Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: Identification of a novel deletion consistent with BRCA1:ψBRCA1 recombination

Authors

  • Melissa A. Brown,

    Corresponding author
    1. Department of Medical and Molecular Genetics, King’s College London (Guy’s Campus), Guy’s Hospital, London, UK
    2. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia
    3. Department of Biochemistry and Molecular Biology, University of Queensland, St. Lucia, Queensland, Australia
    • Department of Biochemistry and Molecular Biology, University of Queensland, St. Lucia, Queensland, 4072 Australia
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  • Li-Jan Lo,

    1. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia
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  • Aurélie Catteau,

    1. Department of Medical and Molecular Genetics, King’s College London (Guy’s Campus), Guy’s Hospital, London, UK
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  • Chun-Fang Xu,

    1. Department of Medical and Molecular Genetics, King’s College London (Guy’s Campus), Guy’s Hospital, London, UK
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  • Geoffrey J. Lindeman,

    1. Walter and Eliza Hall Institute of Medical Research, and Royal Melbourne Hospital, Parkville, Victoria, Australia
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  • Shirley Hodgson,

    1. Department of Medical and Molecular Genetics, King’s College London (Guy’s Campus), Guy’s Hospital, London, UK
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  • Ellen Solomon

    1. Department of Medical and Molecular Genetics, King’s College London (Guy’s Campus), Guy’s Hospital, London, UK
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Abstract

Inherited susceptibility to breast cancer results from germline mutations in one of a number of genes including BRCA1. A significant number of BRCA1-linked familial breast cancer patients, however, have no detectable BRCA1 mutation. This could be due in part to the inability of commonly used mutation-detection techniques to identify mutations outside the BRCA1 coding region. This paper addresses the hypothesis that non-coding region mutations, specifically in the BRCA1 promoter, account for some of these cases. We describe a new and detailed restriction map of the 5′ region of the BRCA1 gene including the nearby NBR2, ψBRCA1, and NBR1 genes and the isolation of a number of new informative hybridization probes suitable for Southern analysis. Using this information we screened DNA from lymphoblastoid cell-lines made from 114 UK familial breast cancer patients and detected one large deletion in the 5′ region of BRCA1. We show that the breakpoints for this deletion are in BRCA1 intron 2 and between NBR2 and exon 2 of ψBRCA1, raising the possibility that this deletion arose via a novel mechanism involving BRCA1BRCA1 recombination. We have also screened 60 familial breast cancer patients from the Australian population, using an amplification refractory mutation system (ARMS) technique described previously by our group, and found one patient with a genotype consistent with a BRCA1 promoter deletion. These findings indicate that germline BRCA1 promoter deletions are a rare and yet significant mutation event and that they could arise via a novel genetic mechanism. Hum Mutat 19:435–442, 2002. © 2002 Wiley-Liss, Inc.

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