Breast cancer risk perception among women who have undergone prophylactic bilateral mastectomy.
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BACKGROUND: Prophylactic bilateral mastectomy is a preventive option for women who are at high risk of developing breast cancer. We compared the perceptions of breast cancer risk among women who had previously undergone prophylactic bilateral mastectomy with objective estimates of their breast cancer risk. METHODS: We asked 75 women in the Canadian province of Ontario who had undergone prophylactic bilateral mastectomy between 1991 and 2000 to provide a complete family history of the cancers that had occurred by the time of their surgery and to indicate their BRCA1 and BRCA2 gene mutation status. This information was used to generate estimates of each woman's risk for breast cancer by using the Gail model, the Claus model, and the BRCAPRO model. Sixty of the women also provided their own estimates of their lifetime risks of developing breast cancer before and after they had prophylactic mastectomy. Risk estimates were compared using Wilcoxon's signed-rank test and Pearson's product-moment correlation analysis. All statistical tests were two-sided. RESULTS: The women estimated that their lifetime risk of developing breast cancer before surgery was, on average, 76% (range = 20%-100%) and after surgery was 11.4% (range = 0%-60%). The mean estimated absolute risk reduction the women attributed to prophylactic mastectomy was 64.8%. The average computer-generated risk estimates were 59% for the 14 women who reported that they carried a BRCA1 or BRCA2 gene mutation and 17% for the other women (of whom 43 had a strong family history of breast cancer and 18 had a limited family history). Breast cancer risk was statistically significantly overestimated by all women except for the known BRCA1 and BRCA2 gene mutation carriers. CONCLUSION: Women who undergo prophylactic bilateral mastectomy have an exaggerated perception of their breast cancer risk before surgery. Formal genetic counseling and genetic testing may result in more accurate risk perceptions to guide women in choosing other preventive options. (+info)
Insulin-like growth factor I polymorphism and breast cancer risk in Jewish women.
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BACKGROUND: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients. OBJECTIVE: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls. METHODS: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212 sporadic and 56 carriers of either a BRCA1 or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent autoradiography. RESULTS: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only (3/536, 0.6%). CONCLUSIONS: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed. (+info)
Androgen receptor CAG repeat length in Jewish Israeli women who are BRCA1/2 mutation carriers: association with breast/ovarian cancer phenotype.
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BRCA1/2 mutation carriers are at an increased risk for developing breast and/or ovarian cancer. Yet, the genetic and environmental factors that govern the phenotypic expression of mutant BRCA1/2 alleles remain elusive. The CAG repeat within exon 1 of the androgen receptor (AR) gene is reportedly associated with breast cancer phenotype in BRCA1 mutation carriers. Two hundred and twenty seven BRCA1/2 mutation carriers were genotyped for the polymorphic AR CAG repeat, and allele size was correlated with breast/ovarian cancer morbidity parameters. Of 227 BRCA1/2 carriers, 169 were BRCA1 mutation carriers and 58 carried a BRCA2 mutation, 149 had breast and/or ovarian cancer and 78 were asymptomatic mutation carriers. The mean age at diagnosis in women with either or both neoplasms was 46.7+/-11.2 years, and that of the asymptomatic group - 45.8+/-9.4 years, a statistically insignificant difference. The AR CAG repeat ranged from eight to 28 in all tested women, and the mean number of the repeats were not statistically different between affected (18.3+/-2.4) and asymptomatic mutation carriers (18.6+/-2.1). The AR CAG repeat among patients with early onset (<42 years) breast cancer was significantly shorter (17.5+/-2.3) compared with asymptomatic individuals (18.6+/-2.1) (P<0.01), and the shorter allele - the younger the age at diagnosis. There is no conclusive evidence of association between AR CAG repeat size and breast or ovarian cancer risk in Jewish BRCA1/2 mutation carriers. A small effect of a short AR CAG allele size on breast cancer at early age (<42 years) cannot be excluded. (+info)
BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis.
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In a screen for DNA repair-defective mutants in the fungus Ustilago maydis, a gene encoding a BRCA2 family member, designated here as Brh2, was identified. A brh2 null allele was found to be defective in allelic recombination, meiosis, and repair of gaps and ionizing radiation damage to the same extent as rad51. Frequent marker loss in meiosis and diploid formation suggested that genomic instability was associated with brh2. This notion was confirmed by molecular karyotype analysis, which revealed gross chromosomal alterations associated with brh2. Yeast two-hybrid analysis indicated interaction between Brh2 and Rad51. Recapitulation in U. maydis of defects in DNA repair and genome stability associated with brh2 means that the BRCA2 gene family is more widespread than previously thought. (+info)
Loss of Brca2 and p53 synergistically promotes genomic instability and deregulation of T-cell apoptosis.
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BRCA2 is a breast cancer susceptibility gene of which the product is thought to be involved in monitoring genome integrity and cell cycle progression. Brca2-null mice have a defect in embryonic cellular proliferation and die in utero. Here we report the generation of T-cell lineage-specific Brca2-deficient (tBrca2(-/-)) mice using the Cre-loxP system. Mice with a flanked by loxP allele of Brca2 were crossed to transgenic mice bearing Cre recombinase driven by the T cell-specific promoter Lck. Thymic cellularity and distribution of subset populations were normal in tBrca2(-/-) mutants. Thymocytes from tBrca2(-/-) mice underwent normal apoptosis in response to a variety of stimuli, and activated tBrca2(-/-) T cells had normal proliferative capacity. tBrca2(-/-) T cells were more likely than wild-type cells to undergo spontaneous apoptosis, but apoptosed normally in response to restimulation or DNA-damaging stress signals. Examination of metaphase spreads of tBrca2(-/-) T cells revealed that the chromosomes often exhibited aberrations such as breaks and tri-radial structures. The level of chromosomal abnormalities was enhanced in T cells from tBrca2(-/-); p53(-/-) double-mutant mice. However, tBrca2(-/-); p53(-/-) T cells did not show the enhanced level of spontaneous apoptosis demonstrated by tBrca2(-/-) T cells, a difference that likely accounts for an increase in cell number and (3)[H]thymidine incorporation of double-mutant T cells in culture compared with either single mutant. Despite this increased T-cell number, the onset of T-cell lymphomas was only marginally accelerated in tBrca2(-/-); p53(-/-) mice compared with p53(-/-) mice. Our results support a role for Brca2 in repairing spontaneous DNA lesions, and suggest that loss of Brca2 enhances the susceptibility of mouse T-lineage cells to chromosomal aberrations and deregulation of apoptosis in the absence of p53. (+info)
BRCA1/2 genetic testing in the community setting.
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PURPOSE: BRCA1/2 genetic testing has been commercially available in the United States since 1996. Most published reports described BRCA1/2 testing as research studies at large academic centers, but less is known about testing in the community. This study evaluates the process and early outcomes of BRCA1/2 genetic testing as a clinical service in the community setting. METHODS: Surveys were mailed to women in the United States whose health care providers ordered BRCA1/2 genetic testing from Myriad Genetic Laboratories from August 1998 through July 2000. Women tested at 149 large academic centers were excluded. Main outcome measures were demographic characteristics, recall of and satisfaction with the genetic testing process, and likelihood of pursuing cancer prevention strategies. RESULTS: Among the 646 respondents, 414 (64%) had a personal history of cancer and 505 (78%) had at least one first-degree relative with breast and/or ovarian cancer. Most subjects (82%) recalled discussions of informed consent before testing (median time, 30 minutes). Genetic results were conveyed during an office visit (57%), by telephone (39%), or by mail (3%). More than 75% of respondents were "very satisfied with the counseling received." Cancer-free subjects with a germline mutation were more likely to consider prevention strategies after receiving the genetic results. CONCLUSION: Virtually all respondents had a personal and/or family history of breast/ovarian cancer. Although pretest and posttest communications were not standardized, overall satisfaction with clinical breast cancer genetic testing was high. Additional follow-up will provide data on future cancer prevention practices and cancer incidence. (+info)
The Fanconi anaemia genome stability and tumour suppressor network.
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Fanconi anaemia (FA) is a rare autosomal recessive disease characterized by increased spontaneous and DNA crosslinker-induced chromosome instability, progressive pancytopenia and cancer susceptibility. An increasing number of genes are involved in FA, including the breast cancer susceptibility gene BRCA2. Five of the FA proteins (FANCA, FANCC, FANCE, FANCF and FANCG) assemble in a complex that is required for FANCD2 activation in response to DNA crosslinks. Active FANCD2 then interacts with BRCA1 and forms discrete nuclear foci. FANCD2 is independently phosphorylated by ATM (the protein whose gene is mutated in ataxia telangiectasia) in response to ionizing radiation. In addition, the FA proteins are interconnected with other nuclear and cytoplasmic factors all related to cellular responses to carcinogenic stress and to caretaker and gatekeeper functions. In this review, the most recently published data on the molecular biology of the FA pathway and its molecular crosstalk with ATM, BRCA1 and BRCA2, proteins involved in xenobiotic and reactive oxygen species metabolism, apoptosis, cell cycle control and telomere stability, are summarized. The currently available data indicate that FA is a central node in a complex nuclear and cytoplasmic network of tumour suppressor and genome stability pathways fully committed to prevent cancer. (+info)
BRCA1 and BRCA2 germline mutations in Sardinian breast cancer families and their implications for genetic counseling.
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BACKGROUND: The Sardinian population is genetically homogeneous and could be useful in understanding better the genetics of a complex disease like breast cancer (BC). PATIENTS AND METHODS: Using a screening assay based on a combination of single-strand conformation polymorphism, denaturing high-performance liquid chromatography and sequence analysis, 47 Sardinian families with three or more BC cases were screened for germline mutations in BRCA1 and BRCA2 genes. RESULTS: Three BRCA1/2 germline sequence variants were identified. While BRCA2-Ile3412Val is a missense variant with unknown functional significance, BRCA2-8765delAG and BRCA1-Lys505ter are two deleterious mutations (due to their predicted effects on protein truncation), which were found in seven families (15%). BRCA2-8765delAG was found in six of eight (75%) BRCA1/2-positive families and seven of 501 (1.4%) unselected and consecutively collected BC patients. Prevalence of BRCA1/2 mutations in BC families was significantly correlated with the total number of female BCs (P <0.01) and increased by the presence of (i) at least one case of ovarian or male BC, or (ii) three generations affected, or (iii) bilateral BC. CONCLUSIONS: Identification of such features should address BC patients and their families to genetic counseling and BRCA1/2 mutational analysis. In addition, this is the first report of a detailed BRCA1/2 mutation screening in Sardinia, having immediate implications for the clinical management of BC families. (+info)