Identification of a novel BRCA1 large genomic rearrangement in a Spanish breast/ovarian cancer family

Suela, Sarai Palanca; Cardeñosa, Eva Esteban; Saéz-González, Esteban; Oltra, Silvestre; Jiménez, Inma de Juan; González, Isabel Chirivella; Huerta, Ángel Segura; Ponce, Carmen Guillén; Dueñas, Eduardo Martínez de; Gilabert, Pascual Bolufer

doi:10.1007/s10549-007-9839-6

Cited by 15 publications

(5 citation statements)

References 18 publications

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“…The deletion of exons 4-6 of BRCA1 (in the literature also referred to as BRCA1 del exons 5-7) detected for a single White non-Afrikaner BC patient is rare, as it has been detected only six times previously, mostly in European countries, namely Germany [25], Croatia [36], Italy [37], Slovenia [38], Spain [39] and Denmark [40]. For some of these deletions, the breakpoints were determined [25,39,40]. Preisler-Adams et al [25] determined that a homologous region of 15 bp between AluSx in intron 3 and AluSc in intron 7 at the crossover site, is responsible for this LGR in German families.…”

Section: Discussionmentioning

confidence: 99%

The contribution of large genomic rearrangements in BRCA1 and BRCA2 to South African familial breast cancer

et al. 2020

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Background Pathogenic variants that occur in the familial breast cancer genes (BRCA1/2) lead to truncated ineffective proteins in the majority of cases. These variants are mostly represented by small deletions/insertions, nonsense- and splice-site variants, although some larger pathogenic rearrangements occur. Currently, their contribution to familial breast cancer (BC) and ovarian cancer (OVC) in South Africa (SA) is unknown. Methods Seven hundred and forty-four patients affected with BC or OVC were screened for larger genomic rearrangements (LGRs) by means of multiplex ligation-dependent probe amplification or Next Generation Sequencing using the Oncomine™ BRCA research assay. Results The patients represented mostly medium to high-risk families, but also included lower risk patients without a family history of the disease, diagnosed at an early age of onset (< 40 years). Eight LGRs were detected (1.1%); seven in BRCA1 with a single whole gene deletion (WGD) detected for BRCA2. These eight LGRs accounted for 8.7% of the 92 BRCA1/2 pathogenic variants identified in the 744 cases. The pathogenic LGRs ranged from WGDs to the duplication of a single exon. Conclusions Larger rearrangements in BRCA1/2 contributed to the overall mutational burden of familial BC and OVC in SA. Almost a quarter of all pathogenic variants in BRCA1 were LGRs (7/30, 23%). The spectrum observed included two WGDs, one each for BRCA1 and BRCA2.

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Section: Discussionmentioning

confidence: 99%

The contribution of large genomic rearrangements in BRCA1 and BRCA2 to South African familial breast cancer

et al. 2020

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“…We hypothesize that this sequence contains a recombinogenic hotspot as assumed for other sequences in Alu elements, as also postulated before. 18,19 Rüdiger et al, 19 suggested that four different rearrangements in the low density lipoprotein receptor gene presented a 26-bp common sequence that functions as a recombinational hotspot. This core sequence contains a pentanucleotide motif (CCAGC), which is also part of chi, an 8-bp sequence known to stimulate recBC-mediated recombination in Escherichia coli.…”

Section: According To Sluiter and Van Rensburg 4 81 And 17 Differentmentioning

confidence: 99%

Genomic characterization of two large Alu-mediated rearrangements of the BRCA1 gene

et al. 2012

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To determine whether a large genomic rearrangement is actually novel and to gain insight about the mutational mechanism responsible for its occurrence, molecular characterization with breakpoint identification is mandatory. We here report the characterization of two large deletions involving the BRCA1 gene. The first rearrangement harbored a 89,664-bp deletion comprising exon 7 of the BRCA1 gene to exon 11 of the NBR1 gene (c.441+1724_oNBR1:c.1073+480del). Two highly homologous Alu elements were found in the genomic sequences flanking the deletion breakpoints. Furthermore, a 20-bp overlapping sequence at the breakpoint junction was observed, suggesting that the most likely mechanism for the occurrence of this rearrangement was nonallelic homologous recombination. The second rearrangement fully characterized at the nucleotide level was a BRCA1 exons 11-15 deletion (c.671-319_4677-578delinsAlu). The case harbored a 23,363-bp deletion with an Alu element inserted at the breakpoints of the deleted region. As the Alu element inserted belongs to a still active AluY family, the observed rearrangement could be due to an insertion-mediated deletion mechanism caused by Alu retrotransposition. To conclude, we describe the breakpoints of two novel large deletions involving the BRCA1 gene and analysis of their genomic context allowed us to gain insight about the respective mutational mechanism.

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“…Of the published studies of the frequency of BRCA1 / 2 LGRs in the Iberian Peninsula or regions thereof [6]–[17], none has specifically examined the population of Galicia (NW Spain), a region with a distinct genetic identity attributable to its historical relative isolation, its cultural identity, and the occurrence of a marked population bottleneck around 1000 years ago [18]. This population features a number of founder mutations [18]–[20], including a BRCA1 mutation, c.211A>G (referred to NM_007294.3; BIC 330A>G), which is present in more than 50% of Galician HBOC families with BRCA1/2 mutations [21].…”

Section: Introductionmentioning

confidence: 99%

Large Genomic Rearrangements of BRCA1 and BRCA2 among Patients Referred for Genetic Analysis in Galicia (NW Spain): Delimitation and Mechanism of Three Novel BRCA1 Rearrangements

et al. 2014

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In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA) to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis) without point mutations or small indels. We identified three different BRCA1 LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of BRCA1 (identified in two unrelated families) and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the BRCA1 LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of BRCA1 exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the BRCA1 LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one BRCA2 LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of BRCA1 LGRs within BRCA1 mutation carriers in Galicia (2.34%, 95% CI: 0.61–7.22) seems to differ from the Spanish population (9.93%, 95% CI: 6.76–14.27, P-value = 0.013) and from the rest of the Iberian population (9.76%, 95% CI: 6.69–13.94, P-value = 0.014).

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Identification of a novel BRCA1 large genomic rearrangement in a Spanish breast/ovarian cancer family

Abstract: The new mutation here reported broadens the mutational spectrum of large rearrangements. Furthermore, the five large rearrangements found in patients non-carriers of BRCA1/BRCA2 mutations reinforce the need of studying BRCA1 large genomic rearrangements in genetic counselling programs.

Cited by 15 publications

References 18 publications

The contribution of large genomic rearrangements in BRCA1 and BRCA2 to South African familial breast cancer

The contribution of large genomic rearrangements in BRCA1 and BRCA2 to South African familial breast cancer

Genomic characterization of two large Alu-mediated rearrangements of the BRCA1 gene

Large Genomic Rearrangements of BRCA1 and BRCA2 among Patients Referred for Genetic Analysis in Galicia (NW Spain): Delimitation and Mechanism of Three Novel BRCA1 Rearrangements

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