MLPA screening in theBRCA1gene from 1,506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases

Abstract

We present a comprehensive analysis of 1,506 German families for large genomic rearrangements (LGRs) in the BRCA1 gene and of 450 families in the BRCA2 gene by the multiplex ligation-dependent probe amplification (MLPA) technique. A total of 32 pathogenic rearrangements in the BRCA1 gene were found, accounting for 1.6% of all mutations, but for 9.6% of all BRCA1 mutations identified in a total of 1,996 families, including 490 with small pathogenic BRCA1/2 mutations. Considering only high risk groups for hereditary breast/ovarian cancer, the prevalence of rearrangements is 2.1%. Interestingly, deletions involving exon 17 of the BRCA1 gene seem to be most frequent in Germany. Apart from recurrent aberrations like del ex17, dupl ex13, and del ex22, accounting for more than 50% of all BRCA1 LGRs, we could fully characterize 11 novel deletions. Moreover, one novel deletion involving exons 1-7 and one deletion affecting the entire BRCA1 gene were identified. All rearrangements were detected in families with: 1) at least two breast cancer cases prior to the age of 51 years; 2) breast and ovarian cancer cases; 3) ovarian cancer only families with at least two ovarian cancer cases; or 4) a single breast cancer case prior to the age of 36 years, while no mutations were detected in breast cancer only families with no or only one breast cancer case prior to the age of 51 years. Analysis for gross rearrangements in 412 high-risk individuals, revealed no event in the BRCA2 gene and only two known CHEK2 mutations. However, in an additional 38 high-risk families with cooccurrence of female breast/ovarian and male breast cancer, one rearrangement in the BRCA2 gene was found. In summary, we advise restricting BRCA1 MLPA screening to those subgroups that revealed LGRs and recommend BRCA2 MLPA screening only for families presenting with cooccurrence of female and male breast cancer.

BRCA1andBRCA2Germline Mutations Screening in Algerian Breast/Ovarian Cancer Families

“…But interestingly, we found by using Long Range PCR technique that our patient with the BRCA1 exon 8 deletion is heterozygous for a 2.6 kb deletion (data not shown). This deletion is different with the 5.7 kb and 3.5 kb deletions identified respectively in the two German patients [13]. Investigations aimed at determining the genomic breakpoint of the BRCA1 exon 2 and exon 8 deletions described in our study are on going.…”

“…We note that the BR-CA1 pathogenic mutation c.181T>G described in this study for the first time in North African populations, is one of the most frequent founder BRCA1 mutations identified in many European countries, Poland, Czech, Germany, Hungary [19]. Contrary to the BRCA1 exon 2 deletion reported here in one Algerian breast/ovarian cancer family which seems never described before, the deletion of exon 8 in BRCA1 gene found in a patient with bilateral breast cancer has been recently reported for the first time in two German patients with hereditary breast cancer [13]. But interestingly, we found by using Long Range PCR technique that our patient with the BRCA1 exon 8 deletion is heterozygous for a 2.6 kb deletion (data not shown).…”

“…Deletions of exons 1a-2, exons 2 and 3 or exon 8 in BRCA1 gene have been already reported in patients from Holland, Italy and Germany, respectively [13,22,23]. Interestingly, most of these patients developed bilateral breast cancer or breast/ovarian cancer.…”

Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia

“…This loss of a part of the conservative BRCT domain is suggested to have a cancer susceptibility effect. Deletion of exons 1 through 24 represents a very rare event and was previously reported in one Spain [8] and one German family [39]. Australian populations [42]; and 0.86% in US HBOC families [43].…”

EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients

“…The main argument against such screening, is that the time and efforts needed for such screening might be used more efficiently by screening more patients but for point mutations only. Previous reports (Engert, et al, 2008;Mazoyer, 2005)suggested that large rearrangements accounted for an average of 10% of the BRCA1 mutational spectrum. Although our present results are lower (5.8%), we can confidently confirm that it is worth searching for BRCA1 large rearrangements in genetic diagnosis, regardless of the patient's family history.…”