Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition

Rouleau, Étienne; Jesson, Béline; Briaux, Adrien; Noguès, Catherine; Chabaud, Valérie; Demange, L.; Sokolowska, Johanna; Coulet, Florence; Barouk-Simonet, Emmanuelle; Bignon, Yves‐Jean; Bonnet, Françoise; Bourdon, Violaine; Bronner, Myriam; Caputo, Sandrine M.; Castéra, Laurent; Delnatte, Capucine; C, Delvincourt; Fournier, Joëlle; Hardouin, Agnès; Muller, Danièle; Peyrat, Jean‐Philippe; Toulas, Christine; Uhrhammer, Nancy; Vidal, Véronique; Stoppa‐Lyonnet, Dominique; Bièche, Ivan; Lidereau, Rosette

doi:10.1007/s10549-012-2009-5

Cited by 21 publications

(22 citation statements)

References 51 publications

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“…In this regard, Rouleau and colleagues [37] used an in-house array CGH platform to search for copy number imbalances in ten genes involved in hereditary breast and ovarian cancer including BRCA1, BRCA2, CHEK2, BARD1, ATM, RAD50, RAD51, BRIP1, RAP80 and PALB2. In a series of 472 patients, they found only three large rearrangements in BRCA1/2 , two in CHEK2 and one intronic deletion in BRIP1 .…”

Section: Discussionmentioning

confidence: 99%

Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients

et al. 2014

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BackgroundGerm line mutations in BRCA1 and BRCA2 (BRCA1/2) and other susceptibility genes have been identified as genetic causes of hereditary breast and ovarian cancer (HBOC). To identify the disease-causing mutations in a cohort of 120 Brazilian women fulfilling criteria for HBOC, we carried out a comprehensive screening of BRCA1/2, TP53 R337H, CHEK2 1100delC, followed by an analysis of copy number variations in 14 additional breast cancer susceptibility genes (PTEN, ATM, NBN, RAD50, RAD51, BRIP1, PALB2, MLH1, MSH2, MSH6, TP53, CDKN2A, CDH1 and CTNNB1).MethodsCapillary sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for detecting point mutations and copy number variations (CNVs), respectively, for the BRCA1 and BRCA2 genes; capillary sequencing was used for point mutation for both variants TP53 R337H and CHEK2 1100delC, and finally array comparative genomic hybridization (array-CGH) was used for identifying CNVs in the 14 additional genes.ResultsThe positive detection rate in our series was 26%. BRCA1 pathogenic mutations were found in 20 cases, including two cases with CNVs, whereas BRCA2 mutations were found in 7 cases. We also found three patients with the TP53 R337H mutation and one patient with the CHEK2 1100delC mutation. Seven (25%) pathogenic mutations in BRCA1/2 were firstly described, including a splice-site BRCA1 mutation for which pathogenicity was confirmed by the presence of an aberrant transcript showing the loss of the last 62 bp of exon 7. Microdeletions of exon 4 in ATM and exon 2 in PTEN were identified in BRCA2-mutated and BRCA1/2-negative patients, respectively.ConclusionsIn summary, our results showed a high frequency of BRCA1/2 mutations and a higher prevalence of BRCA1 (64.5%) gene. Moreover, the detection of the TP53 R337H variant in our series and the fact that this variant has a founder effect in our population prompted us to suggest that all female breast cancer patients with clinical criteria for HBOC and negative for BRCA1/2 genes should be tested for the TP53 R337H variant. Furthermore, the presence of genomic structural rearrangement resulting in CNVs in other genes that predispose breast cancer in conjunction with BRCA2 point mutations demonstrated a highly complex genetic etiology in Brazilian breast cancer families.

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Section: Discussionmentioning

confidence: 99%

Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients

et al. 2014

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“…In BRCA1 , LGRs have been detected with varying frequencies among patients with breast or ovarian cancer. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 In a study of 805 Dutch families with a known predisposition for breast and/or ovarian cancer, those without identified pathogenic BRCA1 or BRCA2 mutations by conventional mutation screening methods (661) were assessed for BRCA1 germline LGRs. 23 A total of 33 families with a deletion or duplication event in BRCA1 were identified, representing 27% of the total 121 pathogenic BRCA1 mutations.…”

Section: Brca Testing: An Overviewmentioning

confidence: 99%

New challenges for BRCA testing: a view from the diagnostic laboratory

Wallace

2016

Eur J Hum Genet

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Increased demand for BRCA testing is placing pressures on diagnostic laboratories to raise their mutation screening capacity and handle the challenges associated with classifying BRCA sequence variants for clinical significance, for example interpretation of pathogenic mutations or variants of unknown significance, accurate determination of large genomic rearrangements and detection of somatic mutations in DNA extracted from formalin-fixed, paraffin-embedded tumour samples. Many diagnostic laboratories are adopting next-generation sequencing (NGS) technology to increase their screening capacity and reduce processing time and unit costs. However, migration to NGS introduces complexities arising from choice of components of the BRCA testing workflow, such as NGS platform, enrichment method and bioinformatics analysis process. An efficient, cost-effective accurate mutation detection strategy and a standardised, systematic approach to the reporting of BRCA test results is imperative for diagnostic laboratories. This review covers the challenges of BRCA testing from the perspective of a diagnostics laboratory.

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“…In order to screen for the presence of deletions of the BRCA1/BRCA1P1 intergenic region in routine diagnostic testing, a PCR assay has been designed that allow DNA amplification in standard conditions only when a deletion has occurred (otherwise the expected PCR fragment is too large to be amplified). These deletions can also be detected like most BRCA1 rearrangements by MLPA (van den Ouweland et al, ), QMPSF (Casilli et al, ), or zoom‐in dedicated CGH‐array (Rouleau et al, ). When performing the dedicated PCR test in routine BRCA1 / BRCA2 screening in our diagnostic laboratory, we obtained with one sample from a breast and ovarian cancer family (Fig.…”

Section: Resultsmentioning

confidence: 99%

Occurrence of a non deleterious gene conversion event in the BRCA1 gene

Tessereau

Léoné

Buisson

et al. 2015

Genes Chromosomes & Cancer

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The duplication in the primate lineage of a portion of the breast and ovarian cancer susceptibility gene BRCA1 has created a BRCA1 pseudogene 45 kb away. Non-allelic homologous recombination (NAHR) between BRCA1 and BRCA1P1 has generated recurrent deleterious germ-line 37-kb deletions encompassing the first two exons of BRCA1, accounting for several breast and ovarian cancer families in various populations. In principle, NAHR intermediates resolution could also lead through a non-crossover configuration to interlocus gene conversion (IGC), but none had been described as yet. Here, we report for the first time an IGC event identified in a breast and ovarian cancer family involving exactly the same segment as that involved in the 37-kb deletions. Close examination of the consequences of this IGC event showed that it does not impact BRCA1 expression. Detailed analysis of the regions of homology between BRCA1 and its pseudogene revealed the specificity of the segment where recombination systematically occurs.

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Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition

Cited by 21 publications

References 51 publications

Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients

Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients

New challenges for BRCA testing: a view from the diagnostic laboratory

Occurrence of a non deleterious gene conversion event in the BRCA1 gene

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