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BRCA2 Mutations (brca2 + mutation)
Terms modified by BRCA2 Mutations Selected AbstractsRELEVANT RISK FOR WOMEN WITH BRCA1 AND BRCA2 MUTATIONSANZ JOURNAL OF SURGERY, Issue 5 2007Colin Furnival PhD, FRACS No abstract is available for this article. [source] BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer,,HUMAN MUTATION, Issue 4 2004Jae Hong Seo Abstract In order to evaluate the role of BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer, 97 patients with sporadic breast cancer were analyzed for mutations in the BRCA1 and BRCA2 coding regions, by using a combination of fluorescent-conformation sensitive gel electrophoresis (F-CSGE) and direct sequencing. Fifty-five distinct sequence variants were detected, which included three pathogenic truncating mutations, 15 missense mutations, 16 polymorphisms, and 21 intronic variants. Twenty-six of these variants have never been previously reported and may be of Korean-specific origin. Two pathogenic BRCA1 mutations (c.922_924delinsT, c.5445G>A) and one pathogenic BRCA2 mutation (c.2259delT) were observed, and two of these (BRCA1 c.5445G>A and BRCA2 c.2259delT) are novel. The total prevalence of germline pathogenic mutations in BRCA1 and/or BRCA2 in Korean sporadic breast cancer is estimated to be about 3.1%. Considering that the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of germline BRCA mutations in sporadic breast cancer patients. Further study using a larger sample size is required to determine the merits of genetic diagnosis and counseling in breast cancer patients. © 2004 Wiley-Liss, Inc. [source] Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: An updateINTERNATIONAL JOURNAL OF CANCER, Issue 9 2006Jacek Gronwald Abstract Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of ,80%, and following the first diagnosis the10-year risk of contralateral breast cancer is ,30%. It has been shown that both tamoxifen and oophorectomy prevent contralateral breast cancer, but it is not clear whether there is a benefit in giving tamoxifen to women who have previously undergone an oophorectomy. Furthermore, the relative degree of protection in BRCA1 and BRCA2 carriers has not been well evaluated. We studied 285 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation, and 751 control women with unilateral breast cancer and a BRCA1 or BRCA2 mutation in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of breast cancer and had been followed for as long as the case for a second primary breast cancer. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilateral cases. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 for carriers of BRCA1 mutations (95% CI, 0.30,0.85) and was 0.42 for carriers of BRCA2 mutations (95% CI, 0.17,1.02). The protective effect of tamoxifen was not seen among women who had undergone an oophorectomy (OR = 0.83; 95%CI, 0.24,2.89) but this subgroup was small. In contrast, a strong protective effect of tamoxifen was apparent among women who were premenopausal or who had undergone natural menopause (OR = 0.44; 95% CI, 0.27,0.65). © 2005 Wiley-Liss, Inc. [source] Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriersINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006André Nkondjock Abstract Although there are several plausible biologic mechanisms whereby coffee consumption might influence the risk of breast cancer, epidemiologic evidence is limited. We assessed the association between coffee consumption and breast cancer risk among high-risk women who carry BRCA mutations. We performed a matched case-control analysis on 1,690 women with a BRCA1 or BRCA2 mutation from 40 centers in 4 countries. Average lifetime coffee consumption was estimated via a self-administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for potential confounders, the ORs for breast cancer in BRCA carriers who habitually drank 0, 1,3, 4,5 and 6 or more cups of coffee were 1.00, 0.90 (95% CI 0.72,1.12), 0.75 (95% CI 0.47,1.19) and 0.31 (95% CI 0.13,0.71; p -trend = 0.02). The effect was limited to the consumption of caffeinated coffee. These results suggest that among women with BRCA gene mutation, coffee consumption is unlikely to be harmful and that high levels of consumption may in fact be related to reduced breast cancer risk. © 2005 Wiley-Liss, Inc. [source] Psychosocial functioning in women who have undergone bilateral prophylactic mastectomyPSYCHO-ONCOLOGY, Issue 1 2004Kelly A. Metcalfe The purpose of this study was to determine the current psychosocial functioning of women who had previously had a bilateral prophylactic mastectomy. Women in the province of Ontario who had undergone prophylactic mastectomy between 1991 and 2000 were asked to complete questionnaires that assessed psychological distress, sexual activity, overall satisfaction with decision to have a prophylactic mastectomy, and body image. Ninety-seven percent of the women were satisfied with their decision to have a prophylactic mastectomy, but young women (<50 years) were less likely to report satisfaction than older women (p=0.001). Women with a strong family history of breast cancer or a BRCA1 or BRCA2 mutation experienced more cancer-related distress than those with a limited family history. Women who had reconstruction following mastectomy reported higher levels of satisfaction with general body shape and appearance than those without reconstruction. In conclusion, the majority of women were satisfied with their decision to undergo prophylactic mastectomy and were not experiencing abnormal levels of psychological distress, low levels of sexual activity, or difficulties with body image. Copyright © 2003 John Wiley & Sons, Ltd. [source] Accuracy of the BRCAPRO model among women with bilateral breast cancerCANCER, Issue 4 2009Kaylene J. Ready MS Abstract BACKGROUND: The likelihood of identifying a BRCA mutation was often calculated using the BRCAPRO model. A previous study suggested that this model may overestimate the chance of detecting a BRCA mutation among women diagnosed with bilateral breast cancer. Studies also suggested that few patients with bilateral breast cancer whose age at first diagnosis is >40 years were mutation carriers. The objectives of this study were to determine the accuracy of the BRCAPRO model among women with bilateral breast cancer and to determine whether their mutation status was dependent on their age at first diagnosis. METHODS: A retrospective chart review was performed. Women who were diagnosed with bilateral or unilateral breast cancer and who had undergone comprehensive BRCA1 and BRCA2 genetic testing at M. D. Anderson Cancer Center between 1997 and 2006 were included in the study. RESULTS: For individuals with pre-test carrier probabilities >31%, the proportion of positive tests was significantly lower than predicted by the BRCAPRO model (P < .05). In addition, the carrier rate of BRCA mutations was significantly higher (P = .002, Fisher exact test) in women with bilateral breast cancer whose age at first diagnosis was ,40 years compared with those diagnosed >40 years. CONCLUSIONS: The BRCAPRO model was overestimating the relative contribution bilateral breast cancer had on the likelihood of detecting a BRCA1 or BRCA2 mutation. Bilateral breast cancer did not appear to be a good indicator of mutation status, particularly for women whose age at first diagnosis is >40 years. Cancer 2009. © 2009 American Cancer Society. [source] Ovarian carcinoma screening in women at intermediate riskCANCER, Issue 2 2005Impact on quality of life, need for invasive follow-up Abstract BACKGROUND Women with family histories suggestive of an increased risk of ovarian carcinoma who have not had a deleterious BRCA1 or BRCA2 mutation identified are commonly suggested to consider ovarian carcinoma screening with transvaginal ultrasound and/or assessment of CA 125 levels. Limited information is available regarding the impact of this approach on either quality of life (QOL) or need for invasive follow-up in this group of women. METHODS From November 1999 to October 2002, 184 women at intermediate risk of ovarian carcinoma were enrolled in a prospective study. Participants were screened with twice yearly transvaginal ultrasound and CA 125 assessments. Impact on QOL was measured using the Mental Component Summary (MCS) score of the Medical Outcomes Studies Short Form-36. Need for invasive follow-up was determined by questionnaire and medical record review. RESULTS In the current study, 135 participants underwent , 1 follow-up assessment. During a mean of 19.8 months of follow-up, 12.9% of ultrasounds and 3.8% of CA 125 assessments were abnormal. The authors reported that 38.5% of participants had , 1 abnormal ovarian screen that required a short interval follow-up. Because of either abnormal bleeding or ultrasound abnormalities, 24% of participants underwent , 1 endometrial sampling. Controlling for a history of breast carcinoma and menopausal status, abnormal ovarian screening results were associated with a decrease in MCS score (P = 0.034), whereas the need for endometrial sampling was not (P = 0.87). CONCLUSIONS Ovarian carcinoma screening in women at intermediate risk was associated with a substantial rate of abnormal screen results, endometrial sampling, and in women with abnormal ovarian screening findings, a decrease in MCS scores. These findings may have important implications for women considering ovarian carcinoma screening and for the design of future ovarian carcinoma screening trials. Cancer 2005. © 2005 American Cancer Society. [source] The contribution of founder mutations to early-onset breast cancer in French-Canadian womenCLINICAL GENETICS, Issue 5 2009P Ghadirian In an ethnically-homogeneous population, it is valuable to identify founder mutations in cancer-predisposing genes. Founder mutations have been found in four breast-cancer-predisposing genes in French-Canadian breast cancer families. The frequencies of the mutant alleles have been measured neither in a large series of unselected breast cancer patients from Quebec, nor in healthy controls. These estimates are necessary to measure their contribution to the hereditary burden of breast cancer in Quebec and to help develop genetic screening policies which are appropriate for the province. We studied 564 French-Canadian women with early-onset invasive breast cancer who were treated at a single Montreal hospital. Patients had been diagnosed at age 50 or less, and were ascertained between 2004 and 2008. We screened all 564 patients for nine founder mutations: four in BRCA1, three in BRCA2 and one each in PALB2 and CHEK2. We also studied 6433 DNA samples from newborn infants from the Quebec City area to estimate the frequency of the nine variant alleles in the French-Canadian population. We identified a mutation in 36 of the 564 breast cancer cases (6.4%) and in 35 of 6443 controls (0.5%). In the breast cancer patients, the majority of mutations were in BRCA2 (54%). However, in the general population (newborn infants), the majority of mutations were in CHEK2 (54%). The odds ratio for breast cancer to age 50, given a BRCA1 mutation, was 10.1 (95% CI: 3.7,28) and given a BRCA2 mutation was 29.5 (95% CI: 12.9,67). The odds ratio for breast cancer to age 50, given a CHEK2 mutation, was 3.6 (95% CI: 1.4,9.1). One-half of the women with a mutation had a first- or second-degree relative diagnosed with breast or ovarian cancer. Thus, it can be concluded that a predisposing mutation in BRCA1, BRCA2, CHEK2 or PALB2 is present in approximately 6% of French-Canadian women with early-onset breast cancer. It is reasonable to offer screening for founder mutations to all French-Canadian women with breast cancer before age 50. The frequency of these mutations in the general population (0.5%) is too low to advocate population-based screening. [source] Family history as a predictor of uptake of cancer preventive procedures by women with a BRCA1 or BRCA2 mutationCLINICAL GENETICS, Issue 5 2008KA Metcalfe Women with a BRCA1 or BRCA2 mutation are at an elevated risk of developing breast and ovarian cancer; however, it is unclear to what extent family history influences the uptake of cancer prevention options.Women with a BRCA1/2 mutation completed a follow-up questionnaire that assessed uptake of cancer preventive options. The pedigree of each woman was reviewed, and information was recorded on cancers diagnosed in relatives. Five hundred and seventeen women were included in the study. Women with a sister with breast cancer were more likely to have a prophylactic mastectomy than those without a sister with breast cancer [odds ratios (OR) = 2.4, p = 0.003]. Uptake of prophylactic mastectomy was significantly lower in women with a mother with ovarian cancer compared with those whose mother did not have ovarian cancer (OR = 0.4, p = 0.01). Having a mother or sister with ovarian cancer significantly predicted the uptake of prophylactic oophorectomy (OR = 1.6, p = 0.04). Women with a BRCA2 mutation were less likely to have a prophylactic oophorectomy than those with a BRCA1 mutation (OR = 0.49, p = 0.0004). Among women with a BRCA1 or BRCA2 mutation, family history predicts the uptake of prophylactic mastectomy and prophylactic oophorectomy. [source] Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterationsGENES, CHROMOSOMES AND CANCER, Issue 3 2002Chiara Ghimenti BARD1 (BRCA1-associated RING domain) was identified by yeast two-hybrid screening as a protein interacting with BRCA1. Somatic and germline mutations of BARD1 have been detected in sporadic breast, ovarian, and endometrial cancers. The present study represents the first description of BARD1 germline mutations in hereditary breast and breast/ovarian cancer patients. We analyzed the BARD1 gene in 40 families with hereditary breast and breast/ovarian cancer, tested negative for BRCA1 and BRCA2 mutations. A mutational analysis by PCR-SSCP on the coding region and the exon,intron splice boundaries of the BARD1 gene yielded four different germline mutations. A group of 20 patients diagnosed with sporadic breast cancer below the age of 40 was also examined and only one germline mutation was found. A study of loss of heterozygosity at the BARD1 locus in neoplastic tissues from patients with BARD1 germline mutations was carried out. In all cases, we were unable to find any evidence for allelic deletions. The involvement of BARD1 mutations in the susceptibility to hereditary breast and breast/ovarian cancer is discussed. [source] Histopathological features of breast cancer in carriers of ATM gene variantsHISTOPATHOLOGY, Issue 5 2006R L Balleine Aims:, Germline variants in the ataxia telangiectasia mutated (ATM) gene have been implicated in increased breast cancer risk. The aim of this study was to determine whether the histopathology of breast cancers occurring in ATM variant carriers is distinctive or resembles the described BRCA1 mutation-associated phenotype. Methods:, The histopathological features of breast cancers occurring in ATM variant carriers from multiple-case breast cancer families were compared with matched controls. The test group included 21 cases of in situ and/or invasive cancer from carriers of either the IVS10-6T,G, 2424V,G or 1420L,F ATM variants in the absence of BRCA1 or BRCA2 mutations. An additional four invasive cancers from carriers of a pathogenic BRCA1 mutation in the context of a familial ATM variant were also examined. Results:, The histopathology of breast cancers in ATM variant-only carriers was not significantly different from controls and known features of BRCA1 mutation-associated cancer were rarely seen. In contrast, these features were prominent in the small group of cases with a pathogenic BRCA1 mutation. Conclusions:, Breast cancer occurring in carriers of ATM variants is not associated with distinctive histopathological features and does not resemble the tumour phenotype commonly observed in BRCA1 mutation carriers. [source] Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer,HUMAN MUTATION, Issue 12 2007Susan J. Ramus Abstract A total of 283 epithelial ovarian cancer families from the United Kingdom (UK) and the United States (US) were screened for coding sequence changes and large genomic alterations (rearrangements and deletions) in the BRCA1 and BRCA2 genes. Deleterious BRCA1 mutations were identified in 104 families (37%) and BRCA2 mutations in 25 families (9%). Of the 104 BRCA1 mutations, 12 were large genomic alterations; thus this type of change represented 12% of all BRCA1 mutations. Six families carried a previously described exon 13 duplication, known to be a UK founder mutation. The remaining six BRCA1 genomic alterations were previously unreported and comprised five deletions and an amplification of exon 15. One of the 25 BRCA2 mutations identified was a large genomic deletion of exons 19,20. The prevalence of BRCA1/2 mutations correlated with the extent of ovarian and breast cancer in families. Of 37 families containing more than two ovarian cancer cases and at least one breast cancer case with diagnosis at less than 60 years of age, 30 (81%) had a BRCA1/2 mutation. The mutation prevalence was appreciably less in families without breast cancer; mutations were found in only 38 out of 141 families (27%) containing two ovarian cancer cases only, and in 37 out of 59 families (63%) containing three or more ovarian cancer cases. These data indicate that BRCA1 and BRCA2 are the major susceptibility genes for ovarian cancer but that other susceptibility genes may exist. Finally, it is likely that these data will be of clinical importance for individuals in families with a history of epithelial ovarian cancer, in providing accurate estimates of their disease risks. Hum Mutat 28(12), 1207,1215, 2007. © 2007 Wiley-Liss, Inc. [source] Germline mutations of BRCA1 and BRCA2 in Korean breast and/or ovarian cancer families,,HUMAN MUTATION, Issue 3 2002Hio Chung Kang Abstract Germline mutations in the BRCA1 and BRCA2 genes are responsible for the predisposition and development of familial breast and/or ovarian cancer. Most mutations of BRCA1 and BRCA2 associated with breast and/or ovarian cancer result in truncated proteins. To investigate the presence of BRCA1 and BRCA2 germline mutations in Korean breast and/or ovarian cancer families, we screened a total of 27 cases from 21 families including two or more affected first- or second-degree relatives with breast and/or ovarian cancer. PTT, PCR-SSCP, and DHPLC analysis, followed by sequencing were used in the screening process. In nine families, we found BRCA1 and BRCA2 germline mutations that comprised four frameshift mutations and five nonsense mutations. All nine mutations led to premature termination producing shortened proteins. Among the nine mutations, three novel BRCA1 mutations (E1114X, Q1299X, 4159delGA) and two novel BRCA2 mutations (K467X, 8945delAA) were identified in this work. © 2002 Wiley-Liss, Inc. [source] BRCA2 gene mutations in Greek patients with familial breast cancer ,,HUMAN MUTATION, Issue 1 2002Athanasios Armakolas Abstract Family history is a well-recognized risk factor for the development of breast cancer. The isolation of BRCA1 and BRCA2 genes, the two major predisposing genes in familial and to early onset breast and ovarian cancer, has resulted to the identification of a large number of families with mutations in these two genes. Despite the large number of distinct mutations detected in both genes, several mutations have been found to recur in unrelated families of diverse geographical origin. We have analyzed 27 Greek patients with familial breast cancer the majority of those having one first and one second degree relatives affected and 28 patients with sporadic breast cancer for BRCA2 germline mutations. The techniques used were single-strand conformation polymorphism analysis (SSCP) followed by sequencing. Furthermore, the clinical presentation and prognosis of BRCA2 associated breast cancer cases was compared to 20 adequately matched for age and date of diagnosis (within one year) sporadic breast cancer patients. We identified three novel BRCA2 mutations (3058delA, 6024delTA, and 4147delG) in the ovarian cancer cluster region (OCCR) and one already known (2024del5) germline BRCA2 gene mutation in five different breast cancer families. The 4147delG mutation was detected in two unrelated patients. BRCA2 germline mutations were correlated with early-onset breast cancer RR=4.77 (95% CI: 0.666-34.463). Although patients with BRCA2 germline mutations did not have a distinct histological phenotype they had an improved overall survival (100% vs 65%). Our findings suggest that there is a cluster of novel mutations in exons 10 and 11 in Greek patients with familial breast cancer. These mutations appear to have a milder clinical phenotype when compared to the rest of the study group. © 2001 Wiley-Liss, Inc. [source] Novel germline BRCA1 and BRCA2 mutations in breast and breast/ovarian cancer families from the Czech Republic ,,HUMAN MUTATION, Issue 6 2001Eva Machackova Abstract Germline mutations in breast cancer susceptibility genes, BRCA1 and BRCA2, are responsible for a substantial proportion of high-risk breast and breast/ovarian cancer families. To characterize the spectrum of BRCA1 and BRCA2 mutations, we screened Czech families with breast/ovarian cancer using the non-radioactive protein truncation test, heteroduplex analysis and direct sequencing. In a group of 100 high-risk breast and breast/ovarian cancer families, four novel frame shift mutations were identified in BRCA1 and BRCA2 genes. In BRCA1, two novel frame shift mutations were identified as 3761-3762delGA and 2616-2617ins10; in BRCA2, two novel frame shift mutations were identified as 5073-5074delCT and 6866delC. Furthermore, a novel missense substitution M18K in BRCA1 gene in a breast/ovarian cancer family was identified which lies adjacent just upstream of the most highly conserved C3HC4 RING zinc finger motif. To examine the tertiary structure of the RING zinc finger domain and possible effects of M18K substitution on its stability, we used threading techniques according to the crystal structure of RAG1 dimerization domain of the DNA-binding protein. © 2000 Wiley-Liss, Inc. [source] On the dynamics of breast tumor development in women carrying germline BRCA1 and BRCA2 mutationsINTERNATIONAL JOURNAL OF CANCER, Issue 8 2008Richard Simon Abstract We used mathematical models to analyze the age-incidence curve of breast carcinoma for individuals carrying a germline mutation in the BRCA1 or BRCA2 gene locus. Although many genomic abnormalities have been identified in breast tumors, we found that a two-stage model fit the data well. A one-hit model was not, however, consistent with the data. The results supported the hypothesis that the first hit represents loss of the wild type BRCA1 or BRCA2 allele as this occurs at a rate very similar to that for loss of the wild-type RB allele in retinoblastoma. Loss of the wild-type BRCA1 or BRCA2 allele appears to destabilize the genome as the second event occurs at a much higher rate. The second event is "rate limiting" in the sense that its occurrence is constrained by the limited number of intermediate cells with doubly mutated BRCA1 or BRCA2 alleles. The second event may not be unique, however. Loss of the wild-type BRCA allele appears to result in an increased rate for subsequent genomic events. A second event increasing proliferation of the partially malignant intermediate clone may lead inexorably to production and selection of cells with additional mutations in genes that facilitate tumor progression. © 2007 Wiley-Liss, Inc. [source] Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patientsINTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Muhammad U. Rashid Abstract Among Asian countries, Pakistan has the highest rates of breast and ovarian cancer. To assess the contribution of the BRCA1 and BRCA2 germ line mutations to these high rates, we conducted the first study of 176 Pakistani breast and ovarian cancer patients, selected on family history and on age of diagnosis. Comprehensive BRCA mutation screening was performed using a range of techniques, including denaturing high-pressure liquid chromatography, single strand conformational polymorphism analysis and protein truncation test, followed by DNA sequencing. Thirty deleterious germ-line mutations were identified in the 176 families (17.0%), including 23 in BRCA1 and 7 in BRCA2. Four mutations, 185delAG, 185insA, S1503X and R1835X, were recurrent; these accounted for 52% of all identified BRCA1 mutations. Haplotype analyses suggested founder effects for 3 of these. The prevalence of BRCA1 or BRCA2 mutations was 42.8% for families with multiple cases of breast cancer, and was 50.0% for the breast/ovarian cancer families. The prevalence of mutations was 11.9% for single cases of early-onset breast cancer (,30 years) and was 9.0% for single cases of early-onset ovarian cancer (,45 years). Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer and early-onset breast and ovarian cancer cases in Pakistan. © 2006 Wiley-Liss, Inc. [source] Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: An updateINTERNATIONAL JOURNAL OF CANCER, Issue 9 2006Jacek Gronwald Abstract Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of ,80%, and following the first diagnosis the10-year risk of contralateral breast cancer is ,30%. It has been shown that both tamoxifen and oophorectomy prevent contralateral breast cancer, but it is not clear whether there is a benefit in giving tamoxifen to women who have previously undergone an oophorectomy. Furthermore, the relative degree of protection in BRCA1 and BRCA2 carriers has not been well evaluated. We studied 285 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation, and 751 control women with unilateral breast cancer and a BRCA1 or BRCA2 mutation in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of breast cancer and had been followed for as long as the case for a second primary breast cancer. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilateral cases. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 for carriers of BRCA1 mutations (95% CI, 0.30,0.85) and was 0.42 for carriers of BRCA2 mutations (95% CI, 0.17,1.02). The protective effect of tamoxifen was not seen among women who had undergone an oophorectomy (OR = 0.83; 95%CI, 0.24,2.89) but this subgroup was small. In contrast, a strong protective effect of tamoxifen was apparent among women who were premenopausal or who had undergone natural menopause (OR = 0.44; 95% CI, 0.27,0.65). © 2005 Wiley-Liss, Inc. [source] A high proportion of founder BRCA1 mutations in Polish breast cancer familiesINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004Bohdan Górski Abstract Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast,ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast,ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast,ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention. © 2004 Wiley-Liss, Inc. [source] Rad51 overexpression rescues radiation resistance in BRCA2-defective cancer cellsMOLECULAR CARCINOGENESIS, Issue 2 2009Erika T. Brown Abstract Breast cancers with BRCA2 mutations exhibit DNA repair defects and are particularly sensitive to radiation. BRCA2 interacts with Rad51 in a complex manner involving internal BRC and C-terminal TR2 domains which play a key role in homologous recombination. BRCA2 expression also modulates Rad51 protein levels such that Rad51 protein is relatively decreased in BRCA2-defective cancer cells. This is mediated in part through BRCA2's capacity to protect Rad51 from caspase-3 proteolytic degradation. In order to distinguish between functional and expression related roles for BRCA2 we studied the results of Rad51 overexpression in mouse and human cells with inactivating BRCA2 mutations. The results show that overexpression of wild-type Rad51 partially rescues BRCA2 deficiency but that overexpression of a caspase-3 resistant Rad51 completely complements the BRCA2 defect in radiation responsiveness. These results indicate that Rad51 can compensate for some aspects of a BRCA2 gene defect and suggest that Rad51 expression levels may be an important modifier of the BRCA2 defective genotype. © 2008 Wiley-Liss, Inc. [source] Impact of BRCA mutations on female fertility and offspring sex ratio,AMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 2 2010Roxana Moslehi Positive selection for inherited mutations in breast and ovarian cancer predisposing genes, BRCA1 and BRCA2, may contribute to the high frequency of BRCA mutations among the Ashkenazi Jewish population. Impact of BRCA mutations on fertility has not been generally explored in epidemiologic studies. There are reports of distorted sex ratios in BRCA carrier families but these findings have been attributed to bias. We investigated the effect of BRCA mutations on female fertility and offspring sex ratio in a study of 260 Ashkenazi Jewish women with ovarian cancer and 331 controls, unselected for age or family history of the disease. Pregnancy success was similar for 96 mutation carrier (0.84) and 164 noncarrier cases (0.87) and controls (0.83). After adjusting for covariates, there were no significant differences between BRCA carrier and noncarrier cases and controls with regards to fertility, despite lower pregnancy rates among all cases compared to controls (P = 0.0049). Male/female sex ratios were significantly lower among offspring of carriers (0.71) than offspring of noncarriers (0.95) or those of the controls (0.99). Comparisons among the three groups yielded statistically significant distortion against males among the offspring of known and obligate BRCA carriers compared to noncarriers (OR = 0.74, 95% CI:0.55,0.99) and controls (OR = 0.71, 95% CI:0.54,0.94). In conclusion, we did not find evidence for an effect of BRCA mutations on female fertility. We found a significant excess of females among the offspring of female carriers of BRCA1 and BRCA2 mutations. Potential contribution of observed sex ratio distortions to positive selection for BRCA mutations may warrant further investigation. Am. J. Hum. Biol., 2010. © 2009 Wiley-Liss, Inc. [source] Hereditary Breast Cancer: Part I. Diagnosing Hereditary Breast Cancer SyndromesTHE BREAST JOURNAL, Issue 1 2008Henry T. Lynch MD Abstract:, Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Most of these cases will be found to be due to a BRCA germline mutation. An estimated additional 15,20% of those affected with BC will have one or more first- and/or second-degree relatives with BC. Therefore, when these numbers are combined, familial BC risk accounts for approximately 20,25% of the total BC burden. However, because of the often limited information on family history in the etiologic assessment of BC, this may be an underestimate. Confounding factors include its phenotypic and genotypic heterogeneity, given the association of HBC with a plethora of differing cancer syndromes. Its most common occurrence is its association with ovarian cancer in the so-called hereditary breast-ovarian cancer syndrome due to BRCA1 and BRCA2 mutations. More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma. Importantly, the age-adjusted incidence of BC in women in the United States fell sharply, by 6.7%, in 2003, when compared with the rate identified in 2002. We postulate that increasing knowledge about the genetics of BC may have partially contributed to the identification of high-risk patients who thereby may have benefited significantly from early diagnosis. [source] Morphological features of TMPRSS2,ERG gene fusion prostate cancer,THE JOURNAL OF PATHOLOGY, Issue 1 2007J-M Mosquera Abstract The TMPRSS2,ETS fusion prostate cancers comprise 50,70% of the prostate-specific antigen (PSA)-screened hospital-based prostate cancers examined to date, making it perhaps the most common genetic rearrangement in human cancer. The most common variant involves androgen-regulated TMPRSS2 and ERG, both located on chromosome 21. Emerging data from our group and others suggests that TMPRSS2,ERG fusion prostate cancer is associated with higher tumour stage and prostate cancer-specific death. The goal of this study was to determine if this common somatic alteration is associated with a morphological phenotype. We assessed 253 prostate cancer cases for TMPRSS2,ERG fusion status using an ERG break-apart FISH assay. Blinded to gene fusion status, two reviewers assessed each tumour for presence or absence of eight morphological features. Statistical analysis was performed to look for significant associations between morphological features and TMPRSS2,ERG fusion status. Five morphological features were associated with TMPRSS2,ERG fusion prostate cancer: blue-tinged mucin, cribriform growth pattern, macronucleoli, intraductal tumour spread, and signet-ring cell features, all with p -values < 0.05. Only 24% (n = 30/125) of tumours without any of these features displayed the TMPRSS2,ERG fusion. By comparison, 55% (n = 38/69) of cases with one feature (RR = 3.88), 86% (n = 38/44) of cases with two features (RR = 20.06), and 93% (n = 14/15) of cases with three or more features (RR = 44.33) were fusion positive (p < 0.001). To our knowledge, this is the first study that demonstrates a significant link between a molecular alteration in prostate cancer and distinct phenotypic features. The strength of these findings is similar to microsatellite unstable colon cancer and breast cancer involving BRCA1 and BRCA2 mutations. The biological effect of TMPRSS2,ERG overexpression may drive pathways that favour these common morphological features that pathologists observe daily. These features may also be helpful in diagnosing TMPRSS2,ERG fusion prostate cancer, which may have both prognostic and therapeutic implications. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Breast magnetic resonance image screening and ductal lavage in women at high genetic risk for breast carcinomaCANCER, Issue 3 2004Anne-Renee Hartman M.D. Abstract BACKGROUND Intensive screening is an alternative to prophylactic mastectomy in women at high risk for developing breast carcinoma. The current article reports preliminary results from a screening protocol using high-quality magnetic resonance imaging (MRI), ductal lavage (DL), clinical breast examination, and mammography to identify early malignancy and high-risk lesions in women at increased genetic risk of breast carcinoma. METHODS Women with inherited BRCA1 or BRCA2 mutations or women with a > 10% risk of developing breast carcinoma at 10 years, as estimated by the Claus model, were eligible. Patients were accrued from September 2001 to May 2003. Enrolled patients underwent biannual clinical breast examinations and annual mammography, breast MRI, and DL. RESULTS Forty-one women underwent an initial screen. Fifteen of 41 enrolled women (36.6%) either had undergone previous bilateral oophorectomy and/or were on tamoxifen at the time of the initial screen. One patient who was a BRCA1 carrier had high-grade ductal carcinoma in situ (DCIS) that was screen detected by MRI but that was missed on mammography. High-risk lesions that were screen detected by MRI in three women included radial scars and atypical lobular hyperplasia. DL detected seven women with cellular atypia, including one woman who had a normal MRI and mammogram. CONCLUSIONS Breast MRI identified high-grade DCIS and high-risk lesions that were missed by mammography. DL detected cytologic atypia in a high-risk cohort. A larger screening trial is needed to determine which subgroups of high-risk women will benefit and whether the identification of malignant and high-risk lesions at an early stage will impact breast carcinoma incidence and mortality. Cancer 2004. © 2004 American Cancer Society. [source] ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutationsCLINICAL GENETICS, Issue 5 2008J Brunet Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC. [source] | |||||||||||||||||||||||||