National Cancer Institute®
Last Modified: February 1, 2002
UI - 11745677
AU - Piek JM; van Diest PJ; Zweemer RP; Jansen JW; Poort-Keesom RJ; Menko FH;
TI - Gille JJ; Jongsma AP; Pals G; Kenemans P; Verheijen RH Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer.
SO - J Pathol 2001 Nov;195(4):451-6
AD - Department of Obstetrics and Gynaecology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
The aim of this study was to investigate the occurrence of (pre)neoplastic lesions in overtly normal Fallopian tubes from women predisposed to developing ovarian carcinoma. The presence of (pre)neoplastic lesions was scored in histological specimens from 12 women with a genetically determined predisposition for ovarian cancer, of whom seven tested positive for a germline BRCA1 mutation. A control group included 13 women. Immunohistochemistry was used to determine the expression of p21, p27, p53, cyclin A, cyclin D1, bcl-2, Ki67, HER-2/neu, and the oestrogen and progesterone receptors. Loss of heterozygosity (LOH) analysis on the BRCA1 locus was also assessed on dysplastic tissue by PCR studies. Of the 12 women with a predisposition for ovarian cancer, six showed dysplasia, including one case of severe dysplasia. Five harboured hyperplastic lesions and in one woman no histological aberrations were found in the Fallopian tube. No hyperplastic, dysplastic or neoplastic lesions were detected in the Fallopian tubes of control subjects. In the cases studied, morphologically normal tubal epithelium contained a higher proportion of Ki67-expressing cells (p=0.005) and lower fractions of cells expressing p21 (p<0.0001) and p27 (p=0.006) than in the control group. Even higher fractions of proliferating cells were found in dysplastic areas (p=0.07) and accumulation of p53 was observed in the severely dysplastic lesion. Expression patterns of other proteins studied, including the hormone receptors, were similar in cases and controls. One subject, a germline BRCA1 mutation carrier, showed loss of the wild-type BRCA1 allele in the severely dysplastic lesion. In conclusion, the Fallopian tubes of women predisposed to developing ovarian cancer frequently harbour dysplastic changes, accompanied by changes in cell-cycle and apoptosis-related proteins, indicating an increased risk of developing tubal cancer. Copyright 2001 John Wiley & Sons, Ltd.
UI - 11701630
AU - Slatkin M; Rannala B
TI - Estimating allele age.
SO - Annu Rev Genomics Hum Genet 2000;1():225-49
AD - Department of Integrative Biology, University of California, Berkeley, California 94720-3140, USA. email@example.com
The age of an allele can be estimated both from genetic variation among different copies (intra-allelic variation) and from its frequency. Estimates based on intra-allelic variation follow from the exponential decay of linkage disequilibrium because of recombination and mutation. The confidence interval depends both on the uncertainty in recombination and mutation rates and on randomness of the genealogy of chromosomes that carry the allele (the intra-allelic genealogy). Several approximate methods to account for variation in the intra-allelic genealogy have been derived. Allele frequency alone also provides an estimate of age. Estimates based on frequency and on intra-allelic variability can be combined to provide a more accurate estimate or can be contrasted to show that an allele has been subject to natural selection. These methods have been applied to numerous cases, including alleles associated with cystic fibrosis, idiopathic torsion dystonia, and resistance to infection by HIV. We emphasize that estimates of allele age depend on assumptions about demographic history and natural selection.
UI - 11782371
AU - Fan S; Ma YX; Wang C; Yuan RQ; Meng Q; Wang JA; Erdos M; Goldberg ID;
TI - Webb P; Kushner PJ; Pestell RG; Rosen EM p300 Modulates the BRCA1 inhibition of estrogen receptor activity.
SO - Cancer Res 2002 Jan 1;62(1):141-51
AD - Department of Radiation Oncology, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
We previously reported that expression of the breast cancer susceptibility gene BRCA1 strongly inhibits the transcriptional activity of the estrogen receptor (ER-alpha) in human breast and prostate cancer cell lines but only weakly inhibits ER-alpha activity in cervical cancer cells (S. Fan et al., Science (Wash. DC), 284: 1354-1356, 1999). We now report that the ability of BRCA1 to repress ER-alpha activity correlates with its ability to induce down-regulation of the cellular levels of the transcriptional coactivator p300 in breast and prostate, but not in cervical cancer cells. On the other hand, BRCA1 failed to alter the expression of the CREB binding protein (CBP), the structural and functional homologue of p300, in any of these cell types. Ectopic expression of either p300 or CBP "rescued" (i.e., reversed) the BRCA1 inhibition of ER-alpha activity, whereas two other nuclear receptor coactivators, the p300/CBP-associated factor (PCAF) and the glucocorticoid receptor-interacting protein-1 (GRIP1), failed to rescue the ER-alpha activity. The rescue function mapped to the cysteine-histidine rich domain CH3, a region of p300/CBP that we found to interact directly with the conserved COOH-terminal activation domain (AF-2) of ER-alpha. p300 and ER-alpha were also found to interact in vivo and to colocalize within the nucleus in breast cancer cells. These findings suggest that the cofactors p300 and CBP modulate the ability of the BRCA1 protein to inhibit ER-alpha signaling. They further suggest that the BRCA1 inhibition of ER-alpha activity may be attributable, at least in part, to the down-regulation of p300.
UI - 11810084
AU - Hebert-Blouin MN; Koufogianis V; Gillett P; Foulkes WD
TI - Fallopian tube cancer in a BRCA1 mutation carrier: rapid development and failure of screening.
SO - Am J Obstet Gynecol 2002 Jan;186(1):53-4
AD - Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
We report a case of fallopian tube cancer that developed in a woman with a germ-line BRCA1 mutation. The notable feature of this case was the extremely rapid growth of the cancer, which precluded early diagnosis. Preventive gynecologic surgery in BRCA1/2 mutation carriers should probably always include bilateral salpingectomy.
UI - 11526726
AU - Saponara R; Menditto A; Russo G; Musone R; Balbi GC; Balbi C
TI - [Review of the literature on BRCA 1 and BRCA 2]
SO - Minerva Ginecol 2001 Feb;53(1 Suppl 1):72-4
AD - Istituto di Clinica Ostetrica e Ginecologica, Seconda Universita degli Studi, Napoli.
UI - 11684443
AU - Pierce AJ; Stark JM; Araujo FD; Moynahan ME; Berwick M; Jasin M
TI - Double-strand breaks and tumorigenesis.
SO - Trends Cell Biol 2001 Nov;11(11):S52-9
AD - Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
The establishment of connections between biochemical defects and clinical disease is a major goal of modern molecular genetics. In this review, we examine the current literature that relates defects in the two major DNA double-strand-break repair pathways--homologous recombination and nonhomologous end-joining--with the development of human tumors. Although definitive proof has yet to be obtained, the current literature is highly suggestive of such a link.
UI - 11718812
AU - Vijg J; van Orsouw N
TI - Searching for genetic determinants of human aging and longevity: opportunities and challenges.
SO - Mech Ageing Dev 2002 Jan;123(2-3):195-205
AD - Sam and Ann Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, 15355 Lambda Drive, San Antonio, TX 78245, USA. firstname.lastname@example.org
One way of testing possible causal relationships between various functional pathways and aging and longevity processes is to comparatively analyze groups of elderly individuals with select phenotypes for sequence variation in all genes participating in these pathways. Such direct association analysis to identify 'candidate pathways' in aging and longevity is theoretically feasible, with the complete sequence of the human genome known and massive gene annotation projects underway. To find all possible sequence variation of a large number of genes in aging populations, efficient genotyping methods are needed. Here, we describe the use of one such method, two-dimensional gene scanning (TDGS), for screening populations of centenarians and controls for polymorphic variation in the large BRCA1 breast cancer susceptibility gene.
UI - 11795442
AU - Narod SA
TI - Hormonal prevention of hereditary breast cancer.
SO - Ann N Y Acad Sci 2001 Dec;952():36-43
AD - The Centre for Research on Women's Health, Women's College Hospital, University of Toronto, Ontario, Canada. email@example.com
Women who carry a mutation in the BRCA1 or BRCA2 genes face a lifetime risk of developing breast cancer that approaches 80%. Among women with predisposing BRCA mutations, the risk of breast cancer is influenced by environmental factors and by modifying genes. Through the study of cohorts of female BRCA1 and BRCA2 carriers, several modifying factors have been identified. The risk of breast cancer is increased by early parity and is decreased by breast feeding, by oophorectomy, and by cigarette smoking. Many of the stragegies for breast cancer prevention involve estrogen deprivation and it is important to consider the acute and long-term effects of induced menopause in young women at high risk for breast cancer. There are no data so far on whether hormonal replacement therapy is hazardous in carriers of BRCA mutations.
UI - 11807889
AU - Hughes C; Lerman C; Schwartz M; Peshkin BN; Wenzel L; Narod S; Corio C;
TI - Tercyak KP; Hanna D; Isaacs C; Main D All in the family: evaluation of the process and content of sisters' communication about BRCA1 and BRCA2 genetic test results.
SO - Am J Med Genet 2002 Jan 15;107(2):143-50
AD - Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. firstname.lastname@example.org
Despite the potential importance of family communication, little is known about the process and content of communicating BRCA1/2 test results to relatives. The objectives of this observational study were to describe the process and content of communicating BRCA1/2 test results to sisters, and to evaluate whether the proband's carrier status influenced communication outcomes. Participants were 43 women who were the first family member to have genetic testing (probands). Probands reported on communication outcomes for 81 sisters. Process and content variables were evaluated 1-month after receipt of BRCA1/2 test results using the Family Communication Questionnaire (FCQ). Overall, BRCA1/2 test results were communicated to 85% of sisters, and carriers communicated their results to significantly more sisters compared to uninformative (96% vs. 76%, FET = 0.02). The most important reason for communicating results was to provide genetic risk information; however, compared to uninformatives, carriers communicated their results to significantly more sisters to obtain emotional support (74%) and to get advice about medical decisions (42%) (FET = 0.001). Carriers also discussed the possibility of discrimination and recommendations for cancer management with significantly more sisters. Among sisters to whom BRCA1/2 test results were not communicated, the most important reason for not sharing test results was because of emotionally distant relationships. The results of this study suggest that probands are likely to quickly communicate their BRCA1/2 test results to relatives and that although needs for social support may motivate family communication, emotionally distant relationships may be a barrier to communication with relatives. Copyright 2001 Wiley-Liss, Inc.
UI - 11809701
AU - Xie W; Mertens JC; Reiss DJ; Rimm DL; Camp RL; Haffty BG; Reiss M
TI - Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study.
SO - Cancer Res 2002 Jan 15;62(2):497-505
AD - Division of Medical Oncology, Department of Internal Medicine, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
Based largely on studies of cell lines in vitro and of transgenic mouse models, disruptions of transforming growth factor (TGF) beta signaling are thought to contribute to the development and progression of human breast cancer. However, whether and how TGF-beta signaling becomes disrupted during human breast cancer development in vivo remains largely unknown. To address this question, we have compared the patterns of expression and activation of the postreceptor components of the TGF-beta signaling pathway, the so-called Smads, in human breast cancer cell lines with those in breast carcinoma specimens. None of the breast carcinoma cell lines were growth arrested by TGF-beta in vitro. Each of the tumor cell lines expressed normal levels of Smad2 and -3. Moreover, TGF-beta treatment induced phosphorylation of Smad2 (Smad2P) in each of these lines, except those that lacked TGF-beta type II receptors. Moreover, only one of the cell lines failed to express Smad4. Among 456 cases of human breast carcinoma assembled in tissue microarrays, the majority (92%) expressed Smad2, Smad2P, as well as Smad4, indicating their ability to proliferate within a microenvironment that contains bioactive TGF-beta. Thirty cases (6.6%) failed to express Smad2P, suggesting the loss of TGF-beta receptor signaling. Nine cases (2%) failed to express Smad4, and 3 of these also failed to express Smad2P. Thus, the phenotypes of breast tumors in vivo paralleled that of human breast cancer cell lines in terms of Smad2P and Smad4 expression. Loss of Smad signaling was not associated with any particular histological subtype, histological or nuclear grade, estrogen- or progesterone receptor expression, or HER2/neu expression. Loss of Smad4 was inversely correlated with the presence of axillary lymph node metastases. Most importantly, among patients with stage II breast cancer, lack of Smad2P expression in the tumor was strongly associated with shorter overall survival. Finally, analysis of a small cohort of hereditary breast cancers failed to reveal any association between BRCA1 or BRCA2 genotype and alterations in Smad signaling.
UI - 11567707
AU - Evans D; Lalloo F; Shenton A; Boggis C; Howell A
TI - Uptake of screening and prevention in women at very high risk of breast cancer.
SO - Lancet 2001 Sep 15;358(9285):889-90
Management of women at high lifetime risk of familial breast cancer is hampered because of limited data concerning the appropriateness of treatment options. Over the past 8 years women at very high (>40%) lifetime risk of breast cancer have had the option of entering two chemoprevention treatment trials, a magnetic resonance imaging (MRI) breast screening study, or a risk-reducing mastectomy (RRM) study. Only 10% of eligible women have entered one of the chemotherapy trials with a similar proportion opting for RRM (>50% in mutation carriers) compared with 60% opting for MRI screening. Future chemotherapy trials will have to be designed to address this poor recruitment.
UI - 11822793
AU - Cappelli M; Surh L; Humphreys L; Verma S; Logan D; Hunter A; Allanson J
TI - Measuring women's preferences for breast cancer treatments and BRCA1/BRCA2 testing.
SO - Qual Life Res 2001;10(7):595-607
AD - Children's Hospital of Eastern Ontario, Ottawa, Canada. email@example.com
In establishing decision models in the treatment and prevention of breast cancer, it is important to evaluate patients' preferences for such interventions. The objectives of the present study were: (i) to characterize women's preferences for breast cancer treatments and BRCA1/BRCA2 testing, using the rating scale and standard gamble techniques; and (ii) to identify factors associated with these quality of life indices. Data were collected from women with breast cancer (n = 60), high-risk relatives of women with breast cancer (n = 58), and women in the general population (n = 51). Regardless of group membership, participants favoured treatment and prevention options that involved minimal physical invasiveness. Women with breast cancer rated lumpectomy and radiation treatment more highly than high-risk relatives and women in the general population. Preferences did not differ according to participants' intentions to undergo BRCA testing. Age was the only demographic variable associated with health state preferences. These findings hold implications for the application of patient preferences to clinical decision making.
UI - 11795532
AU - Vijg J; Perls T; Franceschi C; van Orsouw NJ
TI - BRCA1 gene sequence variation in centenarians.
SO - Ann N Y Acad Sci 2001 Apr;928():85-96
AD - University of Texas Health Science Center, San Antonio 78245, USA. firstname.lastname@example.org
With the ample gene sequence information that has become available with the human genome project virtually completed, it has become possible to identify functional gene variants and their frequencies in elderly populations with different aging-related characteristics. Such a genetic epidemiological approach could lead to new insights with respect to the basic mechanisms of aging and longevity as well as the identification of new targets to prevent or retard some of the late-age adverse effects. Using our recently developed two-dimensional gene scanning (TDGS) technology platform we demonstrate the feasibility of this approach by screening two different populations of centenarians for polymorphic variation in the BRCA1 breast cancer susceptibility gene, one of the many genes involved in genome maintenance. The initial results obtained with this approach suggest differences in BRCA1 genotype frequencies between the centenarian populations and controls.
UI - 11669285
AU - Leung EH; Leung PC; Auersperg N
TI - Differentiation and growth potential of human ovarian surface epithelial cells expressing temperature-sensitive SV40 T antigen.
SO - In Vitro Cell Dev Biol Anim 2001 Sep;37(8):515-21
AD - Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
The epithelial ovarian carcinomas arise in the ovarian surface epithelium (OSE) which is the mesothelial covering of the ovary. Studies of human USE have been hampered by the small amounts and limited lifespan of this epithelium in culture. OSE cells expressing SV40 large T antigen (Tag) or the HPV genes E6 and E7 have increased growth potentials but lack some of the normal characteristics of OSE. In this study, we used conditional SV40 Tag expression to produce OSE cells with increased proliferative potentials but relatively normal phenotypes. Primary OSE cultures from three women, one of whom had a BRCA1 mutation, were infected with a temperature-sensitive Tag construct (tsTag), and from these, 28 monoclonal and four polyclonal lines were isolated. The effects of temperature changes were examined in two monoclonal and two polyclonal lines. At the permissive temperature (34 degrees C), these cell lines underwent 52-71 population doublings (PD) compared to 15-20 PD for normal OSE. Nuclear SV40-Tag and p53 expression, demonstrated by immunofluorescence, showed that tsTag was uniformly present and biologically active in all lines. At 34 degrees C, culture morphologies ranged from epithelial to mesenchymal. The mean percentage of cells expressing the epithelial differentiation marker, keratin. varied between lines from 20 to 97%. Collagen type III, a mesenchymal marker expressed by OSE in response to explantation into culture, was present in 24-43% of cells. At 39 degrees C, tsTag was inactivated by 2 d while nuclear p53 staining diminished to control levels over 2 wk. Over 3 d. the cells assumed more epithelial morphologies, keratin expression reached 85-100% in all lines and collagen expression increased significantly in two lines. The cultures with the BRCA1 mutation expressed the most keratin and the least collage n III at both temperatures. As indicated by beta-galactosidase staining at pH 6.0, changes leading to senescence were initiated at 39 degrees C by 6 h and were present in all cells after 24 h. However, the cells underwent 1-3 population doublings over up to 1 wk before growth arrest and widespread cell death, thus providing an experimental system where large numbers of OSE cells with different genetic backgrounds and growth potentials can be studied without the concurrent influence of Tag.
UI - 11812938
AU - Agoff SN; Mendelin JE; Grieco VS; Garcia RL
TI - Unexpected gynecologic neoplasms in patients with proven or suspected BRCA-1 or -2 mutations: implications for gross examination, cytology, and clinical follow-up.
SO - Am J Surg Pathol 2002 Feb;26(2):171-8
AD - Department of Cytology, Harborview Medical Center/University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195-6100, U.S.A. email@example.com
Identification of inheritable mutations associated with the development of malignancy has led to prophylactic surgeries to remove tissues at risk. We report seven unrelated patients with family histories of breast and/or ovarian cancer, five of whom underwent prophylactic salpingo-oophorectomy with hysterectomy. Four had proven BRCA-1 or -2 mutations. Malignant cells were found unexpectedly in the peritoneal washings of two patients, leading to the discovery of early-stage fallopian tube carcinoma. After changing the sampling technique at our institution, two more cases of unexpected fallopian tube carcinoma in situ were discovered. Another patient had a significant family history and underwent hysterectomy for uterine fibroids, leading to the discovery of fallopian tube carcinoma. Another patient with BRCA-1 mutation had unexpected widespread primary peritoneal papillary serous adenocarcinoma. The final patient had a borderline malignant clear cell adenofibroma. These cases underscore the importance of peritoneal cytology and thorough sampling in the management of patients undergoing hysterectomy with a family history of breast/ovarian cancer and/or known BRCA-1/BRCA-2 mutations. As prophylactic surgeries are becoming more common secondary to advances in molecular diagnostics, pathologists need to be aware that surgical specimens from these patients may require more rigorous examination to uncover early neoplastic changes.
The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.