Abstract for presentation at 11th International Congress of Human Genetics

Genomic re-arrangements account for ~8% of deleterious mutations in the in BRCA1 and BRCA2 genes in a population at risk for HBOC

  • Dr Peter Ainsworth, University of Western Ontario / London Health Sciences Centre, Canada
  • Dr Diane Allingham-Hawkins, North York General Hospital, Toronto, Canada
  • Dr Nancy Carson, University of Ottawa / Children's Hospital of Eastern Ontario, Canada
  • Dr Ronald Carter, McMaster University/Hamilton Health Sciences, Hamilton, Canada
  • Dr Jo-Anna Dolling, McMaster University / Credit Valley Hospital, Canada
  • Dr Hilmi Ozcelik, Mt Sinai Hospital, Toronto, Canada
  • Dr Marsha Speevak, McMaster University / Credit Valley Hospital, Canada
  • Dr Sherry Taylor, Queens University / Kingston General Hospital, Canada

    • Screening of individuals at an elevated risk for Hereditary Breast/Ovarian Cancer (HBOC) is generally dependent on a PCR-based approach to enable the detection of sequence alterations such as point mutations, small deletions and/or insertions. However this methodology is generally unable to detect larger genomic re-arrangements in the presence of the normal homologous allele. Previous reports of southern blot analysis or more recently the multiplex ligation-dependent probe amplification (MLPA) method, have identified genomic rearrangements as a significant factor in inherited deleterious mutations of BRCA1/2 (1, 2). A total of 600 leukocyte-derived DNA/RNA samples were collected by 7 separate Cancer Genetic centres in Ontario, Canada from individuals assessed to be at risk for HBOC. Both BRCA1 and BRCA2 genes in these samples were analyzed by a combination of PTT and limited direct sequencing. Our experience to date suggests that ~15% of these samples will bear a deleterious mutation in either BRCA1 or BRCA2. In an ethics-approved study these samples are also being characterized by dhplc-based heteroduplex analysis to assess the comparative efficacy of this method. Additional screening by MLPA of these samples has been carried out and has identified several genomic re-arrangements including, BR1EX21-24del, BR1EX14-20del, and the recurrent BR1EX13dup, as well as BR2EX1-3del, and BR2EX3del. Genomic re-arrangements affecting multiple contiguous exons were confirmed by repeat MLPA, however because of the possibility of the influence of unidentified SNP’s, long range PCR was used to confirm single exon deletion or duplication events. Assessment of these results indicates that up to 8% of the expected number of deleterious mutations in the BRCA1 or BRCA2 genes result from a genomic re-arrangement. A search for this type of mutation should be part of any BRCA1/2 screening algorithm.
    1. Hogervorst et al. (2003) Cancer Res 63:1449-53
    2. Agata et al (2005) Med Genet 42:e64

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