2009). https://doi.org/10.1007/s10549-008-0088-0

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