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Genetics and Molecular Biology

Print version ISSN 1415-4757

Genet. Mol. Biol. vol.35 no.3 São Paulo  2012 



Prevalence of 185delAG and 5382insC mutations in BRCA1, and 6174delT in BRCA2 in women of Ashkenazi Jewish origin in southern Brazil



Crisle Vignol DillenburgI,*; Isabel Cristina BandeiraI,*; Taiana Valente TubinoI; Luciana Grazziotin RossatoI; Eleonora Souza DiasII; Ana Cristina BittelbrunnIII; Sandra Leistner-SegalI,IV

IBanco de DNA/Tecido de Mama e Ovário, Centro de Pesquisas Experimentais, Hospital de Clínicas de Porto Alegre, RS, Brazil
IIHospital Materno Infantil Presidente Vargas, Porto Alegre, RS, Brazil
IIIServiço de Mastologia,Hospital de Clínicas de Porto Alegre, RS, Brazil
IVLaboratório de Genética Molecular, Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, RS, Brazil

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Certain mutations in BRCA1 and BRCA2 genes are frequent in the Ashkenazi Jewish population. Several factors contribute to this increased frequency, including consanguineous marriages and an event known as a "bottleneck', which occurred in the past and caused a drastic reduction in the genetic variability of this population. Several studies were performed over the years in an attempt to elucidate the role of BRCA1 and BRCA2 genes in susceptibility to breast cancer. The aim of this study was to estimate the carrier frequency of certain common mutations in the BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) genes in an Ashkenazi Jewish population from Porto Alegre, Brazil. Molecular analyses were done by PCR followed by RFLP (ACRS). The carrier frequencies for BRCA1 185delAG and 5382insC were 0.78 and 0 respectively, and 0.4 for the BRCA2 6174deT mutation. These findings are similar to those of some prior studies but differ from others, possibly due to excluding individuals with a personal or family history of cancer. Our sample was drawn from the community group and included individuals with or without a family or personal history of cancer. Furthermore, increased dispersion among Ashkenazi subpopulations may be the result of strong genetic drift and/or admixture. It is therefore necessary to consider the effects of local admixture on the mismatch distributions of various Jewish populations.

Keywords: Ashkenazi Jews, breast cancer, BRCA1, BRCA2, mutation.



Several factors may be responsible for the development of breast and ovarian cancers, but one of the most important described so far is the presence of BRCA1 and BRCA2 (BReast CAncer predisposition gene 1/2) gene mutations. Although hereditary breast cancer accounts for only 5%-10% of recorded cases, individuals with mutations in these genes usually have 40%-80% higher odds of developing breast cancer (Claus et al., 1991; Easton et al., 1995; Schubert et al., 1997). Even though several studies attempted to understand how BRCA1 and BRCA2 mutations could influence cancer susceptibility, the variation in risk among carriers of these mutations is not yet clear. In certain groups, the frequency of mutations in these genes is higher, as observed in Ashkenazi Jews, where BRCA1/2 mutations are present at a rate of 2%-3% (Neuhausen et al., 1996; Roa et al., 1996; Levy-Lahad et al., 1997). In this group, the three most frequently found mutations are: 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2, and more than 12% of the women who develop breast cancer bear one of these mutations (King et al., 2003). Population studies corroborate the hypothesis that these common mutations in BRCA1 and BRCA2, which are frequent in Ashkenazi Jews, are involved in predisposition to hereditary breast cancer (Neuhausen et al., 1996; Offit et al., 1996). The Ashkenazi Jewish population is prone to a series of genetic diseases, including cancers, blood disorders, and biochemical disorders, possibly due to a genetic bottleneck phenomenon followed by a period of rapid population growth, which are likely to have produced the conditions that led to a high frequency of many alleles associated with such genetic diseases (Goodman, 1979; Risch et al., 2003).

This study was approved by the Hospital de Clinicas de Porto Alegre Research Ethics Committee (#04-208), which is recognized by the Office for Human Research Protections as an Institutional Review Board (IRB0000921). After obtaining informed consent, blood samples were collected from 330 female subjects during a Jewish community festivity in the city of Porto Alegre, southern Brazil.

Each of the volunteers reported the birthplace of her mother, grandmother, and in a few cases, greatgrandmother, and also completed an epidemiological questionnaire. Ashkenazi Jewish origin was confirmed in 255 women, thus excluding from the total sample 75 individuals who are only part Jewish.

DNA was extracted from peripheral blood using a standard salt precipitation technique described by Miller et al. (1988). Samples were stored in a DNA biobank at -20 ºC until analysis. Molecular analysis was initially performed by PCR of exons 2 and 20 for BRCA1 gene mutations and exon 11 for the BRCA2 mutation, followed by 1% agarose gel electrophoresis and staining with ethidium bromide. Mutations were identified using the ACRS (Amplification Created Restriction Site) technique as described by Rohlfs et al. (1997). The restriction enzymes used were DdeI (185delAG), BstNI (5382insC) and EcoRI (6174delT) (all from New England Biolabs). The digested fragments were visualized on 3% agarose gel electrophoresis stained with ethidium bromide. Statistical analysis of mutation frequencies was performed using the Stata 7.0 program (StataCorp, College Station, TX, USA).

Regarding BRCA1 results, we found a carrier frequency of 0.78 (2/255; 95%CI 0.10-2.8) for 185delAG and no mutated alleles for 5382insC. For the 6174delT BRCA2 mutation, we found a carrier frequency of 0.4 (1/255; 95%CI 2.45-8.08). Comparative data regarding similar studies conducted with Ashkenazi Jews worldwide are shown in Table 1.

Epidemiological data from the participants of the present study showed that, of the three positive results for the tested mutations, all subjects had a family history of cancer and two had a personal one. One of the women who were positive for the 185delAG mutation died of breast cancer, and several cases of various types of cancer were reported in her family (twin sister, two brothers, aunt and maternal cousin). The subject who was positive for a 6174delT mutation had a personal history of ovarian cancer and a family history of breast cancer (paternal grandmother).

Struewing et al. (1997) found 120 positive results for the common mutations described here. Of the 5,318 participants tested for BRCA1, 41 exhibited the 185delAG mutation and 20 were positive for 5382insC. Tests for the BRCA2 mutation involved 5,087 participants, 59 of whom exhibited the 6174delT mutation. Among the 120 mutation-positive subjects, 8.9% had a personal history of breast or ovarian cancer and 3.8% had first-degree relatives with such cancers. Nevertheless, the study shows that there could be unequal penetrance depending on the mutation found, supporting the hypothesis of heterogeneity of the allelic risk conferred by the different mutations (Antoniou et al., 2003).

Claus et al. (1998) studied the correlation between cancer and multiple factors which could be involved in its development. These factors included ethnic group, age at menarche and first pregnancy, familial inheritance, and others. Correlations corroborated through statistical tests showed a close relationship between epidemiological data and cases of breast cancer.

The etiology of familial breast cancer is complex and involves genetic and environmental factors, such as hormonal and lifestyle factors. Understanding familial aggregation is the key to understanding the causes of breast cancer and facilitating development of effective prevention and treatment strategies (John et al., 2004).

Several studies based on frequency estimates of common BRCA1/2 mutations found a correlation between susceptibility to or development of cancer and presence of these mutations. Analysis of the genetic identity of populations prone to developing a series of diseases, such as Ashkenazi Jews, and identification of the epidemiologic factors involved in the personal and familial history of these individuals is, thus, of great value for genetic counseling and for developing new therapies seeking to provide more individualized treatment for better clinical response.



We would like to thank all women who took part in this study. This research was supported by the HCPA Institutional Research Fund (FIPE-HCPA). ICB received a CAPES grant. SLS is a CNPq research fellow.



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Send correspondence to:
Sandra Leistner-Segal
Laboratório de Genética Molecular, Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre
Rua Ramiro Barcelos 2350
90035-903 Porto Alegre RS, Brazil

Received: January 19, 2012
Accepted: June 1, 2012.



Associate Editor: Jeremy A. Squire
License information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
* The two first authors contributed equally to this work.

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