LargeBRCA1 gene deletions are found in 3% of German high-risk breast cancer families

Hartmann, Carolin; John, Anika L.; Klaes, Ruediger; Hofmann, Wera; Bielen, Rainer; Koehler, Rolf; Janssen, Bart; Bartram, Claus R.; Arnold, Norbert; Zschocke, Johannes

doi:10.1002/humu.9291

Cited by 71 publications

(51 citation statements)

References 12 publications

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“…Compared to other studies, our LGR detection rate was similar to the one in Czech 5.8% [37] or German population 5.3% [38]. Deletion of exons 21-22 in BRCA1 gene was previously reported in Czech population [37].…”

Section: It Seems Thatsupporting

confidence: 86%

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

Konečný

Milly

Zavodna

et al. 2011

Breast Cancer Res Treat

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Germline mutations in the BRCA1/2 genes account for the majority of hereditary breast ovarian cancer (HBOC).Identification of causal mutations may have significant impact on clinical management of such families. Despite high mutation detection rate, many HBOC cases remain without identified cause. These cases warrant use of several analysis methods, such as those for large genomic rearrangements and DNA copy number changes, or analysis other genes, shown to be associated with increased HBOC risk.We assessed 585 Slovak HBOC for presence of mutations in BRCA genes. Sequencing revealed mutations in 100 families, representing 17.1% (88% and 12% of mutations were located in BRCA1 and BRCA2, respectively).Four of the mutations, c.80+4del4, c.1938_1947del10 and c.1166delG in BRCA1 and c.6589delA in BRCA2 gene have been described only in Slovak population. Using MLPA analysis, we detected two large genomic rearrangements in 3 families, a deletion of exons 21 and 22, and a rare deletion of a whole BRCA1 gene. Twentyseven different variants of uncertain clinical effect (4 novel) and 14 distinct SNP BRCA1 haplotypes were detected. Their potential effect was considered using the prediction software packages Align GVGD, Pmut and Polyphen.We observed that the best clinical criterion for the initiation of BRCA1 analysis is the presence of breast cancer at 40 years of age in the association with the presence of ovarian cancer diagnosed around the age of 50.Conversely, the best clinical criterion for starting with BRCA2 analysis is the presence of breast cancer diagnosed in older age (above 50), or the presence of breast cancer in conjunction with carcinomas at different sites e.g. prostate, colorectum, ovary, uterus. Finally we have seen that the analyses of other HBOC risk gene TP53 and specific mutation in CHEK2*c.1100delC in Slovak HBOC families were not efficient since no mutations were found in these genes. 2

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Section: It Seems Thatsupporting

confidence: 86%

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

Konečný

Milly

Zavodna

et al. 2011

Breast Cancer Res Treat

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“…Both Hartman et al (20 ) and Bunyan et al (22 ) suggested that, in their study populations, MLPA may be marginally more cost effective as a first line of screening in the clinical setting. This may also be true in the Spanish population.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2006

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“…Recently, the MLPA (Multiplex Ligation-dependent Probe Amplification) assay was introduced as an additive diagnostic tool 36 to detect this type of mutation, which is estimated to occur in up to 10% in BRCA1 and less in BRCA2. 37,38 Therefore, MLPA is currently used in addition to either scanning, for example by DHPLC, and subsequent direct sequencing or direct sequencing only.…”

Section: Current Status Of the Scanning Methods Evaluatedmentioning

confidence: 99%

Diagnostic accuracy of methods for the detection of BRCA1 and BRCA2 mutations: a systematic review

et al. 2007

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As sequence analysis for BRCA1 and BRCA2 mutations is both time-and cost-intensive, current strategies often include scanning techniques to identify fragments containing genetic sequence alterations. However, a systematic assessment of the diagnostic accuracy has been lacking so far. Here, we report on a systematic review to assess the internal and external validity of current scanning techniques. Inclusion criteria were: controlled design, investigators blinded, and tests suitable as a scanning tool for the whole genes BRCA1 and BRCA2. Outcome parameters were sensitivity, specificity, and positive and negative predictive values compared to direct sequencing. Out of 3816 publications, 10 studies reporting on 12 methods met our inclusion criteria. The internal and external validity of most of these studies was limited. Sensitivities were reported to be 100% for enzymatic mutation detection (EMD), multiple-dye cleavase fragment length polymorphism (MD-CFLP), fluorescence-based conformation-sensitive gel electrophoresis (F-CSGE), RNA-based sequencing, restriction endonuclease fingerprinting-single strand conformation polymorphism (REF-SSCP), stop codon (SC) assay, and denaturing high-performance liquid chromatography (DHPLC). Sensitivity was 50-96% for SSCP, 88-91% for two-dimensional gene scanning (TDGS), 76% for conformation-sensitive gel electrophoresis (CSGE), 75% for protein truncation test (PTT), and 58% for micronucleus test (MNT). Specificities close to 100% were reported, except for MNT. PTT and SC assay are only able to detect truncating mutations. Most studies were designed to introduce new experimental approaches or modifications of established methods and require further evaluation. F-CSGE, REF-SSCP, RNA-based sequencing, EMD, and MD-CFLP will need further evaluation before their use in a routine setting can be considered. SSCP, MNT, PTT, CSGE, and TDGS cannot be recommended because of their low sensitivity. DHPLC outperforms all other methods studied. However, none of the four studies evaluating DHPLC was performed on BRCA2.

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LargeBRCA1 gene deletions are found in 3% of German high-risk breast cancer families

Cited by 71 publications

References 12 publications

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

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

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

Diagnostic accuracy of methods for the detection of BRCA1 and BRCA2 mutations: a systematic review

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