Abstract
BackgroundGermline mutations in either of the two tumor-suppressor genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast and ovarian cancer cases. Most of these mutations consist of deletions, insertions, nonsense mutations, and splice variants, however an increasing number of large genomic rearrangements have been identified in these genes.MethodsWe analysed BRCA1 and BRCA2 genes by direct sequencing and MLPA. We confirmed the results by an alternative MLPA kit and characterized the BRCA1 deletion by Array CGH.ResultsWe describe the first case of a patient with no strong family history of the disease who developed early-onset bilateral breast cancer with a de novo complete BRCA1 gene deletion in the germinal line. The detected deletion started from the region surrounding the VAT1 locus to the beginning of NBR1 gene, including the RND2, ΨBRCA1, BRCA1 and NBR2 complete genes.ConclusionThis finding supports the large genomic rearrangement screening of BRCA genes in young breast cancer patients without family history, as well as in hereditary breast and ovarian cancer families previously tested negative for other variations.
Highlights
Germline mutations in either of the two tumor-suppressor genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast and ovarian cancer cases
Most of the reported BRCA1 and BRCA2 mutations are characterized by deletions, insertions, nonsense mutations and splice variants that result in a truncated protein
We report the first case of a patient with no strong family history of the disease, with a de novo complete BRCA1 gene deletion demonstrated by Array Comparative Genome Hybridization (CGH) that developed early-onset bilateral breast cancer
Summary
Germline mutations in either of the two tumor-suppressor genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast and ovarian cancer cases. Most of these mutations consist of deletions, insertions, nonsense mutations, and splice variants, an increasing number of large genomic rearrangements have been identified in these genes. About 5-10% of all breast cancers are estimated to be hereditary, and germline mutations in the tumor-suppressor genes BRCA1 (MIM#113705) and BRCA2 (MIM#600185) are found in a proportion of this group [2,3]. LGRs in BRCA1 are responsible for between 0 and 27% of all BRCA1 disease-causing mutations identified in different populations [9] whereas in the case of BRCA2 these rearrangements are rare, except for a Portuguese population with a founder rearrangement [c.156_157insAlu (NG_012772.1:g.8686_8687insAlu)] that explains more than a quarter of BRCA mutations [9,10]
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