Heterogeneous prevalence of recurrent BRCA1 and BRCA2 mutations in Spain according to the geographical area: implications for genetic testing

Díez, Orland; Gutiérrez‐Enríquez, Sara; Balmañà, Judith

doi:10.1007/s10689-009-9301-5

Cited by 27 publications

(29 citation statements)

References 14 publications

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“…In addition, it was detected in other two Chilean families in a previous report [10], for a total of six unrelated carrier families in the Chilean population. This 4-pb deletion is also the third most frequent BRCA2 mutation in Spain [16,25,26], and it was found in 6 of 59 (10.2%) families from different geographic areas of this country. Three of these Spaniard families are from Castilla-Leon [27,28].…”

Section: Recurrent Mutationsmentioning

confidence: 85%

Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families

González‐Hormazábal

Gutiérrez-Enríquez

Gaete

et al. 2010

Breast Cancer Res Treat

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The distribution of BRCA1/2 germline mutations in breast/ovarian cancer (BC/OC) families varies among different populations. In the Chilean population, there are only two reports of mutation analysis of BRCA1/2, and these included a low number of BC and/or OC patients. Moreover, the prevalence of BRCA1/2 genomic rearrangements in Chilean and in other South American populations is unknown. In this article, we present the mutation-detection data corresponding to a set of 326 high-risk families analyzed by conformation-sensitive gel electrophoresis and heteroduplex analysis. To determine the contribution of BRCA1/2 LGRs in Chilean BC patients, we analyzed 56 high-risk subjects with no pathogenic BRCA1/2 point mutations. Germline BRCA1/2 point mutations were found in 23 (7.1%) of the 326 Chilean families. Families which had at least three BC and/or OC cases showed the highest frequency of mutations (15.9%). We identified 14 point pathogenic mutations. Three recurrent mutations in BRCA1 (c.187_188delAG, c.2605_2606delTT, and c.3450_3453delCAAG) and three in BRCA2 (c.4969_4970insTG, c.5374_5377delTATG, and c.6503_6504delTT) contributed to 63.6 and 66.7% of all the deleterious mutations of each gene, which may reflect the presence of region-specific founder effects. Taken together BRCA1/2 recurrent point mutations account for 65.2% (15/23) of the BRCA1/2 (+) families. No large deletions or duplications involving BRCA1/2 were identified in a subgroup of 56 index cases negative for BRCA1/2 point mutations. Our study, which is the largest conducted to date in a South American population, provides a comprehensive analysis on the type and distribution of BRCA1/2 mutations and allelic variants.

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Section: Recurrent Mutationsmentioning

confidence: 85%

Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families

González‐Hormazábal

Gutiérrez-Enríquez

Gaete

et al. 2010

Breast Cancer Res Treat

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“…(2011) [18], show that the mutation probably originated in Scandinavia or Northern Russia, was then disseminated in European populations and thus could have entered Brazil through one or more of the several large European immigration waves in the 18 th and 19 th centuries. A detailed understanding of its entrance and distribution in Brazil, remains to be determined [45,46]. …”

Section: Discussionmentioning

confidence: 99%

Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome

Ewald

Izetti

Vargas

et al. 2011

Hered Cancer Clin Pract

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About 5-10% of breast and ovarian carcinomas are hereditary and most of these result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish ascendance, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations, c.68_69del (185delAG) and c.5266dup (5382insC) in BRCA1 and c.5946del (6174delT) in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer. Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%). This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p = 0.023). The BRCA1 c.68_69del and BRCA2 c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1 c.68_69del and BRCA2 c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. In high-risk patients, a negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1 c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be further assessed in a larger well characterized high-risk cohort.

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“…One BRCA1 mutation, c.68_69delAG, was found in three different patients. This mutation accounts for the 30.4% BRCA1 mutations in the Mediterranean area [22]. Although only found once in our series, mutations c.211A>G, c.5123C>A in BRCA1 , and c.3264dupT in BRCA2 are also considered recurrent in the Spanish population [22].…”

Section: Resultsmentioning

confidence: 77%

Genetic Testing in Hereditary Breast and Ovarian Cancer Using Massive Parallel Sequencing

Ruiz

Llort

Yagüe

et al. 2014

BioMed Research International

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High throughput methods such as next generation sequencing are increasingly used in molecular diagnosis. The aim of this study was to develop a workflow for the detection of BRCA1 and BRCA2 mutations using massive parallel sequencing in a 454 GS Junior bench top sequencer. Our approach was first validated in a panel of 23 patients containing 62 unique variants that had been previously Sanger sequenced. Subsequently, 101 patients with familial breast and ovarian cancer were studied. BRCA1 and BRCA2 exon enrichment has been performed by PCR amplification using the BRCA MASTR kit (Multiplicom). Bioinformatic analysis of reads is performed with the AVA software v2.7 (Roche). In total, all 62 variants were detected resulting in a sensitivity of 100%. 71 false positives were called resulting in a specificity of 97.35%. All of them correspond to deletions located in homopolymeric stretches. The analysis of the homopolymers stretches of 6 bp or longer using the BRCA HP kit (Multiplicom) increased the specificity of the detection of BRCA1 and BRCA2 mutations to 99.99%. We show here that massive parallel pyrosequencing can be used as a diagnostic strategy to test for BRCA1 and BRCA2 mutations meeting very stringent sensitivity and specificity parameters replacing traditional Sanger sequencing with a lower cost.

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Heterogeneous prevalence of recurrent BRCA1 and BRCA2 mutations in Spain according to the geographical area: implications for genetic testing

Cited by 27 publications

References 14 publications

Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families

Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families

Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome

Genetic Testing in Hereditary Breast and Ovarian Cancer Using Massive Parallel Sequencing

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