共查询到20条相似文献,搜索用时 15 毫秒
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Zsofia K. Stadler Emmanuel Saloustros Nichole A. L. Hansen Alice E. Schluger Noah D. Kauff Kenneth Offit Mark E. Robson 《Breast cancer research and treatment》2010,123(2):581-585
A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations
in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2–4% of such families. The extent to which major genomic rearrangements
in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast
and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious
mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement
testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test
probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4–88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects
with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim. 相似文献
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S. M. Domchek M. M. Gaudet J. E. Stopfer M. H. Fleischaut J. Powers N. Kauff K. Offit K. L. Nathanson M. Robson 《Breast cancer research and treatment》2010,119(2):409-414
Genetic testing for BRCA1 and BRCA2 mutations in family members of individuals with known deleterious mutations can distinguish between patients at high risk
of disease and those who are not. Some studies have suggested that individuals testing negative for known familial mutations
(true negatives), may still have a higher risk of breast cancer (BC) than the general population. We have examined a prospectively
followed cohort of true negative women in the US. Subjects were close relatives of known BRCA1 and BRCA2 mutation carriers who had undergone genetic testing, were negative for the known familial mutation, and were unaffected at
the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER
incidence rates. Among 375 true negatives, two invasive and two in situ BC and no ovarian cancers were diagnosed with mean
follow up of 4.9 years (total of 1,962 person-years). Four invasive BC were expected, whereas two were observed, for an age-adjusted
SIR of 0.52 (95% CI 0.13–2.09). We observed more cases of in situ BC (n = 2) than were expected (n = 0.9; SIR = 2.30; 95% CI 0.57–9.19). There were no cases of ovarian cancer observed; 0.4 case was expected. In this prospective
study of women who were unaffected at the time of genetic testing and who were negative for the known familial mutation in
BRCA1/2, no excess risk of invasive BC was observed. Our data suggest that such women in the US should adhere to population-based
guidelines for breast cancer screening. 相似文献
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Jin Ho Kim Doo Ho Choi Dae Yeon Cho Sei Hyun Ahn Byung Ho Son Bruce G. Haffty 《Breast cancer research and treatment》2010,122(1):303-306
PALB2 is a recently discovered breast cancer susceptibility gene, and mutations in the gene have been demonstrated to confer about
twofold higher risk of breast cancer. Truncating mutations in PALB2 gene have been identified in varied populations. However, PALB2’s significance to breast cancer has not been investigated in the Korean population. In this study, we evaluated the frequency
of PALB2 1592delT and 229delT mutations in 300 Korean breast cancer patients diagnosed with either familial or early-onset breast
cancer. All patients were confirmed negative for BRCA1 and BRCA2 mutations. Neither 1592delT nor 229delT mutations was found in any of the study cohort. Our results imply that these mutations
are absent or rare in Korean patients who are negative for BRCA1 and BRCA2 mutations. We found no evidence to recommend screening for these mutations in the Korean population. However, PALB2 mutations have been demonstrated infrequent and inhomogeneous across investigated populations. Thus, screening the whole
PALB2 gene for novel mutations is required to elucidate its significance in predisposition to breast cancer in Korean women. 相似文献
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Peter Kang Shivaani Mariapun Sze Yee Phuah Linda Shushan Lim Jianjun Liu Sook-Yee Yoon Meow Keong Thong Nur Aishah Mohd Taib Cheng Har Yip Soo-Hwang Teo 《Breast cancer research and treatment》2010,124(2):579-584
Endoxifen is the key active metabolite of Tamoxifen, a widely used breast cancer drug. Orally administered Tamoxifen, is extensively metabolized by cytochrome P450 (CYP) enzymes, namely CYP3A4 and CYP2D6, into active metabolites, especially Endoxifen. Due to genetic polymorphism of CYP2D6, significant numbers of women metabolize Tamoxifen to varying degree and may not receive the optimal benefit from Tamoxifen treatment. We show that oral administration of Endoxifen achieved the optimally effective systemic levels reliably, which may eliminate variability associated with Tamoxifen metabolism that leads to unpredictability in efficacy. Furthermore, use of Endoxifen may avoid a potential serious drug interaction found between Tamoxifen and commonly used selective serotonin reuptake inhibitors, antidepressants. Endoxifen was active in inhibiting the growth of various breast tumor cell lines in NCI 60-Cell Line Screen. Orally administered Endoxifen is rapidly absorbed and systemically available when tested in female rats. The Endoxifen-treated rats showed 787% higher exposure (AUC0–∞) and 1,500% higher concentration (C max) levels of Endoxifen when compared with Tamoxifen. Oral Endoxifen administration once a day for 28 consecutive days at dosages 2, 4, and 8 mg/kg proved safe and resulted in progressive inhibition of the growth of the human mammary tumor xenografts in female mice. This is the first ever in vivo report on Endoxifen as a potentially new therapeutic agent for breast cancer. 相似文献
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Abnormalities in several genes are known to confer susceptibility to breast cancer. In the present study, we investigated the incidence of allelic imbalance at the BRCA1, BRCA2 and TP53 loci, in 82 sporadic breast carcinomas using a bank of highly polymorphic microsatellite markers located at the BRCA1, BRCA2 and TP53 regions. Genetic alterations were observed in 58/82 (71%) cases in at least one microsatellite marker, at one of the three regions. Twenty-seven out of 82 (33%) cases exhibited loss of heterozygosity (LOH) at BRCA1 locus while in 20/82 (34%) cases LOH was observed for the BRCA2 region. Allelic deletions were detected in 28/82 (34%) cases for the TP53 locus. Our results suggest that allelic deletion at the above genetic loci play an important role to the development of sporadic breast tumours. 相似文献
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Orland Diez Sara Gutiérrez-Enríquez Carmen Mediano Miriam Masas Cristina Saura Neus Gadea Judith Balma?a 《Breast cancer research and treatment》2010,121(1):221-225
Germ line mutations in either of the two major breast cancer predisposition genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast/ovarian cancer. Identification of breast cancer patients carrying
mutations in any of these genes is primarily based on a positive family history of breast/ovarian cancer or early onset of
the disease. In the course of mutation screening of the BRCA1 and BRCA2 genes in a hospital based series of patients with risk factors for hereditary breast/ovarian cancer, we identified a novel
germ line mutation in the BRCA2 gene (c.51dupA) in a patient with early onset bilateral breast cancer and no family history of the disease. None of her parents
carried the mutation, and paternity was confirmed. Subsequent molecular analysis demonstrated that the mutation was a novel
de novo germ line mutation located in the paternal allele of the BRCA2 gene. 相似文献
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Background
Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls. 相似文献12.
Victor R. Grann Priya R. Patel Judith S. Jacobson Ellen Warner Daniel F. Heitjan Maxine Ashby-Thompson Dawn L. Hershman Alfred I. Neugut 《Breast cancer research and treatment》2011,125(3):837-847
Comparative effectiveness research has become an integral part of health care planning in most developed countries. In a simulated cohort of women, aged 30–65, who tested positive for BRCA1 or BRCA2 mutations, we compared outcomes of mammography with and without MRI, prophylactic oophorectomy with and without mastectomy, mastectomy alone, and chemoprevention. Methods: Using Treeage 9.02 software, we developed Markov models with 25,000 Monte Carlo simulations and conducted probabilistic sensitivity analysis. We based mutation penetrance rates, breast and ovarian cancer incidence, and mortality rates, and costs in terms of 2009 dollars, on published studies and data from the Surveillance, Epidemiology, and End Results (SEER) Program and the Centers for Medicare and Medicaid Services. We used preference ratings obtained from mutation carriers and controls to adjust survival for quality of life (QALYs). Results: For BRCA1 mutation carriers, prophylactic oophorectomy at 1,741 per QALY, was more cost effective than both surgeries and dominated all other interventions. For < i > BRCA2 < /i > carriers, prophylactic oophorectomy, at1,741 per QALY, was more cost effective than both surgeries and dominated all other interventions. For BRCA2 carriers, prophylactic oophorectomy, at 4,587 per QALY, was more cost effective than both surgeries. Without quality adjustment, both mastectomy and BSO surgeries dominated all other interventions. In all simulations, preventive surgeries or chemoprevention dominated or were more cost effective than screening because screening modalities were costly. Conclusion: Our analysis suggested that among BRCA1/2 mutation carriers, prophylactic surgery would dominate or be cost effective compared to chemoprevention and screening. Annual screening with MRI and mammography was the most effective strategy because it was associated with the longest quality-adjusted survival, but it was also very expensive. 相似文献
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Comparative disease pattern of a patient with a novel BRCA2 truncation and knockout models for BRCA2
Josefa Salgado Cristina Gutiérrez Carmen Gil Maitane Robles Jesús García-Foncillas 《Breast cancer research and treatment》2010,123(1):291-293
We report a novel germline 490delCT mutation in BRCA2 gene, detected in a 38-year-old woman with breast cancer. The mutation originates a premature stop at codon 99, leading to
a truncated protein, and has not been documented in any published report to the best of our knowledge. 相似文献
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Orland Diez Sara Gutiérrez-Enríquez Miriam Masas Anna Tenés Carme Yagüe Angels Arcusa Gemma Llort 《Breast cancer research and treatment》2010,123(2):587-590
We report a novel complex mutation that consists of a deletion of 12 bp and an insertion of 2 bp (c.8402_8413del12ins2bp) in the exon 18 of the BRCA2 gene. This is a frameshift mutation that causes a disruption of the translational reading frame resulting in a stop codon downstream in the 2729 position of the BRCA2 protein. The mutation was present in a Spanish hereditary male/female breast cancer family. 相似文献
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Monique Saintot Hélène Mathieu-Daude Cécile Astre Jean Grenier Joelle Simony-Lafontaine Mariette Gerber 《International journal of cancer. Journal international du cancer》2002,97(5):574-579
The role of plasma oxidant-antioxidant status in survival after breast cancer surgery was investigated in a cohort of patients (n = 363) hospitalized in Southern France between 1989 and 1992. The median follow-up was 8 years after surgery for histologically confirmed breast cancer. Plasma analyses were performed after diagnosis and before surgery and adjuvant therapy. We found an inverse relationship between plasma lipoperoxides (MDA) and tumor size at diagnosis, together with higher lipoperoxide levels in node-negative tumors than in node-positive ones (TNM). The longitudinal approach revealed an increased risk of recurrence for patients with plasma lipoperoxides in the highest tertile of the sample (RR = 2.1, 95% CI 1.1-4.0). In addition, the risk of recurrence increased (RR = 1.7, 95%CI 1.0-3.0), after adjustment for the known prognostic factors (TNM), for patients with plasma lipid-adjusted vitamin E levels of over 22 micromol/l. The risk of breast cancer death was twice as great for patients with plasma lipid-adjusted vitamin E levels above this value. Excesses of plasma lipoperoxides and vitamin E appear to be factors in poor prognosis for breast cancer-specific survival (OVS) and disease-free survival (DFS), respectively, independent of tumor characteristics at diagnosis. Several hypotheses are advanced to explain the possible role of plasma vitamin E as a factor in poor prognosis for survival. 相似文献
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Bartsch R Rottenfusser A Wenzel C Dieckmann K Pluschnig U Altorjai G Rudas M Mader RM Poetter R Zielinski CC Steger GG 《Journal of neuro-oncology》2007,85(3):311-317
Background: Brain metastases are frequently encountered in Her2 positive advanced breast cancer. It is still not clear, if trastuzumab
treatment should be continued following their diagnosis. In this analysis we evaluated if trastuzumab was able to influence
time to in-brain progression (TTP) and overall survival (OS). For this reason, we compared patients who continued on trastuzumab
with a historical control group.
Patients and Methods: Seventeen Her2 positive patients receiving whole brain radiotherapy for brain metastases and continuing on trastuzumab were
identified. As historical control group, thirty-six patients treated before 2002 were identified from a breast cancer database.
We performed a multivariate analysis (Cox regression) to explore which factors were potentially able to significantly influence
TTP and OS.
Results: Median TTP was 6 months, range 1–33+ months. Median OS was 7 months, range 1–38 months. Seventeen patients received trastuzumab
after WBRT. Factors associated with prolonged TTP were KPS (p = 0.001), and intensified local treatment (p = 0.004). A trend towards longer TTP was observed in patients treated with trastuzumab (p = 0.068). OS was significantly influenced by KPS (p < 0.001), and continued antibody therapy (p = 0.001).
Conclusion: Two parameters were significantly associated with prolonged OS: KPS and trastuzumab. While there was a trend towards prolonged
TTP in patients with trastuzumab treatment after WBRT, this did not reach statistical significance. It appears therefore reasonable
to suggest continuation of antibody therapy in patients with good performance status despite disease spreading to the brain.
Concerning activity of trastuzumab in brain metastases themselves, no final conclusion is possible. 相似文献
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Yumi?Endo Yu?Dong Naoto?Kondo Nobuyasu?Yoshimoto Tomoko?Asano Yukari?Hato Mayumi?Nishimoto Hiroyuki?Kato Satoru?Takahashi Ryoichi?Nakanishi Tatsuya?Toyama
Background
Human epidermal growth factor receptor 2 (HER2) gene amplification/overexpression is a major therapeutic target in breast cancer, and has been introduced as a predictive biomarker to identify patients who may benefit from therapy with anti-HER2 agents. HER2 somatic mutations have been reported, and these may influence the effect of HER2-targeted drugs.Methods
Here, we sought HER2 mutations in a group of 135 Japanese breast cancer patients with HER2-positive tumors. We analyzed HER2 mutations by direct Sanger sequencing of two major areas, the extracellular domain at position 309–310 and the kinase domain between 755 and 781.Results
Two patients with the HER2 somatic mutation S310F in the extracellular domain were found in this series. One patient with the S310F mutation had a node-negative invasive ductal carcinoma classified as HER2 2+ by the HercepTest and fluorescence in situ hybridization (FISH) positive, and which was estrogen receptor (ER)-negative and progesterone receptor (PgR)-negative. Another patient with the S310F mutation had an apocrine carcinoma with seven lymph nodes positive for metastasis, classified as HER2 3+ by the HercepTest, but which was FISH-negative, as well as ER-negative and PgR-negative. Both patients had received adjuvant single-agent trastuzumab therapy, and had no local recurrence or distant metastasis for five and three years after surgery, respectively.Conclusions
Our data show that HER2 mutations are rare in HER2-positive Japanese breast cancer patients. The two mutations found in this study were identical, S310F. We suggest that in vitro experiments to determine whether the S310F mutation could be involved in resistance to anti-HER2 drugs are worthwhile in future.20.
Aouatef Riahi Mohamel el Ghourabi Asma Fourati Habiba Chaabouni-Bouhamed 《Breast cancer (Tokyo, Japan)》2017,24(2):238-244