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

Shiri-Sverdlov, Ronit; Oefner, Peter J.; Green, Limor; Baruch, Ruth Gershoni; Wagner, Teresa; Kruglikova, Anna; Haitchick, Samario; Hofstra, Robert M.W.; Papa, Moshe Z.; Mulder, Inge A.; Rizel, Shulamit; Sade, Revital Bruchim Bar; Dagan, Efrat; Abdeen, Ziad; Goldman, Boleslaw; Friedman, Eitan

doi:10.1002/1098-1004(200012)16:6<491::aid-humu6>3.3.co;2-a

Cited by 27 publications

(37 citation statements)

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“…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].…”

Section: Discussionmentioning

confidence: 87%

“…Founder mutations in the BRCA1 (MIM# 113705) gene (185delAG and 5382insC) are considered to be responsible for approximately 30% of Ashkenazi Jewish breast-ovarian cancer families, depending on the number of breast and ovarian cancers [Tonin et al, 1996;Shiri-Sverdlov et al, 2000]. However, a large fraction of families do not carry any of these mutations.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2002

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Communicated by Jacques S. BeckmannThe 185delAG and 5382insC founder mutations account for the majority of mutations identified in BRCA1 in Ashkenazi Jewish breast and breast-ovarian cancer families. Few non-founder BRCA1 mutations have been identified to date in these families. We initially screened a panel of 245 Ashkenazi Jewish breast-ovarian cancer families with an affected proband and at least one other case of breast or ovarian cancer for founder mutations in BRCA1 and BRCA2. Founder mutations were identified in 85 families (185delAG in 44 families, 5382insC in 16 families, and the BRCA2 6174delT in 25 families). The 160 negative families were then screened for the entire BRCA1 gene by a combination of DGGE and PTT. We identified one novel frameshift mutation in BRCA1 in exon 14 (4572del22) that truncated the protein at codon 1485. The family contained three cases of early-onset ovarian cancer (41 years, 43 years, and 52 years) and one case of breast cancer (at age 54 years subsequent to an ovarian cancer). In addition, three missense variants of unknown significance (exon 11 C3832T (P1238L), exon 15 G4654T (S1512I), and exon 15 G4755A (D1546N)) were found in single families.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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

et al. 2002

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“…Analysis for the BRCA1 185delAG mutation was carried out using a PCR-directed mutagenesis assay to introduce a restriction site that distinguishes between the wild-type and the mutant allele, as previously described and used by us. 6,26 Confirmation of any suspect sample was done using sequencing of the same amplicon.…”

Section: Analysis For the 185delag Brca1 Mutationmentioning

confidence: 99%

Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations

et al. 2012

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The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora B2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of B5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) B650 years ago, and into the Iraqi-Jewish community B450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.

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“…In the Ashkenazim, founder mutations in BLM, BRCA1, BRCA2, FANCC, MSH2 and APC that are associated with susceptibility to cancer have been described 4,6,[20][21][22] . Together with the APC allele encoding I1307K (10% carrier frequency in Ashkenazim with CRC) and BLM Ash (1.3% carrier frequency), which are associated with susceptibility to CRC without MSI, and the MSH2 allele encoding A636P (0.6% carrier frequency), which is associated with susceptibility to CRC with MSI, the identification of MLH1 415G→C (1.3% carrier frequency) should help identify Ashkenazim at greater risk for CRC.…”

Section: Wt/ai Ratiomentioning

confidence: 99%

The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer

et al. 2004

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Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. We looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability (MSI) phenotype. Association studies identified a new MLH1 variant (415G→C, resulting in the amino acid substitution D132H) in ∼1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually do not have the MSI defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G→C mutation. The new MLH1 variant confers a high risk of CRC and identifies a previously unrecognized mechanism in microsatellite-stable tumors. These studies suggest that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than previously assumed.To identify variant alleles in MLH1, MSH2 or MSH6 with high sensitivity and specificity, we designed a new high-density oligonucleotide array (HNPCC Chip) that uses improved bioinformatic

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

Cited by 27 publications

References 0 publications

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

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

Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations

The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer

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