The contribution of germline rearrangements to the spectrum of BRCA2 mutations

Casilli, Federica

doi:10.1136/jmg.2005.040212

Cited by 56 publications

(47 citation statements)

References 10 publications

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“…Kwong et al (17) showed that the rearrangement rate was 8.7% in the Chinese population. French and Czech population frequencies were 6-7.7%, and a high frequency of BRCA2 gene rearrangements was determined in the French population (15). Rearrangement frequencies were between 3-3.7% in Australian and Korean populations (9,13).…”

Section: Discussionmentioning

confidence: 91%

“…Most (25/27) rearrangements were found in patients with hereditary ovarian cancer (7). The rearrangement ratio (40.9%) given by Aktaş et al (7) for patients with ovarian cancer who had family histories was very high according to the international literature (4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The second study investigated the rearrangement ratio in patients with hereditary breast cancer, but with a small sample size.…”

Section: Discussionmentioning

confidence: 97%

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Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer

Yazıcı

Kilic

Akdeniz

et al. 2018

Eur J Breast Health

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IntroductionBreast cancer is the most common cancer among women worldwide and causes significant morbidity and mortality (1). According to the 2009 statistics of the Turkish Statistical Institute (TUIK), the leading cancer and the seventh-most-frequent cancer among women were breast and ovarian carcinoma, respectively. Among Turkish women, the incidence of breast cancer and ovarian carcinoma is 23% and 3.9%, respectively. Therefore, breast and ovarian carcinoma are important health problems for Turkish society. Furthermore, consanguineous marriages, especially among first cousins, are quite common in Turkey. This may lead to higher cancer risks, especially in families with cancer histories. It is very important to detect hereditary cancer risk using genetic testing for individuals in high-risk families as well as genetic testing, if applied correctly. Hence it is very important to determine the limits and content of genetic tests.Several factors increase the risk of breast cancer such as family history, reproductive history, diet, hormone use, radiation exposure, obesity, sedentary lifestyle, lack of breast-feeding, and exogenous hormone replacement therapy (1). Among these, a family history with breast and ovarian cancer in several generations is present in about 15-20% of all cases (2). Germline mutations of two major tumor suppressor genes, BRCA1 and BRCA2, are inherited in an autosomal dominant pattern and have links to breast and ovarian cancer (3). These two mutated genes increase the risk of breast cancer by 87% and 44% for ovarian cancer over the lifetime of female patients (4, 5). BRCA1 and BRCA2 participate in cellular functions such as cell growth, cell division, and genetic instability. Eur J Breast Health 2018; 14: 93-99 DOI: 10.5152/ejbh.2017.3799 93 ABSTRACT Objective: The current rearrangement ratio of BRCA1 and BRCA2 genes is not known in the Turkish population. Rearrangements are not routinely investigated in many Turkish laboratories. This creates problems and contradictions between clinics. Therefore, the aim of this study was to evaluate the distribution and frequency of rearrangements in BRCA1 and BRCA2 genes in high-risk families and to clarify the limits of BRCA1 and BRCA2 testing in Turkey. Frequency of Rearrangements Versus Materials and Methods:The study included 1809 patients at high risk of breast cancer or ovarian cancer. All patients were investigated for both small indels and rearrangements of BRCA genes using DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis. Results:The overall frequency of rearrangements was 2% (25/1262). The frequency of rearrangements was 1.7% (18/1086) and 4% (9/206) in patients with breast cancer and ovarian cancer, respectively. The frequency of rearrangements was 3.7% (8/215) in patients with triple-negative breast cancer. The rearrangement rate was 7.7% (2/26) in patients with both breast and ovarian cancer. Conclusions:Rearrangements were found with high rates and were strongly associated with bilateral and triple-...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 97%

Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer

Yazıcı

Kilic

Akdeniz

et al. 2018

Eur J Breast Health

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“…Screening for large genomic rearrangements of BRCA1 was performed for all probands with a combination of the multiplex ligation-dependent probe amplification method and the quantitative multiplex PCR of short fluorescent fragment method. 11,12 These analyses failed to reveal obviously pathogenic mutations. All patients and controls gave signed informed consent.…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes

et al. 2011

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A large fraction of sequence variants of unknown significance (VUS) of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 may induce splicing defects. We analyzed 53 VUSs of BRCA1 or BRCA2, detected in consecutive molecular screenings, by using five splicing prediction programs, and we classified them into two groups according to the strength of the predictions. In parallel, we tested them by using functional splicing assays. A total of 10 VUSs were predicted by two or more programs to induce a significant reduction of splice site strength or activation of cryptic splice sites or generation of new splice sites. Minigene-based splicing assays confirmed four of these predictions. Five additional VUSs, all at internal exon positions, were not predicted to induce alterations of splice sites, but revealed variable levels of exon skipping, most likely induced by the modification of exonic splicing regulatory elements. We provide new data in favor of the pathogenic nature of the variants BRCA1 c.212+3A4G and BRCA1 c.5194À12G4A, which induced aberrant out-of-frame mRNA forms. Moreover, the novel variant BRCA2 c.7977À7C4G induced in frame inclusion of 6 nt from the 3¢ end of intron 17. The novel variants BRCA2 c.520C4T and BRCA2 c.7992T4A induced incomplete skipping of exons 7 and 18, respectively. This work highlights the contribution of splicing minigene assays to the assessment of pathogenicity, not only when patient RNA is not available, but also as a tool to improve the accuracy of bioinformatics predictions. Keywords: variants of unknown significance; splicing defects; splicing reporter minigene; breast and ovarian cancer; BRCA1 and BRCA2 INTRODUCTIONThe interpretation of variants of unknown significance (VUS) found in the molecular screenings of the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, is essential for genetic counseling of patients and their families and for the implementation of new therapies targeted to carriers of BRCA mutations, such as those based on poly-(ADP-ribose) polymerase inhibitors. 1 The number of these variants already exceeds that of the reported pathogenic mutations, and is expected to increase rapidly with the use of new high throughput sequencing technologies that are based on massive parallel sequencing. 2 It is now widely accepted that RNA analyses should be used to improve the assessment of pathogenicity of sequence variation, because a large fraction of sequence variants, both intronic and exonic, may induce splicing defects. However, in many cases, patient RNA is either not available or it has been obtained in ways that do not ensure its stability. Moreover, it is sometimes difficult to detect the mRNA affected by a truncating mutation because of the activation of the nonsense-mediated mRNA decay pathway. 3 Functional assays of the effect of VUS on RNA splicing, using patient genomic DNA and a splicing reporter hybrid minigene,

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“…Women who have inherited mutations in the BRCA1 or BRCA2 (BRCA1/2) genes have substantially increased risk of breast cancer, with a lifetime risk of 56% to 84% (14)(15)(16)(17). A majority of the BRCA1/2 mutations reported cause protein truncation through indels, nonsense mutations, splice variants or rearrangements (18)(19)(20)(21). A large number of sequence variants with unknown effect on the phenotype have also been detected in BRCA1/2, and several studies have tried to determine their clinical significance (22,23).…”

Section: Introductionmentioning

confidence: 99%

Mammary Tumor Development in Dogs Is Associated with BRCA1 and BRCA2

et al. 2009

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Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of ∼4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer.

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The contribution of germline rearrangements to the spectrum of BRCA2 mutations

Abstract: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.

Cited by 56 publications

References 10 publications

Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer

Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer

Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes

Mammary Tumor Development in Dogs Is Associated with BRCA1 and BRCA2

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