Novel genomic rearrangements in the BRCA1 gene detected in Greek breast/ovarian cancer patients.

The identification of genomic rearrangements in breast/ovarian cancer families has widened the mutational spectrum of the BRCA1 gene, increasing the number of patients who can benefit from molecular screening. More than 60 different BRCA1 genomic rearrangements with mapped breakpoints have been reported up to date, in all exons of the gene. The proportion of BRCA1 mutations due to genomic rearrangements varies from 8 to 27% in different populations, probably due to both ethnic diversity and the technical approach employed. In order to estimate the contribution of BRCA1 genomic rearrangements to hereditary breast/ovarian cancer (HBOC) predisposition in Greek families, probands from 95 families with breast/ovarian history but negative for point mutations or small insertions/deletions in BRCA1 and BRCA2 genes, were screened using Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF). Two large deletions of 4.2 and 4.4 kb were identified in exons 20 and 24 respectively. Additional screening, using diagnostic primers for the above deletions in exons 20 and 24, performed on another 86 probands from families with breast/ovarian cancer history and 210 cases of sporadic breast/ovarian cancer resulted in the identification of two more large genomic rearrangements. One, identified in a familial case, identical to the previous exon 24 deletion and a second, identified in a case reported as sporadic, 3.2 kb deletion involving exon 20 and reported elsewhere in another Greek patient. Three out of four genomic rearrangements described in this study were detected in patients who had developed both breast and ovarian cancer; thus suggesting a correlation between the specific phenotype and the high probability of detecting inherited rearrangements in BRCA1.

Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients.

127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast/ovarian cancer families bearing deleterious mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings with previously reported mutation data reveals that in a total of 287 Greek breast/ovarian cancer families, 46 and 13 carry a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management of breast-ovarian cancer families on a national healthcare system level.