M. Montagna et al., Identification of a 3 kb Alu-mediated BRCA1 gene rearrangement in two breast ovarian cancer families, ONCOGENE, 18(28), 1999, pp. 4160-4165
Most of the hereditary breast cancers are attributed to constitutive altera
tions of either BRCA1 or BRCA2 genes; nonetheless, germline mutations of th
ese genes in 'high risk' families are found less frequently than expected f
rom linkage data. Recent findings suggest that major genomic rearrangements
of the BRCA1 gene might account for at least some of the apparently mutati
on negative cases. We studied 60 affected probands belonging to families wi
th a strong history of breast and/or ovarian cancer who scored negative for
BRCA1 gene mutations by PTT and SSCP analysis, DNA was analysed by the Sou
thern blotting procedure using three different restriction enzymes, and tno
probes obtained by RT-PCR of the 5' and 3' BRCA1 coding sequence. A 3 kb d
eletion encompassing exon 17 and causing a frameshift mutation was identifi
ed in two independently ascertained families. RT-PCR and long-range DNA PCR
were employed to characterize the rearrangement that was finally shown to
be the result of a recombination between tno very similar Alu repeats. This
type of mutation is not identified by the conventional methods of mutation
detection which are based on PCR amplification of single exons, Therefore,
further search for gene rearrangements is needed to better define the prop
ortion of 'high risk' families that might be explained by gross genomic alt
erations of the BRCA1 gene.