Analysis of BRCA1/BRCA2 genes’ contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women

Distelman-Menachem, Tal; Shapira, Tal; Laitman, Yael; Kaufman, Bella; Barak, Frida; Tavtigian, Sean V.; Friedman, Eitan

doi:10.1007/s10689-008-9216-6

Cited by 11 publications

(9 citation statements)

References 41 publications

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“…The existence of large genomic rearrangement was not excluded. However, at least among Ashkenazim, the contribution of such genomic events to the overall burden of inherited predisposition to breast cancer is limited [11,35]. Moreover, the representation of the non Jewish populations may have been suboptimal, as these represent families from three medical centers, which may under represent some sects in the non Jewish populations in Israel.…”

Section: Discussionmentioning

confidence: 99%

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

Laitman

Borsthein

Stoppa‐Lyonnet

et al. 2010

Breast Cancer Res Treat

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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.

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Section: Discussionmentioning

confidence: 99%

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

Laitman

Borsthein

Stoppa‐Lyonnet

et al. 2010

Breast Cancer Res Treat

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“…Our report is the first to assess for the presence of large deletions and rearrangements exclusively using the commercially available technology currently in use in the United States (Myriad Genetic Laboratories, Salt Lake City, UT), as opposed to the research technologies employed by the previous investigators. With the addition of this study, a total of 311 AJ probands from high-risk families have now been reported as testing negative for genomic rearrangements using currently available technological methods [17,24,25].…”

Section: Discussionmentioning

confidence: 99%

“…Several factors may contribute to this incongruity, including genetic drift, overestimation of mutation risk by existing models, mutations in as yet undiscovered cancer susceptibility genes, or the presence of structural alterations, such as large deletions or insertions within the BRCA genes not detected by PCR-based sequence analysis. In three studies reported to date, no major genomic rearrangements were identified among approximately 200 Ashkenazi breast or ovarian cancer patients [17,24,25] using cDNA analysis [24] or Multiplex Ligation-dependent Probe Amplification (MLPA) [17,24,25]. In one study, a significant number of genomic rearrangements were initially identified by MLPA; however, none were confirmed by quantitative polymerase chain reaction (PCR) [25].…”

Section: Introductionmentioning

confidence: 99%

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

Stadler

Saloustros

Hansen

et al. 2010

Breast Cancer Res Treat

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A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.

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“…The frame shift mutation 10323delCins11 occurring in exon 27 also should be regarded as belonging to changes of indefinite biological effect (according to BIC). The group of detected mutations is completed with nine intron changes in exons 8,11,12,14,15,17,22 and a G203A change in the non-encoding 5 0 UTR segment of exon 2.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, 5467insT, 6174delT and 6192delAT mutations exert a particular effect on double DNA strand repair function and strongly predispose to breast cancer development. The 6174delT mutation included in the BIC [13] database is the change occurring most frequently in the population of Ashkenazi Jews, both women and men with breast cancer Codick et al [14] and also Distelman-Menachem et al [15].…”

Section: Discussionmentioning

confidence: 99%

Novel germline mutations in BRCA2 gene among breast and breast-ovarian cancer families from Poland

et al. 2010

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Identification of mutations in the BRCA2 gene and estimation of their clinical consequences for women and men treated in the Maria Sklodowska-Curie Memorial Cancer Center Warsaw, Poland in the years 1998-2008. The probands (97 women and 8 men) had a family history of breast and ovarian cancer (median age 46). The presence of molecular changes was examined in DNA isolated from peripheral blood lymphocytes. Germline mutations in 27 exons of the BRCA2 gene were screened by 'touchdown' PCR amplification, DHPLC and sequencing. Missense mutations were classified by multiple-sequences alignments of orthologous BRCA2 protein sequences with T-Coffee software. 39 molecular changes (8 novel) were identified in the BRCA2 gene in 105 investigated patients. In 12 patients the following pathogenic mutations were identified: 5467insT, 6174delT, 6192delAT, 6675delTA, 8141del5, 9152delT, 9326insA, 9631delC, IVS23-2A > G and E394X. The presence of 10 missense type mutations was detected including the following: D1420O, T1915 M, N3124I. The determination of pathogenic status of molecular variants detected in BRCA2 gene, described in the BIC mutation database as 'UV' depends on many parameters. Important is the assessment of the evolutionary conservation of their protein sequences and studying of the frequency of molecular variants detected in breast cancer patients and in population. A high diversity was found of the pathogenic mutations detected in BRCA2 gene in the Polish population.

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Analysis of BRCA1/BRCA2 genes’ contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women

Abstract: Major gene rearrangements involving BRCA1 BRCA2 contribute little to the burden of inherited predisposition of breast cancer in Ashkenazi Jews.

Cited by 11 publications

References 41 publications

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

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

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

Novel germline mutations in BRCA2 gene among breast and breast-ovarian cancer families from Poland

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