Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer

Abstract

In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) account for the majority of germline mutations in high-risk breast and/or ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG, Tyr978Ter, and a handful of "private" mutations have been reported anecdotally within both genes. In this study we attempted to determine the spectrum of BRCA1 and BRCA2 mutations in high-risk Jewish individuals, non-carriers of any of the predominant Jewish mutations. We employed multiplex PCR and denaturing gradient gel electrophoresis (DGGE) analysis for BRCA2, and combined denaturing high performance liquid chromatography (DHPLC) and protein truncation test (PTT) for BRCA1, complemented by DNA sequencing. We screened 47 high-risk Jewish individuals, 26 Ashkenazis, and 21 non-Ashkenazis. Overall, 13 sequence alterations in BRCA1 and eight in BRCA2 were detected: nine neutral polymorphisms and 12 missense mutations, including five novel ones. The novel missense mutations did not co-segregate with disease in BRCA1 and were detected at rates of 6.25% to 52.5% in the general population for BRCA2. Our findings suggest that except for the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, there are only a handful of pathogenic mutations within these genes. It may imply novel genes may underlie inherited susceptibility to breast/ovarian cancer in Jewish individuals.

Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel

“…Among non Ashkenazi Jews, there were six pathogenic mutations in BRCA1 (n = 3) and BRCA2 (n = 3) genes with two mutations detected in two families-overall a mutation detection rate of 8.9%. These data on the rate of BRCA1 and BRCA2 mutations in non Ashkenazim are in line with our own published data [29] as well as those of Palma and coworkers [11], but well below the report of Frank and co-workers of *21.6% among Jewish non carriers of the predominant mutations [32]. Thus, although full mutational analysis of BRCA1 BRCA2 in non Ashkenazi Jews is warranted, clearly other genes underlie the majority of inherited predisposition to breast/ovarian cancer in this subset of individuals.…”

Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel

“…Among non Ashkenazi Jews, there were six pathogenic mutations in BRCA1 (n = 3) and BRCA2 (n = 3) genes with two mutations detected in two families-overall a mutation detection rate of 8.9%. These data on the rate of BRCA1 and BRCA2 mutations in non Ashkenazim are in line with our own published data [29] as well as those of Palma and coworkers [11], but well below the report of Frank and co-workers of *21.6% among Jewish non carriers of the predominant mutations [32]. Thus, although full mutational analysis of BRCA1 BRCA2 in non Ashkenazi Jews is warranted, clearly other genes underlie the majority of inherited predisposition to breast/ovarian cancer in this subset of individuals.…”

Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families

“…It has been hypothesized that the reproductive isolation of the Ashkenazi population has resulted in an under-representation of mutations seen in other populations [32]. This is supported by the fact that the three founder mutations continue to account for the vast majority of mutations in this population (96% in our series) and the detection of non-founder mutations is relatively rare.…”

A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families

“…Other groups have reported no non-founder truncating BRCA1 mutations in series of Ashkenazi Jewish women, but several missense variants were observed [Shiri-Sverdlov et al, 2000;Kauff et al, 2002].…”

Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel

“…Among non Ashkenazi Jews, there were six pathogenic mutations in BRCA1 (n = 3) and BRCA2 (n = 3) genes with two mutations detected in two families-overall a mutation detection rate of 8.9%. These data on the rate of BRCA1 and BRCA2 mutations in non Ashkenazim are in line with our own published data [29] as well as those of Palma and coworkers [11], but well below the report of Frank and co-workers of *21.6% among Jewish non carriers of the predominant mutations [32]. Thus, although full mutational analysis of BRCA1 BRCA2 in non Ashkenazi Jews is warranted, clearly other genes underlie the majority of inherited predisposition to breast/ovarian cancer in this subset of individuals.…”

Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families

“…It has been hypothesized that the reproductive isolation of the Ashkenazi population has resulted in an under-representation of mutations seen in other populations [32]. This is supported by the fact that the three founder mutations continue to account for the vast majority of mutations in this population (96% in our series) and the detection of non-founder mutations is relatively rare.…”

A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families

“…Other groups have reported no non-founder truncating BRCA1 mutations in series of Ashkenazi Jewish women, but several missense variants were observed [Shiri-Sverdlov et al, 2000;Kauff et al, 2002].…”

Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel

“…Among non Ashkenazi Jews, there were six pathogenic mutations in BRCA1 (n = 3) and BRCA2 (n = 3) genes with two mutations detected in two families-overall a mutation detection rate of 8.9%. These data on the rate of BRCA1 and BRCA2 mutations in non Ashkenazim are in line with our own published data [29] as well as those of Palma and coworkers [11], but well below the report of Frank and co-workers of *21.6% among Jewish non carriers of the predominant mutations [32]. Thus, although full mutational analysis of BRCA1 BRCA2 in non Ashkenazi Jews is warranted, clearly other genes underlie the majority of inherited predisposition to breast/ovarian cancer in this subset of individuals.…”

Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families

“…It has been hypothesized that the reproductive isolation of the Ashkenazi population has resulted in an under-representation of mutations seen in other populations [32]. This is supported by the fact that the three founder mutations continue to account for the vast majority of mutations in this population (96% in our series) and the detection of non-founder mutations is relatively rare.…”

A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families

“…Other groups have reported no non-founder truncating BRCA1 mutations in series of Ashkenazi Jewish women, but several missense variants were observed [Shiri-Sverdlov et al, 2000;Kauff et al, 2002].…”