Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families

Abstract

Introduction: A strong family history of breast and/or ovarian cancer can often be explained by small insertions, deletions, or substitutions in BRCA1 or BRCA2 and large genomic rearrangements in BRCA1. However, there is little evidence that genomic rearrangements are a major factor in BRCA2 associated breast cancer and the frequencies of rearrangements in BRCA1 in large clinic based populations are unknown. Objective: To investigate the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large clinic based population at high risk of developing breast and/or ovarian cancer. Methods: Multiplex ligation dependent probe amplification was used to comprehensively screen BRCA1 and/or BRCA2 in 312 index cases. Results: Three novel deletions detected in BRCA2 were found exclusively in families with at least one case of male breast cancer. Novel rearrangements in BRCA1 were detected mostly in families with both breast and ovarian cancer. Families with these mutations were significantly younger at average age of cancer diagnosis. Conclusion: Screening for large genomic rearrangements in both BRCA1 and BRCA2 is strongly supported by this study, in particular in multiple case breast/ovarian families with a young age of onset (BRCA1) and families containing at least one case of male breast cancer (BRCA2). Inheritance of a germline mutation in a cancer susceptibility gene accounts for 5-10% of all breast and ovarian cancer, and a higher proportion of cancers associated with a strong family history of the disease. From the initial linkage studies in the early 1990s it was predicted that mutations in BRCA1 and BRCA2 would account for a large proportion of multiple case families. 1 However, despite extensive mutation analysis, the rate of detection of mutations in these genes rarely rises above 30% in the family cancer clinical setting and has never reached the expected high frequency, even in families with multiple cases of the disease in successive generations. Until recently, the testing of BRCA1 and BRCA2 has been focussed on the identification of point mutations or small deletions and insertions.2 Another mechanism of gene inactivation, namely the rearrangement of large tracts of genomic DNA, may be responsible for a proportion of the undetected mutations and many families previously found to be mutation negative might harbour hitherto undiscovered rearrangements. [3][4][5] Homologous recombination between repeated DNA sequences is believed to be a major cause of the genetic instability that results in genomic deletions, duplications, or other rearrangements. The high density of Alu repeat sequences in BRCA1 (42%) and both Alu (20%) and non-Alu (27%) repetitive DNA in BRCA2 supports the likelihood that these genes may be susceptible to inactivation by homologous recombination. 6 The first rearrangement described in BRCA1 was a 1 kb deletion that included the loss of exon 17. 7 Since that time, up to 30 different genomic rearrangements, both deletions and duplications, ranging in size from 510 bp to 37 kb, have...

Evidence for Common Ancestral Origin of a Recurring BRCA1 Genomic Rearrangement Identified in High-Risk Hispanic Families

“…Adding the three BRCA1 del (ex 9-12) mutations found among the sequence negative cases brings the overall prevalence of BRCA mutations in the cohort to 34% (37 of 110)-the large rearrangement representing 8.8% (3 of 37) of all BRCA carriers. This proportion of rearrangements among BRCA1-positive individuals is consistent with previous studies in European and American populations (3,4,6,(28)(29)(30)(31).…”

Genomic Rearrangements at the BRCA1 Locus in Spanish Families with Breast/Ovarian Cancer

“…A recent study performed in Australian and New Zealand families found BRCA1 LGRs in 2.2% of the negative families (19 ). The entry criteria in the latter study were similar to those in study I.…”

“…After sequencing, the deletion was shown to encompass nucleotides 47840 to 52790. The breakpoints involved alu sequences, because it has been reported for other BRCA1 deletions (19 ). Family CIC-US1 has an MLPA profile suggestive of an exon 14 deletion.…”

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

“…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. The situation is less clear for BRCA2 because previous studies, including those from our team (Casilli, et al, 2006;Tournier, et al, 2004), were based on smaller series and selected high-risk families (Agata, et al, 2005;Engert, et al, 2008;Woodward, et al, 2005). These studies led to the overall conclusion that BRCA2 genomic rearrangements are worth investigating in high-risk families.…”