Identification of a large rearrangement of theBRCA1 gene using colour bar code on combed DNA in an American breast/ovarian cancer family previously studied by direct sequencing

Editor—Linkage data suggest that BRCA1 and BRCA2 gene alterations account for the majority of hereditary breast/ovarian cancer cases.1 Though comprehensive screening of the BRCA1 gene has been attempted on a number of occasions, only two thirds of expected mutations have been detected so far.1-3 Most efforts have relied on standard PCR techniques, including direct sequencing, single strand conformation polymorphism (SSCP) analysis, heteroduplex analysis (HDA), denaturing gradient gel electrophoresis (DGGE), and protein truncation testing (PTT), with a focus on point and small mutations.2 The relatively low rate of detection of BRCA1 gene mutations may be because of the existence of large rearrangements, which are not detected by such approaches. Supporting this hypothesis, a number of large rearrangements, ranging from 0.5 to 23.8 kb and spanning the entire BRCA1 gene, have recently been detected by Southern blotting, analysis of BRCA1 lymphocyte transcripts, and long range PCR.4-14 In most cases, the characterised rearrangements are the result of unequal recombination events between Alu sequences, which cover 41.5% of BRCA1 introns.15 Here we report the identification, using colour bar coding on combed DNA, of a previously undescribed large rearrangement of the BRCA1 gene in an American breast/ovarian cancer family with ancestors from France and Germany (fig1). Figure 1 Pedigree of American family IC2361. Current ages or ages at death are indicated below each symbol. Tumour locations (T) and ages at diagnosis (Dx) are reported. The arrow indicates the patient studied. The index case was diagnosed with breast cancer at the age of 30 and ovarian cancer at the age of 49. She had one sister with breast cancer diagnosed at the age of 35, another sister with ovarian cancer diagnosed at the age of 35, and a paternal grandmother with breast cancer diagnosed at the age of 41. The …