The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals

Struewing, Jeffery P.; Abeliovich, Dvorah; Peretz, Tamar; Avishai, Naaman; Kaback, Michael M.; Collins, Francis S.; Brody, Lawrence C.

doi:10.1038/ng1095-198

Cited by 599 publications

(318 citation statements)

References 22 publications

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“…A common ancestor is likely to explain recurrent mutations in a defined geographical region, although this has not yet been confirmed with haplotype analysis for our population. This has clearly been shown in a number of defined ethnic and geographical populations (Struewing et al, 1995;Johannsson et al, 1996;Peelan et al, 1997;Richards et al, 1997;Thorlacius et al, 1997). Redesigning primers for SSCP/HD analysis of the regionally detected mutations allows a cheap initial mutation detection strategy and is likely to be the most appropriate approach in a regionally based diagnostic genetics laboratory.…”

Section: Discussionmentioning

confidence: 79%

BRCA1 mutations in southern England

Eccles

Englefield²,

Soulby³

et al. 1998

Br J Cancer

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Summary If genetic testing for breast and ovarian cancer predisposition is to become available within a public health care system there needs to be a rational and cost-effective approach to mutation analysis. We have screened for BRCA 1 mutations in 230 women with breast cancer, all from the Wessex region of southern England, in order to establish the parameters on which to base a cost-effective regional mutation analysis strategy. Truncating mutations were detected in 10/155 (6.5%) consecutive cases selected only for diagnosis under the age of 40 (nine of these ten women had a strong family history of breast or ovarian cancer), 3/61 (4.9%) bilateral-breast cancer cases (all three mutations occurring among women for whom the first cancer was diagnosed under 40 years) and 8/30 (26.6%) breast cancer cases presenting to the genetics clinic (for whom a strong family history of breast and/or ovarian cancer was present). Ten different mutations were detected in 17 families, but three of these accounted for 10/17 (59%) of the families. The cost of screening the population for mutations in the entire BRCA 1 gene is unacceptably high. However, the cost of screening a carefully selected patient cohort is low, the risk of misinterpretation much less and the potential clinical benefits clearer.Keywords: BRCA 1; breast cancer; ovarian cancer; mutation analysisWith the cloning of BRCAI in 1994 (Miki et al, 1994) and BRCA2 in 1995(Wooster et al, 1995 it is now possible to screen breast or ovarian cancer patients for the presence of germline mutations. Together these genes account for about 75% of families with a highly penetrant dominantly inherited breast and/or ovarian cancer family history. There is at least one other highly penetrant breast cancer predisposition gene to be discovered (Rebbeck et al, 1997;Schubert et al, 1997;Serova et al, 1997) and undoubtedly many others of lower penetrance. Mutations in BRCAJ and BRCA2 are scattered throughout these very large genes and current methods of mutation analysis are far from perfect. Most of the available techniques detect only about 70-80% of causative mutations. A negative result from a mutation screen, in most circumstances, means very little in terms of altering the breast cancer risk to other relatives (Eeles, 1996; Healy, 1997). In families with a striking occurrence of apparently dominantly inherited breast cancer, however, the finding of a mutation can greatly refine the prediction of cancer risk and help to inform clinician and patient alike when making decisions about, for example, preventive surgery or cancer treatment.Mutation analysis is already available in a few genetics centres in the UK as part of a comprehensive molecular genetics service. As referrals for advice about inherited cancer risks escalate so do expectations for genetic testing to be provided. A rational approach to such testing is needed. We have reviewed three clinically selected groups for whom testing might be indicated and performed a comprehensive screen for mutations in BRCA 1. Using these ...

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Section: Discussionmentioning

confidence: 79%

BRCA1 mutations in southern England

Eccles

Englefield²,

Soulby³

et al. 1998

Br J Cancer

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“…These estimates were based on studies of breast and ovarian cancer families and thus may select for women who have other mutations that further pre-dispose to cancer. Population-based studies revealed that specific germ-line mutations of BRCA1 (185delAG and 5382insC) or BRCA2 (6174delT) occurred relatively frequently in Ashkenazi Jews (up to 1% each); and their combined frequency exceeded 2% (Streuwing et al, 1995(Streuwing et al, , 1997Roa et al, 1996). This contrasts with an estimated BRCA1 mutation frequency in the general population of about 0.06% .…”

Section: Population-based Studiesmentioning

confidence: 91%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

238

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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“…Inherited mutations in the human BRCA1 gene predispose individuals to early onset breast and ovarian cancer Futreal et al, 1994;Castilla et al, 1994;Friedman et al, 1994;Struewing et al, 1995;Shattuck Eidens et al, 1995;Merajver et al, 1995b). Elaboration of the disease in these individuals is frequently associated with loss of the wild type allele Cornelis et al, 1995;Merajver et al, 1995a) thus, genetically BRCA1 behaves like a tumor suppressor gene.…”

Section: Introductionmentioning

confidence: 99%

Differential subcellular localization, expression and biological toxicity of BRCA1 and the splice variant BRCA1-Δ11b

et al. 1997

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The mechanism of BRCA1 tumor suppression in human breast and ovarian cells is the focus of intense investigation. In this report, full length BRCA1 (230 kDa) introduced into cells with CMV promoter constructs was nuclear when transgene expression was low whereas high expression resulted in cytoplasmic accumulation, aberrant nuclear and cell morphology. A nuclear localization signal (NLS) was mapped to BRCA1 amino acid positions 262 ± 570. We describe a splice variant, BRCA1-D11b, missing the majority of exon 11 including the NLS. Exogenous BRCA1-D11b (110 kDa) was cytoplasmic and, unlike the full-length protein, overexpression of the protein encoded by the variant did not appear to be toxic. RNA probe titrations and RT ± PCR demonstrated that BRCA1 and D11b transcripts are coexpressed in a wide variety of cells and tissues. Interestingly, BRCA1-D11b message was greatly reduced or absent in several breast and ovarian tumor lines relative to exon 11 transcripts and a D9,10 splice variant. Taken together our results suggest that fulllength BRCA1 and BRCA1-D11b may have distinct roles in cell growth regulation and tumorigenesis.

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The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals

Cited by 599 publications

References 22 publications

BRCA1 mutations in southern England

BRCA1 mutations in southern England

BRCA1 gene in breast cancer

Differential subcellular localization, expression and biological toxicity of BRCA1 and the splice variant BRCA1-Δ11b

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