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

Abstract

Three mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) predominate among high risk breast ovarian cancer Ashkenazi Jewish families, with few "private" mutations described. Additionally, the spectrum of BRCA1 and BRCA2 germline mutations among high risk Jewish non Ashkenazi and non Jewish Israelis is undetermined. Genotyping by exon-specific sequencing or heteroduplex analysis using enhanced mismatch mutation analysis was applied to 250 high risk, predominantly cancer affected, unrelated Israeli women of Ashkenazi (n = 72), non Ashkenazi (n = 90), Moslem (n = 45), Christian Arabs (n = 21), Druze (n = 17), and non Jewish Caucasians (n = 5). All Jewish women were prescreened and did not harbor any of the predominant BRCA1 or BRCA2 Jewish mutations. Age at diagnosis of breast cancer (median ± SD) (n = 219) was 40.1 ± 11.7, 45.6 ± 10.7, 38.7 ± 9.2, 45.5 ± 11.4 ± and 40.7 ± 8.1 years for Ashkenazi, non Ashkenazi, Moslem, Christian, and Druze participants, respectively. For ovarian cancer (n = 19) the mean ages were 45.75 ± 8.2, 57.9 ± 10.1, 54 ± 8, 70 ± 0, and 72 ± 0 for these origins, respectively. Overall, 22 (8.8%) participants carried 19 clearly pathogenic mutations-10 BRCA1 and 9 BRCA2 (3 novel): 3 in Ashkenazim, 6 in 8 non-Ashkenazim, 6 in 7 Moslems, 2 in Druze, and 2 in non Jewish Caucasians. Only three mutations (c.1991del4, C61G, A1708E) were detected in 2 seemingly unrelated families of Moslem and non- Ashkenazi origins. There were no inactivating mutations among 55 Ashkenazi high risk breast cancer only families. In conclusion, there are no predominant recurring germline mutations in BRCA1 or BRCA2 genes among ethnically diverse Jewish and non Jewish high risk families in Israel.

BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina

“…As the family D was self-reported as half-non AJ, the resulting prevalence for BRCA1/2 non AJ mutation excluding this family results to be 5 out of 76 cases (6.6%). This rate is line with previous studies, although there are only a few that have reported such a focused analysis ( 10 – 13 ). In those previous studies the rates were 4-5% of fully genotyped AJ cases.…”

BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina

“…As the family D was self-reported as half-non AJ, the resulting prevalence for BRCA1/2 non AJ mutation excluding this family results to be 5 out of 76 cases (6.6%). This rate is line with previous studies, although there are only a few that have reported such a focused analysis ( 10 – 13 ). In those previous studies the rates were 4-5% of fully genotyped AJ cases.…”

Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel

“…For the mostly Ashkenazi Jewish high risk families, none of the 500 individuals from seemingly independent families was found to harbor the 4075delAG*BRCA2 mutation. These data are consistent with data reported by us [12] and by the Memorial Sloan Kettering Cancer Center in New York [7], where the rate of any ''private mutation'' in both BRCA1 and BRCA2 in Jewish Ashkenazi high risk families is 4-5% if there are ovarian cancer cases, and less than 2% in families with site specific breast cancer. Thus, it seems that specific genotyping for the 4075delAG*BRCA2 mutation is of no added value as a routine test for Ashkenazi Jewish high risk families.…”

“…In Jewish high risk families of North African origin, there is a paucity of mutations in high risk families: our own data [12] show that none of 27 high risk North African women carried either a BRCA1 or a BRCA2 mutations when full analysis of both genes is applied. Noteworthy, in the present study, 7/264 individuals of North African ancestry carried the same mutation-a rate of 2.65%.…”

Breast cancer risk prediction accuracy in Jewish Israeli high-risk women using the BOADICEA and IBIS risk models

“…The fact that BRCA mutations tested were predominantly detected in Ashkenazi (and to a lesser extent Iraqi) high-risk families is also a limitation. Yet the rate of 'private' family-specific mutations in the Ashkenazi and non-Ashkenazi high-risk women is 4•7 and 8•8%, respectively (Laitman et al, 2011). Thus, the majority of women tested are indeed non-BRCA mutation carriers.…”

BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina

“…As the family D was self-reported as half-non AJ, the resulting prevalence for BRCA1/2 non AJ mutation excluding this family results to be 5 out of 76 cases (6.6%). This rate is line with previous studies, although there are only a few that have reported such a focused analysis ( 10 – 13 ). In those previous studies the rates were 4-5% of fully genotyped AJ cases.…”

Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel

“…For the mostly Ashkenazi Jewish high risk families, none of the 500 individuals from seemingly independent families was found to harbor the 4075delAG*BRCA2 mutation. These data are consistent with data reported by us [12] and by the Memorial Sloan Kettering Cancer Center in New York [7], where the rate of any ''private mutation'' in both BRCA1 and BRCA2 in Jewish Ashkenazi high risk families is 4-5% if there are ovarian cancer cases, and less than 2% in families with site specific breast cancer. Thus, it seems that specific genotyping for the 4075delAG*BRCA2 mutation is of no added value as a routine test for Ashkenazi Jewish high risk families.…”

“…In Jewish high risk families of North African origin, there is a paucity of mutations in high risk families: our own data [12] show that none of 27 high risk North African women carried either a BRCA1 or a BRCA2 mutations when full analysis of both genes is applied. Noteworthy, in the present study, 7/264 individuals of North African ancestry carried the same mutation-a rate of 2.65%.…”

Breast cancer risk prediction accuracy in Jewish Israeli high-risk women using the BOADICEA and IBIS risk models

“…The fact that BRCA mutations tested were predominantly detected in Ashkenazi (and to a lesser extent Iraqi) high-risk families is also a limitation. Yet the rate of 'private' family-specific mutations in the Ashkenazi and non-Ashkenazi high-risk women is 4•7 and 8•8%, respectively (Laitman et al, 2011). Thus, the majority of women tested are indeed non-BRCA mutation carriers.…”

BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina

“…As the family D was self-reported as half-non AJ, the resulting prevalence for BRCA1/2 non AJ mutation excluding this family results to be 5 out of 76 cases (6.6%). This rate is line with previous studies, although there are only a few that have reported such a focused analysis ( 10 – 13 ). In those previous studies the rates were 4-5% of fully genotyped AJ cases.…”

Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel

“…For the mostly Ashkenazi Jewish high risk families, none of the 500 individuals from seemingly independent families was found to harbor the 4075delAG*BRCA2 mutation. These data are consistent with data reported by us [12] and by the Memorial Sloan Kettering Cancer Center in New York [7], where the rate of any ''private mutation'' in both BRCA1 and BRCA2 in Jewish Ashkenazi high risk families is 4-5% if there are ovarian cancer cases, and less than 2% in families with site specific breast cancer. Thus, it seems that specific genotyping for the 4075delAG*BRCA2 mutation is of no added value as a routine test for Ashkenazi Jewish high risk families.…”

“…In Jewish high risk families of North African origin, there is a paucity of mutations in high risk families: our own data [12] show that none of 27 high risk North African women carried either a BRCA1 or a BRCA2 mutations when full analysis of both genes is applied. Noteworthy, in the present study, 7/264 individuals of North African ancestry carried the same mutation-a rate of 2.65%.…”

Breast cancer risk prediction accuracy in Jewish Israeli high-risk women using the BOADICEA and IBIS risk models

“…The fact that BRCA mutations tested were predominantly detected in Ashkenazi (and to a lesser extent Iraqi) high-risk families is also a limitation. Yet the rate of 'private' family-specific mutations in the Ashkenazi and non-Ashkenazi high-risk women is 4•7 and 8•8%, respectively (Laitman et al, 2011). Thus, the majority of women tested are indeed non-BRCA mutation carriers.…”