National Cancer Institute®
Last Modified: March 1, 2002
UI - 11748305
AU - Eng C; Brody LC; Wagner TM; Devilee P; Vijg J; Szabo C; Tavtigian SV;
TI - Nathanson KL; Ostrander E; Frank TS; Steering Committee of the Breast Cancer Information Core (BIC) Consortium Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1.
SO - J Med Genet 2001 Dec;38(12):824-33
AD - Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. firstname.lastname@example.org
While sequence analysis is considered by many to be the most sensitive method of detecting unknown mutations in large genes such as BRCA1, most published estimates of the prevalence of mutations in this gene have been derived from studies that have used other methods of gene analysis. In order to determine the relative sensitivity of techniques that are widely used in research on BRCA1, a set of blinded samples containing 58 distinct mutations were analysed by four separate laboratories. Each used one of the following methods: single strand conformational polymorphism analysis (SSCP), conformation sensitive gel electrophoresis (CSGE), two dimensional gene scanning (TDGS), and denaturing high performance liquid chromatography (DHPLC). Only the laboratory using DHPLC correctly identified each of the mutations. The laboratory using TDGS correctly identified 91% of the mutations but produced three apparent false positive results. The laboratories using SSCP and CSGE detected abnormal migration for 72% and 76% of the mutations, respectively, but subsequently confirmed and reported only 65% and 60% of mutations, respectively. False negatives therefore resulted not only from failure of the techniques to distinguish wild type from mutant, but also from failure to confirm the mutation by sequence analysis as well as from human errors leading to misreporting of results. These findings characterise sources of error in commonly used methods of mutation detection that should be addressed by laboratories using these methods. Based upon sources of error identified in this comparison, it is likely that mutations in BRCA1 and BRCA2 are more prevalent than some studies have previously reported. The findings of this comparison provide a basis for interpreting studies of mutations in susceptibility genes across many inherited cancer syndromes.
UI - 11750836
AU - Petit JY; Greco M; EUSOMA
TI - Quality control in prophylactic mastectomy for women at high risk of breast cancer.
SO - Eur J Cancer 2002 Jan;38(1):23-6
AD - Division of Plastic Surgery, European Institute of Oncology, via Ripamonti 435, Milan, Italy. email@example.com
UI - 11773283
AU - Geisler JP; Hatterman-Zogg MA; Rathe JA; Buller RE
TI - Frequency of BRCA1 dysfunction in ovarian cancer.
SO - J Natl Cancer Inst 2002 Jan 2;94(1):61-7
AD - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City 52242, USA.
BACKGROUND: Ovarian cancer is one of the most common hereditary cancers in women. Mutations in the BRCA1 gene increase a woman's risk of ovarian cancer. Testing for BRCA1 mutations is cumbersome and impractical for large populations. Therefore, we developed an efficient strategy to detect various types of BRCA1 dysfunction and also determined the relative frequency of BRCA1 dysfunction in ovarian cancer. METHODS: Tumors from 221 patients with epithelial ovarian cancer were screened for loss of heterozygosity (LOH) at the BRCA1 locus. BRCA1 complementary DNA (cDNA) and genomic DNA from all cancers with BRCA1 LOH (106 tumors) or noninformative status (15 tumors) were polymerase chain reaction (PCR) amplified and analyzed for protein truncation in a coupled transcription/translation test. When truncated BRCA1 protein was detected, the BRCA1 gene from both the tumor and a paired blood sample was sequenced. When BRCA1 expression in tumor cDNA was not detected with a protein truncation test, a methylation-specific PCR was used to determine whether the promoter region of BRCA1 was methylated and thus inactivated. All statistical tests were two-sided. RESULTS: Fifty-one (23.1%) of 221 tumors had BRCA1 dysfunction, including 18 with germline mutations, 15 with somatic mutations, and 18 with monoallelic or biallelic hypermethylated promoters. By the consideration of only tumors with LOH or that were noninformative, the efficiency for detecting BRCA1 dysfunction improved to 45 (37.2%) of 121 tumors. Therefore, LOH/noninformative was a strong predictor of mutation status (Fisher's exact test, P<.001). However, this subset of tumors did not include those with BRCA1 missense mutations (estimated at six [2.7%] of 221 not detected by our method) or biallelic promoter methylation (estimated at six [2.7%] of 221). CONCLUSIONS: BRCA1 dysfunction in ovarian cancer is common and occurs via multiple mechanisms. The use of LOH, rather than a family history of ovarian cancer, as a first step in a screening strategy, followed by protein truncation testing, appears to increase the chance of identifying tumors with BRCA1 dysfunction.
UI - 11832208
AU - Venkitaraman AR
TI - Cancer susceptibility and the functions of BRCA1 and BRCA2.
SO - Cell 2002 Jan 25;108(2):171-82
AD - University of Cambridge, CRC Department of Oncology, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, United Kingdom. firstname.lastname@example.org
Inherited mutations in BRCA1 or BRCA2 predispose to breast, ovarian, and other cancers. Their ubiquitously expressed protein products are implicated in processes fundamental to all cells, including DNA repair and recombination, checkpoint control of cell cycle, and transcription. Here, I examine what is known about the biological functions of the BRCA proteins and ask how their disruption can induce susceptibility to specific types of cancer.
UI - 11857083
AU - Baldeyron C; Jacquemin E; Smith J; Jacquemont C; De Oliveira I; Gad S;
TI - Feunteun J; Stoppa-Lyonnet D; Papadopoulo D A single mutated BRCA1 allele leads to impaired fidelity of double strand break end-joining.
SO - Oncogene 2002 Feb 21;21(9):1401-10
AD - UMR 218 du CNRS, Institut Curie, Section de Recherche, Paris 75248, cedex05, France.
Heterozygosity for mutations in the BRCA1 gene in humans confers high risk for developing breast cancer, but a biochemical basis for this phenotype has not yet been determined. Evidence has accumulated implicating BRCA1, in the maintenance of genomic integrity and the protection of cells against DNA double strand breaks (DSB). Here we present evidence that human cells heterozygous for BRCA1 mutations exhibit impaired DNA end-joining, which is the major DSB repair pathway in mammalian somatic cells. Using an in vivo host cell end-joining assay, we observed that the fidelity of DNA end-joining is strongly reduced in three BRCA1(+/-) cell lines in comparison to two control cell lines. Moreover, cell-free BRCA1(+/-) extracts are unable to promote accurate DNA end-joining in an in vitro reaction. The steady-state level of the wild type BRCA1 protein was significantly lower than the 50% expected in BRCA1(+/-) cells and thus may underlie the observed end-joining defect. Together, these data strongly suggest that BRCA1 is necessary for faithful rejoining of broken DNA ends and that a single mutated BRCA1 allele is sufficient to impair this process. This defect will compromise genomic stability in BRCA1 germ-line mutation carriers, triggering the genetic changes necessary for the initiation of neoplastic transformation.
UI - 11709053
AU - Mullan PB; McWilliams S; Quinn J; Andrews H; Gilmore P; McCabe N;
TI - McKenna S; Harkin DP Uncovering BRCA1-regulated signalling pathways by microarray-based expression profiling.
SO - Biochem Soc Trans 2001 Nov;29(Pt 6):678-83
AD - Cancer Research Centre, Department of Oncology, Queen's University Belfast, University Floor, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, N. Ireland, UK.
The introduction of microarray technology to the scientific and medical communities has dramatically changed the way in which we now address basic biomedical questions. Expression profiling using microarrays facilitates an experimental approach where alterations in the transcript level of entire transcriptomes can be simultaneously assayed in response to defined stimuli. We have used microarray analysis to identify downstream transcriptional targets of the BRCA1 (Breast Cancer 1) tumour-suppressor gene as a means of defining its function. BRCA1 has been implicated in the predisposition to early onset breast and ovarian cancer and while its exact function remains to be defined, roles in DNA repair, cell-cycle control and transcriptional regulation have been implied. In the current study we have generated cell lines with tetracycline-regulated, inducible expression of BRCA1 as a tool to identify genes, which might represent important effectors of BRCA1 function. Oligonucleotide array-based expression profiling identified a number of genes that were upregulated at various times following inducible expression of BRCA1 including the DNA damage-responsive gene GADD45 (Growth Arrest after DNA Damage). Identified targets were confirmed by Northern blot analysis and their functional significance as BRCA1 targets examined.
UI - 11816590
AU - Wang J; Xu D; Kawde AN; Polsky R
TI - Metal nanoparticle-based electrochemical stripping potentiometric detection of DNA hybridization.
SO - Anal Chem 2001 Nov 15;73(22):5576-81
AD - Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces 88003, USA.
A new nanoparticle-based electrical detection of DNA hybridization, based on electrochemical stripping detection of the colloidal gold tag, is described. In this protocol, the hybridization of a target oligonucleotide to magnetic bead-linked oligonucleotide probes is followed by binding of the streptavidin-coated metal nanoparticles to the captured DNA, dissolution of the nanometer-sized gold tag, and potentiometric stripping measurements of the dissolved metal tag at single-use thick-film carbon electrodes. An advanced magnetic processing technique is used to isolate the DNA duplex and to provide low-volume mixing. The influence of relevant experimental variables, including the amounts of the gold nanoparticles and the magnetic beads, the duration of the hybridization and gold dissolution steps, and the parameters of the potentiometric stripping operation upon the hybridization signal, is examined and optimized. Transmission electron microscopy micrographs indicate that the hybridization event leads to the bridging of the gold nanoparticles to the magnetic beads. Further signal amplification, and lowering of the detection limits to the nanomolar and picomolar domains, are achieved by precipitating gold or silver, respectively, onto the colloidal gold label. The new electrochemical stripping metallogenomagnetic protocol couples the inherent signal amplification of stripping metal analysis with discrimination against nonhybridized DNA, the use of microliter sample volumes, and disposable transducers and, hence, offers great promise for decentralized genetic testing.
UI - 11786575
AU - Ben David Y; Chetrit A; Hirsh-Yechezkel G; Friedman E; Beck BD; Beller
TI - U; Ben-Baruch G; Fishman A; Levavi H; Lubin F; Menczer J; Piura B; Struewing JP; Modan B; National Israeli Study of Ovarian Cancer Effect of BRCA mutations on the length of survival in epithelial ovarian tumors.
SO - J Clin Oncol 2002 Jan 15;20(2):463-6
AD - Department of Gynecology, Haemek Medical Center, Afula.
PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v. 37.8 months; 3-year survival, 65.8% v. 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.
UI - 11786581
AU - Schwartz MD; Peshkin BN; Hughes C; Main D; Isaacs C; Lerman C
TI - Impact of BRCA1/BRCA2 mutation testing on psychologic distress in a clinic-based sample.
SO - J Clin Oncol 2002 Jan 15;20(2):514-20
AD - Department of Oncology, Georgetown University, and Lombardi Cancer Center, Washington, DC 20007, USA. email@example.com
PURPOSE: Despite the increasingly widespread availability of BRCA1 and BRCA2 genetic testing, little is known about the psychologic impact of such testing in the clinical setting. The objective of this study was to examine the long-term psychologic impact of receiving BRCA1/2 test results within a clinic-based testing program. PATIENTS AND METHODS: The participants were 279 high-risk women who underwent genetic counseling and testing for alterations in the BRCA1/2 genes. At baseline (before genetic testing) and at 6 months after the disclosure of mutation status, we measured perceived risk for breast and ovarian cancer, cancer-specific distress, and general distress. We examined the impact of the test result on each of these outcomes at the 6-month follow-up. Analyses were conducted separately for probands and their relatives who were unaffected with cancer. RESULTS: We found no effect of test result among affected probands. Among unaffected relatives, we found that participants who received definitive negative test results exhibited significant reductions in perceived risk and distress compared with participants who received positive test results. Importantly, relatives who received positive test results did not exhibit increased distress or perceived risk. CONCLUSION: These results suggest that clinic-based BRCA1/2 testing can lead to psychologic benefits for individuals who receive negative test results. At 6 months after disclosure, those who receive positive or uninformative test results do not exhibit increased psychologic distress or perceived risk.
UI - 11846806
AU - Hegardt C; Johannsson OT; Oredsson SM
TI - Rapid caspase-dependent cell death in cultured human breast cancer cells induced by the polyamine analogue N(1),N(11)-diethylnorspermine.
SO - Eur J Biochem 2002 Feb;269(3):1033-9
AD - Department of Animal Physiology, Lund University, Sweden. Cecilia.Hegardt@zoofys.lu.se
The spermine analogue N(1),N(11)-diethylnorspermine (DENSPM) efficiently depletes the cellular pools of putrescine, spermidine and spermine by down-regulating the activity of the polyamine biosynthetic enzymes and up-regulating the activity of the catabolic enzyme spermidine/ spermine N(1)-acetyltransferase (SSAT). In the breast cancer cell line L56Br-C1, treatment with 10 microm DENSPM induced SSAT activity 60 and 240-fold at 24 and 48 h after seeding, respectively, which resulted in polyamine depletion. Cell proliferation appeared to be totally inhibited and within 48 h of treatment, there was an extensive apoptotic response. Fifty percent of the cells were found in the sub-G(1) region, as determined by flow cytometry, and the presence of apoptotic nuclei was morphologically assessed by fluorescence microscopy. Caspase-3 and caspase-9 activities were significantly elevated 24 h after seeding. At 48 h after seeding, caspase-3 and caspase-9 activities were further elevated and at this time point a significant activation of caspase-8 was also found. The DENSPM-induced cell death was dependent on the activation of the caspases as it was inhibited by the general caspase inhibitor Z-Val-Ala-Asp fluoromethyl ketone. The results are discussed in the light of the L56Br-C1 cells containing mutated BRCA1 and p53, two genes involved in DNA repair.
UI - 11855879
AU - Leitao M; Boyd J
TI - Preoperative CA-125 levels in patients with hereditary compared to sporadic epithelial ovarian carcinoma.
SO - Gynecol Oncol 2002 Mar;84(3):413-5
AD - Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
OBJECTIVE: The aim of this study was to determine whether a significant difference in preoperative CA-125 levels exists between patients with BRCA-associated hereditary ovarian carcinoma and those with sporadic ovarian carcinoma and whether the CA-125 level predicts the probability of optimal cytoreductive surgery. METHODS: From a retrospective cohort of 189 consecutive ovarian cancer patients genotyped for BRCA mutation status, data on preoperative CA-125 levels were available for 49/88 (56%) hereditary cases and 43/101 (43%) sporadic cases. Data on the extent of surgical cytoreduction were obtained for all 92 patients with available CA-125 data. Comparison of preoperative CA-125 levels between hereditary and sporadic groups was assessed using the Kruskal-Wallis chi(2) test. Correlation of surgical cytoreduction with preoperative CA-125 level was assessed using Fisher's exact test. RESULTS: Mean preoperative CA-125 levels were not significantly different among BRCA1 (2289 U/ml), BRCA2 (2586 U/ml), and sporadic (3307 U/ml) cases (P = 0.5). For hereditary cases, optimal cytoreduction was achieved in 59% of patients with preoperative CA-125 levels of <500 U/ml and in 52% of patients with preoperative levels >500 U/ml. For sporadic cases, optimal cytoreduction was achieved in 62% of patients with CA-125 levels of <500 U/ml and in 20% of patients with levels >500 U/ml (P = 0.01). CONCLUSIONS: Preoperative CA-125 levels are not significantly different for patients with hereditary compared to sporadic ovarian carcinoma. The probability of optimal cytoreduction is independent of the preoperative CA-125 level for hereditary cases, but optimal cytoreduction is significantly less likely for sporadic cases with CA-125 levels of >500 U/ml.
UI - 11857748
AU - Llort G; Munoz CY; Tuser MP; Guillermo IB; Lluch JR; Bale AE; Franco MA
TI - Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain.
SO - Hum Mutat 2002 Mar;19(3):307
AD - Unidad de Consejo Genetico. Servicio de Prevencion y Control del Cancer, Instituto Catalonian National Cancer Institute, Barcelona, Spain.
BRCA1 and BRCA2 mutations underlie a substantial proportion of all hereditary breast cancer. The mutational spectrum in these genes is very broad, with hundreds of different BRCA mutations reported worldwide. However, high frequency founder mutations make up a substantial fraction of all mutations in some ethnic groups. We directly sequenced BRCA1 and BRCA2 in 35 Spanish breast/ovarian cancer families and found 13 mutations of which 3 had been reported previously in Spain. The ten novel mutations are: IVS5+1 G>A, 1491delA, Leu1086Ter, and Gln895Ter in BRCA1; Glu49Ter, 5373delGTAT, 5947delCTCT, 6672delTA, 8281insA, and Pro3039Leu (which also involves a splice site) in BRCA2. Our data, in combination with previous reports, indicate that 14 mutations have been seen recurrently in Spanish families. Analyzing these 14 mutations in 42 previously untested breast/ovarian cancer families revealed only two families testing positive, one for BRCA1 185delAG and one for BRCA2 9254delATCAT. While several mutations have been found recurrently in Spain, none appear to be high frequency founder mutations based on studies of breast and ovarian cancer families. Copyright 2002 Wiley-Liss, Inc.
UI - 11857749
AU - Khoo US; Chan KY; Cheung AN; Xue WC; Shen DH; Fung KY; Ngan HY; Choy KW;
TI - Pang CP; Poon CS; Poon AY; Ozcelik H Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: a founder mutation of BRCA1 identified in the Chinese population.
SO - Hum Mutat 2002 Mar;19(3):307-8
AD - Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Previous mutational analysis for BRCA gene mutations in sporadic ovarian cancer occurring in Chinese patients in Hong Kong identified six germline BRCA1 mutations and one germline BRCA2 mutation, six of which were novel (Khoo et al., 2000). Knowledge of BRCA gene mutations in the Chinese population is relatively scant. In this study, we focussed on whether any of these mutations could be recurrent in our Chinese population, making use of archival paraffin embedded tissue. A consecutive series of 214 ovarian cancer cases, half of Southern Chinese origin from Hong Kong whilst the other half of Northern Chinese origin from Beijing were used for the study. We identified one further novel mutation, 1081delG, in BRCA1. This was found to occur in two unrelated individuals with shared haplotype as revealed by allelotype analysis, thus demonstrating founder effect. Two other recurrent mutations were also identified, the 2371-2372delTG mutation in BRCA1 and the 3337C>T mutation in BRCA2 recurring in two and three unrelated individuals respectively, giving an overall prevalence 4.7% of recurrent BRCA mutations in ovarian cancer in the Southern Chinese population. Most importantly, all our recurrent mutation carriers were identified from Southern Chinese patients from Hong Kong whilst such mutations were absent in samples from the Northern Chinese. Our findings indicate possible heterogeneity in the BRCA genotype between Northern and Southern Chinese. The identification of a founder mutation and two recurrent mutations moreover, has important implications towards screening strategies for breast and ovarian cancer among Chinese of southern ancestral origin who are now dispersed throughout the world. Copyright 2002 Wiley-Liss, Inc.
UI - 11715007
AU - Kauff ND; Scheuer L; Robson ME; Glogowski E; Kelly B; Barakat R; Heerdt
TI - A; Borgen PI; Davis JG; Offit K Insurance reimbursement for risk-reducing mastectomy and oophorectomy in women with BRCA1 or BRCA2 mutations.
SO - Genet Med 2001 Nov-Dec;3(6):422-5
AD - Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
PURPOSE: Risk-reducing surgery is an important option for women with BRCA1 and BRCA2 mutations. There are reports in the literature that insurance reimbursement for these procedures varies greatly. Because health insurance coverage significantly affects medical decision-making, current information regarding reimbursement practices of third-party payers is needed. METHODS: Retrospective study of hospital billing records of 38 women with documented BRCA1 or BRCA2 mutations who underwent either a risk-reducing mastectomy or a risk-reducing oophorectomy between March 1, 1997, and July 30, 2000. RESULTS: Complete billing and reimbursement information was available for 35 women undergoing a total of 39 risk-reducing surgeries. A total of 38 of 39 (97%) risk-reducing surgeries were covered in full, less applicable coinsurance and deductibles. The rate of insurance reimbursement did not vary with type of insurance, personal history of cancer, or type of procedure. CONCLUSION: Insurance carriers reimbursed the vast majority of BRCA mutation carriers undergoing risk-reducing surgery.
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