Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families

Xu, Chun‐Fang; Chambers, Julie A.; Nicolai, Hans; Brown, Melissa A.; Hujeirat, Yasir; Mohammed, Shehla; Hodgson, Shirley; Kelsell, David P.; Spurr, Nigel K.; Bishop, D. Timothy; Solomon, Ellen

doi:10.1002/(sici)1098-2264(199702)18:2<102::aid-gcc4>3.3.co;2-a

Cited by 30 publications

(35 citation statements)

References 19 publications

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“…They did not identify themselves as Jewish. This is the most common founder mutation in the Ashkenazi Jewish population, but has also been reported on occasion in other ethnic groups [9,11,12,29,31] including individuals from the United Kingdom that do not share the same Ashkenazi Jewish haplotype [32].…”

Section: Discussionmentioning

confidence: 55%

A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas

Donenberg

Lunn

Curling³

et al. 2010

Breast Cancer Res Treat

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The Bahamas is a group of islands in the Caribbean with a high incidence of early onset breast cancer. In isolated populations, the identification of founder mutations in cancer predisposing genes may facilitate genetic testing and counseling. To date, six distinct BRCA1 mutations have been found in patients from cancer families from the Bahamas. The frequencies of these mutant alleles have not been measured in a large series of unselected breast cancer patients from Bahamas. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history of cancer. All patients were screened for six mutations in the BRCA1 gene that have previously been reported in cancer patients from the Bahamas. A mutation was identified in 49 of the 214 breast cancer patients (23%). The mutation frequency was particularly high in women diagnosed before age 50 (33%) in women with a first-degree relative with breast or ovarian cancer (41%) and in women with bilateral breast cancer (58%). Approximately 23% of unselected cases of breast cancer in the Bahamian population are attributable to a founder mutation in the BRCA1 gene-this is the highest reported mutation prevalence for any country studied to date. Genetic testing for these mutations is advisable for all women diagnosed with breast cancer in the Bahamas.

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Section: Discussionmentioning

confidence: 55%

A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas

Donenberg

Lunn

Curling³

et al. 2010

Breast Cancer Res Treat

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“…p53-PIK3CA interactions alternate mRNA transcripts. Similarly to PIK3CA (this study), BRCA1 has two alternate first exons, and two alternate promoters upstream that produce these alternate transcripts (Xu et al, 1997). For BRCA1, the longer mRNA transcript that also has a higher GC content forms a stable secondary structure, which inhibits efficient translation resulting in lower levels of the protein (Sobczak and Krzyzosiak, 2002).…”

Section: Discussionmentioning

confidence: 82%

Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer

Astanehe¹,

Arenillas²,

Wasserman³

et al. 2008

Journal of Cell Science

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Inactivation of the transcription factor and tumor suppressor p53, and overexpression or mutational activation of PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), are two of the most common deleterious genomic changes in cancer, including in ovarian carcinomas. We investigated molecular mechanisms underlying interactions between these two mediators and their possible roles in ovarian tumorigenesis. We identified two alternate PIK3CA promoters and showed direct binding of and transcriptional inhibition by p53 to one of these promoters. Conditional suppression of functional p53 increased p110α transcripts, protein levels and PI3K activity in immortalized, non-tumorigenic ovarian surface epithelial (OSE) cells, the precursors of ovarian carcinoma. Conversely, overexpression of p53 by adenoviral infection and activation of p53 by γ-irradiation both diminished p110α protein levels in normal OSE and ovarian cancer cells. The demonstration that p53 binds directly to the PIK3CA promoter and inhibits its activity identifies a novel mechanism whereby these two mediators regulate cellular functions, and whereby inactivation of p53 and subsequent upregulation of PIK3CA might contribute to the pathophysiology of ovarian cancer.

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“…The 185delAG mutation has been found in families of Ashkenazi and non-Ashkenazi origin almost always associated with a common haplotype for four microsatellite markers, although in some families of non-Jewish origin it is linked to a different haplotype (Berman et al, 1996b;Xu et al, 1997). This strong association suggests a Ôfounder effectÕ for this mutation.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of BRCA1 and BRCA2 Jewish mutations in Spanish breast cancer patients

et al. 1999

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The most commonly detected mutations in BRCA1 are 185delAG in exon 2, and 5382insC in exon 20, which have a frequency in the Ashkenazi Jewish population of 0.9% and 0.1%, respectively (Struewing et al, 1995;Roa et al, 1996). The 185delAG mutation has been frequently identified in women with breast cancer who are of Jewish ancestry (Bar-sade et al, 1998), almost always sharing the same haplotype described in Ashkenazim, and in different populations, including the Spanish population (Osorio et al, 1998). The 6174delT BRCA2 mutation, in exon 11, occurs very frequently (1.5%) among Ashkenazi Jews, but also appears in nonJewish individuals (Berman et al, 1996a).Nowadays, about 80% of Jews are of Ashkenazim origin. They originated in present day Israel, and migrated to Eastern Europe. From the 3rd century until the end of the 15th century, Spain was one of the main areas of settlement for Sephardic Jews (Keller, 1969). After this period, they were expelled and migrated, but some of them remained in the Peninsula after forced conversion to Christianity. We evaluated the prevalence of 185delAG, 5382insC and 6174delT mutations in Spanish breast cancer patients, bearing in mind the possible presence of Sephardic Jewish ancestors among this population. PATIENTS AND METHODSWe studied the 185delAG and 5382insC mutations in the BRCA1 gene in 108 families of women with breast/ovarian cancer, and 190 women regarded as sporadic cases of breast cancer, 90% of them diagnosed between the ages of 16 and 40 years. The BRCA2 6174delT mutation was analysed in 77 of these families, and in 171 women with sporadic breast cancer.Families were selected if they met the following criteria: three or more close relatives with breast and/or ovarian cancer (highrisk families), two affected relatives (moderate-risk), and one or two second-degree affected relatives or late age of onset (lowrisk). All patients gave informed consent for testing before providing blood samples to obtain genomic DNA.Mutation detection was accomplished by polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and direct sequencing. RESULTSOnly two patients with a moderate-and high-risk family history of breast cancer showed the 185delAG BRCA1 mutation. No other variations were detected. One patient had early-onset breast and ovarian cancer (diagnosed at 34 years) and the other had breast and ovarian cancer (at 51 and 55 years, respectively). In both cases the probandÕs mother was affected with breast cancer.Four microsatellite markers (D17S855, D17S1322, D17S1323 and D17S327) were analysed to obtain the haplotype of the members from the two families with the mutation. In both families, the carriers of the mutation showed the same haplotype as reported in Ashkenazim with the 185delAG mutation (Tonin et al, 1995;Neuhausen et al, 1996). In one family, the Sephardic Jewish origin could be confirmed by the known ancestors. We extended this study to 20 control chromosomes and this haplotype was absent in all of them (Table 1). DISCUSSIONGiven the prese...

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Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families

Cited by 30 publications

References 19 publications

A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas

A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas

Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer

Prevalence of BRCA1 and BRCA2 Jewish mutations in Spanish breast cancer patients

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