National Cancer Institute®
Last Modified: June 1, 2002
UI - 12011131
AU - Grann VR; Jacobson JS; Thomason D; Hershman D; Heitjan DF; Neugut AI
TI - Effect of prevention strategies on survival and quality-adjusted survival of women with BRCA1/2 mutations: an updated decision analysis.
SO - J Clin Oncol 2002 May 15;20(10):2520-9
AD - Herbert Irving Comprehensive Cancer Center, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 W 168th Street, New York, NY 10032, USA.
PURPOSE: This study updates findings regarding the effects of prophylactic surgery, chemoprevention, and surveillance on the survival and quality-adjusted survival of women who test positive for BRCA1/2 mutations. MATERIALS AND METHODS: Markov modeling of outcomes was performed in a simulated cohort of 30-year-old women who tested positive for BRCA1/2 mutations. The model incorporated breast and ovarian cancer incidence rates from the literature and mortality rates from the Surveillance, Epidemiology, and End Results Program. Quality adjustment of survival estimates were obtained from a survey of women aged 33 to 50 years. Sensitivity analyses were performed of varied assumptions regarding timing and effects of preventive measures on cancer incidence and adverse effects. RESULTS: A 30-year-old woman could prolong her survival beyond that associated with surveillance alone by use of preventive measures: 1.8 years with tamoxifen, 2.6 years with prophylactic oophorectomy, 4.6 years with both tamoxifen and prophylactic oophorectomy, 3.5 years with prophylactic mastectomy, and 4.9 years with both surgeries. She could prolong her quality-adjusted survival by 2.8 years with tamoxifen, 4.4 years with prophylactic oophorectomy, 6.3 years with tamoxifen and oophorectomy, and 2.6 years with mastectomy, or with both surgeries. The benefits of all of these strategies would decrease if they were initiated at later ages. CONCLUSION: Women who test positive for BRCA1/2 mutations may derive greater survival and quality adjusted survival benefits than previously reported from chemoprevention, prophylactic surgery, or a combination. Observational studies and clinical trials are needed to verify the results of this analysis of the long-term benefits of preventive strategies among BRCA1/2-positive women.
UI - 12011224
AU - Hemminki A; Zinn KR; Liu B; Chaudhuri TR; Desmond RA; Rogers BE; Barnes
TI - MN; Alvarez RD; Curiel DT In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus.
SO - J Natl Cancer Inst 2002 May 15;94(10):741-9
AD - Division of Human Gene Therapy and Gene Therapy Center, Department of Medicine, University of Alabama at Birmingham, 35294-3300, USA. email@example.com
BACKGROUND: Adenovirus-based gene therapy is a promising approach to treat advanced cancers that are resistant to other treatments. However, many primary cells lack the requisite coxsackie-adenovirus receptor (CAR), limiting the in vivo efficacy of gene therapy. Recently, a modified adenovirus that is not dependent on CAR expression for infectivity was developed. We used noninvasive imaging to investigate the in vivo antitumor efficacy of gene therapy using this adenovirus in an animal model of ovarian cancer. METHODS: The adenoviral vectors RGDTKSSTR (CAR-independent) and AdTKSSTR (CAR-dependent) express herpes simplex virus thymidine kinase (TK) for molecular chemotherapy and the human somatostatin receptor subtype 2 (SSTR) for noninvasive nuclear imaging. Subcutaneous or peritoneal human xenograft ovarian cancers were established from highly aggressive SKOV3.ip1 cells in immune-deficient mice. Adenoviral constructs were infected intratumorally or intraperitoneally once a day for 3 days. Control mice received three injections, one per day, of Ad5Luc1, a CAR-dependent adenoviral vector that includes a luciferase marker gene. The somatostatin analogue (99m)Tc-P2045 was used for noninvasive in vivo imaging of RGDTKSSTR that was injected into subcutaneous tumors. For mice with peritoneal tumors, survival was compared among the different treatment groups using Kaplan-Meier analysis with the log-rank statistic. All statistical tests were two-sided. RESULTS: Tumor-associated RGDTKSSTR could be detected 15 days after introduction of the vector. In the subcutaneous model, tumors injected with RGDTKSSTR were statistically significantly smaller than those injected with AdTKSSTR (P<.001). In the intraperitoneal model, mice treated with RGDTKSSTR lived longer (survival at day 45 = 63.6%; 95% confidence interval [CI] = 35.2% to 92.0%) than those treated with AdTKSSTR (survival at day 45 = 0%) or Ad5Luc1 (survival at day 45 = 18.1%; 95% CI = 0.0% to 41.0%). DISCUSSION: RGDTKSSTR shows antitumor efficacy against ovarian cancer in vivo in animal models. The virus can be imaged noninvasively and may have the potential to be a useful agent for treating ovarian cancer.
UI - 11836210
AU - Nguyen DV; Rocke DM
TI - Tumor classification by partial least squares using microarray gene expression data.
SO - Bioinformatics 2002 Jan;18(1):39-50
AD - Center for Image Processing and Integrated Computing, University of California, Davis, CA 95616, USA. firstname.lastname@example.org
MOTIVATION: One important application of gene expression microarray data is classification of samples into categories, such as the type of tumor. The use of microarrays allows simultaneous monitoring of thousands of genes expressions per sample. This ability to measure gene expression en masse has resulted in data with the number of variables p(genes) far exceeding the number of samples N. Standard statistical methodologies in classification and prediction do not work well or even at all when N < p. Modification of existing statistical methodologies or development of new methodologies is needed for the analysis of microarray data. RESULTS: We propose a novel analysis procedure for classifying (predicting) human tumor samples based on microarray gene expressions. This procedure involves dimension reduction using Partial Least Squares (PLS) and classification using Logistic Discrimination (LD) and Quadratic Discriminant Analysis (QDA). We compare PLS to the well known dimension reduction method of Principal Components Analysis (PCA). Under many circumstances PLS proves superior; we illustrate a condition when PCA particularly fails to predict well relative to PLS. The proposed methods were applied to five different microarray data sets involving various human tumor samples: (1) normal versus ovarian tumor; (2) Acute Myeloid Leukemia (AML) versus Acute Lymphoblastic Leukemia (ALL); (3) Diffuse Large B-cell Lymphoma (DLBCLL) versus B-cell Chronic Lymphocytic Leukemia (BCLL); (4) normal versus colon tumor; and (5) Non-Small-Cell-Lung-Carcinoma (NSCLC) versus renal samples. Stability of classification results and methods were further assessed by re-randomization studies.
UI - 11972384
AU - Reedy M; Gallion H; Fowler JM; Kryscio R; Smith SA
TI - Contribution of BRCA1 and BRCA2 to familial ovarian cancer: a gynecologic oncology group study.
SO - Gynecol Oncol 2002 May;85(2):255-9
AD - Division of Gynecologic Oncology, University of Kentucky, Lexington, KY 40536, USA.
OBJECTIVES: The aim of the study was to determine the prevalence of BRCA1 and BRCA2 germline mutations among ovarian cancer patients ascertained to have a family history of ovarian cancer. METHODS: Ovarian cancer patients were eligible if they had a family history of cancer that met any one of the following criteria: (1) a first-degree relative with ovarian cancer; (2) a second-degree relative with ovarian cancer plus a first-degree relative with breast cancer (diagnosed younger than 50 years of age); or (3) a first- and a second-degree relative with breast cancer (diagnosed younger than 50 years of age). The entire coding sequence of BRCA1 and exon 11 of BRCA2 were screened for germline alterations by single-strand conformation polymorphism analysis. RESULTS: Of 26 eligible patients screened for mutations, 12 had deleterious alterations, 8 in BRCA1 and 4 in BRCA2. A correlation was noted between the presence of a BRCA1 mutation and the strength of family history of breast ovarian cancer, with the likelihood of a mutation increasing with the number of affected relatives (P = 0.0002). No association was detected between the location of mutations in BRCA1 and the ratio of ovarian cancer cases relative to breast cancer (P = 0.28). CONCLUSIONS: Mutations in BRCA1 or BRCA2 are present in about 50% of ovarian cancer patients with at least one first-degree relative with disease, and in 70% of patients with two or more relatives with ovarian cancer. (c) 2002 Elsevier Science (USA).
UI - 11972385
AU - Kim JS; Lee SH; Cho YS; Choi JJ; Kim YH; Lee JH
TI - Enhancement of the adenoviral sensitivity of human ovarian cancer cells by transient expression of coxsackievirus and adenovirus receptor (CAR).
SO - Gynecol Oncol 2002 May;85(2):260-5
AD - Clinical Research Center, Samsung Biomedical Research Institute, Seoul 135-710, Korea.
OBJECTIVE: The coxsackievirus and adenovirus receptor (CAR) is known to be a primary receptor for attachment during adenovirus infection of target cells and thus is closely related to adenoviral infection efficiency. To extend this notion to human ovarian cancer, we investigated the difference in expression levels of CAR in human ovarian cancer cell lines and whether their adenoviral sensitivities are enhanced by transient transfection of the CAR gene. METHODS: Adenoviral infection efficiency was examined by flow cytometry analysis, beta-galactosidase staining, and beta-galactosidase activity assay. Expression of the CAR-specific mRNA and protein was analyzed by reverse transcription polymerase chain reaction and flow cytometry, respectively. RESULTS: Expression of CAR in human ovarian cancer cell lines (SKOV3, 2774, PA-1, and OVCAR3) appeared to be correlated with their susceptibilities to adenovirus-mediated gene delivery. The 2774 and PA-1 cells expressing an easily detectable level of CAR on the cell surface showed a higher susceptibility to infection with both AdCMVGFP and AdRSVbetagal than SKOV3 and OVCAR3 cells, both of which had hardly detectable levels of CAR. Ectopic expression of the CAR gene by transient transfection of these ovarian cancer cells resulted in a dramatic increase in their adenoviral sensitivities. CONCLUSION: These data show that the expression of CAR is closely related to susceptibility to adenovirus infection in human ovarian cancer cells. These results indicate that the CAR gene can be a useful tool in boosting the efficiency of adenoviral vector-mediated gene therapy against human ovarian cancer. (c) 2002 Elsevier Science (USA).
UI - 12026741
AU - Burgess MM; d'Agincourt-Canning L
TI - Genetic testing for hereditary disease: attending to relational responsibility.
SO - J Clin Ethics 2001 Winter;12(4):361-72
AD - Centre for Applied Ethics, University of British Columbia, Vancouver, British Columbia. email@example.com
UI - 11962511
AU - Talarico T; Cullinane CM; Gray PJ; Webster LK; Deacon GB; Phillips DR
TI - Nuclear and mitochondrial distribution of organoamidoplatinum(II) lesions in cisplatin-sensitive and -resistant adenocarcinoma cells.
SO - Anticancer Drug Des 2001 Apr-Jun;16(2-3):135-41
AD - Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, Australia.
The DNA binding pattern of the organoamidoplatinum(II) compound 1a is of considerable interest because of its known activity against cisplatin-resistant cells. The activity of 1a appears to be due at least in part to a greater cellular uptake than cisplatin into cisplatin-resistant cells, but little is known of the DNA reactions of the organoamidoplatinum(II) compounds. In this study the level of DNA cross-linking and total DNA lesions formed by 1 a were measured by gene-specific Southern hybridization cross-linking assays and by quantitative PCR in cisplatin-sensitive (2008) and in cisplatin-resistant 2008/R human adenocarcinoma cell lines. The surprising result was that the major difference between cisplatin and 1a was that the number of interstrand cross-links induced by 1a were approximately 5-fold greater than that induced by cisplatin in the nuclear (but not mitochondrial) DNA of resistant cells, even though the total number of lesions were essentially the same in both sensitive and resistant cells. This result suggests that the extent of interstrand cross-linking is a critical determinant of the cellular response to 1a and that the enhanced uptake of 1a into resistant cells results in this elevated level of cross-linking, leading to good activity of 1a against cisplatin-resistant cells. It remains unclear as to why 1a exhibits such selective damage to nuclear DNA, and insight into the molecular aspects of this selectivity will provide new opportunities for the further development of new platinum-based agents with activity against cisplatin-resistant cells.
UI - 11979449
AU - Osorio A; de la Hoya M; Rodriguez-Lopez R; Martinez-Ramirez A; Cazorla
TI - A; Granizo JJ; Esteller M; Rivas C; Caldes T; Benitez J Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer.
SO - Int J Cancer 2002 May 10;99(2):305-9
AD - Department of Human Genetics, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain. firstname.lastname@example.org
The BRCA1 and BRCA2 genes are responsible for a high proportion of familial breast cancer; germline mutations in these genes confer a lifetime risk of about 70% for developing breast cancer. Most of the described deleterious mutations are small deletions or insertions that originate a truncated protein; however, in many cases, they are amino acid changes whose significance is unknown. In these cases, there are some tests that can analyze the meaning of these variants, but most remain unclassified. The BRCA genes are tumor suppressors and it is believed that complete loss of the wild-type allele is a common mechanism of inactivation in tumors from patients carrying a germline deleterious mutation in these genes; if this is true, loss of heterozygosity (LOH) analysis in the tumor sample could help to distinguish if a rare variant is either a deleterious mutation or a common polymorphism. In the present study, we performed LOH analysis at the BRCA loci in 47 tumors from patients who belonged to high-risk breast cancer families and were carriers of any type of alteration in these genes. Our results suggest that (i) loss of the wild-type allele is the most common mechanism of inactivation in tumors from patients who carry a deleterious mutation in any of the genes, (ii) this loss is not common when we analyze familial tumors not associated with mutations in BRCA and (iii) LOH can be used to clarify variants of unknown significance in the BRCA genes. Copyright 2002 Wiley-Liss, Inc.
UI - 12015763
AU - Yang DH; Smith ER; Cohen C; Wu H; Patriotis C; Godwin AK; Hamilton TC;
TI - Xu XX Molecular events associated with dysplastic morphologic transformation and initiation of ovarian tumorigenicity.
SO - Cancer 2002 May 1;94(9):2380-92
AD - Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
BACKGROUND: Disabled-2 (Dab2), a candidate tumor suppressor of ovarian carcinoma, frequently (around 80%) loses its expression in ovarian tumors. Expression of exogenous Dab2 in tumor cell lines negatively regulates growth and suppresses the downstream signal of the Ras/mitogen activated protein kinase mitogenic pathway. The inactivation of Dab2 is believed to be an early event in ovarian tumorigenicity. METHODS: The authors analyzed the correlation among expression of Dab2, presence of basement membrane (collagen IV and laminin), morphologic alteration of the surface epithelial cells, and expression of the mitotic index marker Mib-1 in 50 archived ovarian tumors by an immunohistochemical approach. The stainings of Dab2, Mib-1, collagen IV, and laminin in premalignant lesions bordering both normal and neoplastic ovarian surface epithelium from adjacent slides were analyzed in 50 ovarian tumors. RESULTS: In these 50 ovarian tumors, the percentage of Mib-1 positive tumor cells distributed in a wide range, from 1% to 75%, and there has no strong correlation with the expression of Dab2. However, in the premalignant regions bordering tumor and normal ovarian surface epithelium, the loss of Dab2 expression closely correlated with the dysplastic morphologic transition and Mib-1 expression of the ovarian surface epithelial cells. In 20 foci in 12 out of the 50 tumors, a transition from normal to neoplastic morphology within a contiguous epithelium was observed, and in all cases the morphologic change correlated with the loss of Dab2 staining. In addition, the collagen and laminin staining of the basement membrane were absent or weakened in pre-malignant epithelium prior to loss of Dab2 expression in all these 20 cases. Nevertheless, collagen IV and laminin were detectable in established adenomas on the same tumor slides. CONCLUSIONS: The loss of Dab2 is closely associated with the transition of ovarian surface epithelial cells to premalignant states and is likely involved in the initiation of ovarian tumorigenicity. Transient loss of collagen IV and laminin in the basement membrane of the premalignant epithelium and subsequent inactivation of Dab2 are common early events associated with tumorigenicity of the ovarian surface epithelium. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10497
UI - 11882011
AU - Liu Y; Ganesan TS
TI - Tumour suppressor genes in sporadic epithelial ovarian cancer.
SO - Reproduction 2002 Mar;123(3):341-53
AD - ICRF Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Ovarian cancer is the most frequent cause of death from gynaecological malignancies in the western world, and sporadic epithelial ovarian cancer is its most predominant form. The aetiology of sporadic ovarian cancer remains unknown. Genetic studies have enabled a better understanding of the evolution of tumour progression. A major focus of research has been to identify tumour suppressor genes implicated in sporadic ovarian cancer over the past decade. Several tumour suppressor genes have been identified by strategies such as positional cloning and differential expression display. Further research is warranted to understand fully their contribution to the pathogenesis of sporadic ovarian cancer.
UI - 11992549
AU - Kudoh K; Ichikawa Y; Yoshida S; Hirai M; Kikuchi Y; Nagata I; Miwa M;
TI - Uchida K Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer.
SO - Int J Cancer 2002 Jun 1;99(4):579-82
AD - Department of Obstetrics and Gynecology, Self Defense Force Sendai Hospital, Miyagi 983-8580, Japan. email@example.com
To define the involvement of p16/CDKN2 and p15/MTS2 tumor-suppressor genes for response to chemotherapy in primary epithelial ovarian cancer, we analyzed alterations of the gene in 45 patients who were treated with primary cytoreductive surgery followed by 6 courses of cis-diamminedichloroplatinum (II) (cisplatin)-based combination chemotherapy. Homozygous deletion of p16/CDKN2 and p15/MTS2 genes was found in 8 (18%) and 15 (33%) cases, respectively. Response to the chemotherapy was confirmed by finding at second surgery after the chemotherapy in 26 patients, resulting in 17 responders and 9 nonresponders. The abundance of gene deletion in nonresponders (56%) was significantly higher (p = 0.0463) when compared to that in responders (18%). Moreover, the deletion of genes was a significant poor prognostic factor (p = 0.0441) in advanced ovarian cancer. These results suggest that deletion of p16/CDKN2 and/or p15/MTS2 is a potential indicator for poor chemotherapy response and adverse prognosis in ovarian cancer patients. Copyright 2002 Wiley-Liss, Inc.
UI - 11161856
AU - Paley PJ; Swisher EM; Garcia RL; Agoff SN; Greer BE; Peters KL; Goff BA
TI - Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis.
SO - Gynecol Oncol 2001 Feb;80(2):176-80
AD - Department of OB/GYN, Division of Gynecologic Oncology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
OBJECTIVE: BRCA-1 and BRCA-2 germline mutations increase the risk of ovarian and breast cancer. Primary cancer of the fallopian tube is rare; however, recent evidence suggests that patients harboring a germline mutation conferring an increased risk of ovarian cancer may be at risk for fallopian tube cancer as well. We discuss the finding of occult fallopian tube cancer diagnosed at surgical prophylaxis in women harboring BRCA-1 mutations. METHODS/RESULTS: Two patients undergoing surgical prophylaxis to address an increase in ovarian cancer risk were discovered to harbor occult primary fallopian tube carcinoma on final pathology review. Mutational analysis confirmed the presence of a deleterious mutation in BRCA-1 in both patients. CONCLUSION: Currently, consensus opinions regarding ovarian cancer surgical prophylaxis in gene mutation carriers do not include hysterectomy as part of the preventative procedure. This report as well as a growing number of cases of fallopian tube cancer reported in known BRCA-1 and BRCA-2 mutation carriers has important implications for recommendations regarding surgical prophylaxis in these women.
UI - 11454891
AU - Hortobagyi GN; Ueno NT; Xia W; Zhang S; Wolf JK; Putnam JB; Weiden PL;
TI - Willey JS; Carey M; Branham DL; Payne JY; Tucker SD; Bartholomeusz C; Kilbourn RG; De Jager RL; Sneige N; Katz RL; Anklesaria P; Ibrahim NK; Murray JL; Theriault RL; Valero V; Gershenson DM; Bevers MW; Huang L; Lopez-Berestein G; Hung MC Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial.
SO - J Clin Oncol 2001 Jul 15;19(14):3422-33
AD - Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. firstname.lastname@example.org
PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial. PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12). RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites. CONCLUSION: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.
UI - 12039933
AU - Berry DA; Iversen ES Jr; Gudbjartsson DF; Hiller EH; Garber JE; Peshkin
TI - BN; Lerman C; Watson P; Lynch HT; Hilsenbeck SG; Rubinstein WS; Hughes KS; Parmigiani G BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
SO - J Clin Oncol 2002 Jun 1;20(11):2701-12
AD - Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA. email@example.com
PURPOSE: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. PATIENTS AND METHODS: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. RESULTS: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. CONCLUSION: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.
UI - 11975680
AU - Zhang GL; Xu KL
TI - Loss of heterozygosity at chromosome 3p in epithelial ovarian cancer in China.
SO - Int J Gynecol Cancer 2002 Mar-Apr;12(2):198-201
AD - Department of Gynecological Oncology, Shanghai Cancer Hospital, Fu Da University, Shanghai, China.
The aim of this investigation was to determine the relationship between 3p loss of heterozygosity (LOH) and the pathogenesis of ovarian cancer. Fifty cases of epithelial ovarian tumor, including 40 cases with malignant tumors and 10 cases with benign tumors, were examined by polymerase chain reaction (PCR) with D3s1228 and D3s1038 microsatellite polymorphism markers at 3p. Thirty-two of the 40 cases (80%) with ovarian cancer showed LOH at 3p14 or 3p25, but only 1 of 10 cases (10.0%) with benign ovarian tumor showed 3p LOH. Among them, 24 cases (60.0%) had LOH at 3p14 and 16 cases (40.0%) at 3p25, as well as 8 cases (20.0%) with codeletion on both 3p14 and 3p25. According to FIGO staging, the frequency of LOH at 3p in ovarian cancer patients with stage IIIa or IIIb was higher than that in patients with stage I or II (P < 0.05), but there was no relationship between 3p LOH and the pathologic types in epithelial ovarian cancer (P > 0.05). Since 3p LOH commonly occurs in epithelial ovarian cancer and LOH at 3p14 and 3p25 correlates to the staging of ovarian cancer, it is suggested that there are some candidate ovarian TSGs harbored in the 3p region and that the detection of 3p LOHs may be used as a genetic marker for monitoring the development of ovarian cancer.
UI - 11894135
AU - Sylvain V; Lafarge S; Bignon YJ
TI - Dominant-negative activity of a Brca1 truncation mutant: effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse ovarian cancer cell line.
SO - Int J Oncol 2002 Apr;20(4):845-53
AD - Laboratoire d'Oncologie Moleculaire, Centre Jean Perrin, BP 392, 63 011 Clermont-Ferrand Cedex 1, France.
In order to generate an in vitro mouse model for the study of human ovarian cancers, we compared the effects of a truncated Brca1 mutant expression on cellular phenotype with those of a full-length sense and antisense Brca1 expression in the ID-8 mouse epithelial ovarian cancer cell line. The examined cellular processes include proliferation, tumorigenicity in syngeneic mice in vivo and sensitivity/resistance to several cytotoxic drugs. We found that the expression of a spontaneous truncated Brca1 mutant in ID-8 cells which contain two endogenous wild-type Brca1 alleles led to a dominant-negative effect of Brca1, demonstrated by an increase in tumorigenicity in vivo and in chemosensitivity. Expression of a truncated Brca1 mutant in a mouse epithelial ovarian cancer cell line could thus provide a powerful in vitro model for the study of human BRCA1-related ovarian tumorigenesis.
UI - 12048272
AU - Euhus DM; Smith KC; Robinson L; Stucky A; Olopade OI; Cummings S; Garber
TI - JE; Chittenden A; Mills GB; Rieger P; Esserman L; Crawford B; Hughes KS; Roche CA; Ganz PA; Seldon J; Fabian CJ; Klemp J; Tomlinson G Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO.
SO - J Natl Cancer Inst 2002 Jun 5;94(11):844-51
AD - The University of Texas Southwestern Medical Center at Dallas, 75390-9155, USA. david.euhus@UTSouthwestern.edu
BACKGROUND: Because BRCA gene mutation testing is costly, occasionally uninformative, and frequently associated with ethical and legal issues, careful patient selection is required prior to testing. Estimation of BRCA gene mutation probability is an important component of pretest counseling, but the accuracy of these estimates is currently unknown. We measured the performance of eight cancer risk counselors and of a computer model, BRCAPRO, at identifying families likely to carry a BRCA gene mutation. METHODS: Eight cancer risk counselors and the computer model BRCAPRO estimated BRCA gene mutation probabilities for 148 pedigrees selected from an initial sample of 272 pedigrees. The final sample was limited to pedigrees with a proband affected by breast or ovarian cancer and BRCA1 and BRCA2 gene sequencing results unequivocally reported as negative or positive for a deleterious mutation. Sensitivity, specificity, negative predictive value, positive predictive value, and areas under receiver operator characteristics (ROC) curves were calculated for each risk counselor and for BRCAPRO. All statistical tests were two sided. RESULTS: Using a greater-than-10% BRCA gene mutation probability threshold, the median sensitivity for identifying mutation carriers was 94% (range = 81% to 98%) for the eight risk counselors and 92% (range = 91% to 92%) for BRCAPRO. Median specificity at this threshold was 16% (range = 6% to 34%) for the risk counselors and 32% (range = 30% to 34%) for BRCAPRO (P =.04). Median area under the ROC curves was 0.671 for the risk counselors (range = 0.620 to 0.717) and 0.712 (range = 0.706 to 0.720) for BRCAPRO (P =.04). There was a slight, but not statistically significant, improvement in all counselor performance measures when BRCAPRO-assigned gene mutation probability information was included with the pedigrees. CONCLUSIONS: Sensitivity for identifying BRCA gene mutation carriers is similar for experienced risk counselors and the computer model BRCAPRO. Because the computer model consistently demonstrated superior specificity, overall discrimination between BRCA gene mutation carriers and BRCA gene mutation noncarriers was slightly better for BRCAPRO.
UI - 12014634
AU - Jin X; Burke W; Rothman K; Lin J
TI - Resistance to p53-mediated growth suppression in human ovarian cancer cells retain endogenous wild-type p53.
SO - Anticancer Res 2002 Mar-Apr;22(2A):659-64
AD - Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0936, USA.
Cancer cells containing mutated p53 are sensitive to the re-introduction of the wild-type (wt) p53. We sought to determine whether ovarian cancer cells that retain wt p53 are sensitive to the re-introduction of wt p53. Our results demonstrated that A2780 and PA-1 cells, which retain wt p53, are more resistant to apoptosis and growth suppression induced by exogenous expression of wt p53 than SKOV-3 and Caov-3 cells that contain mutated p53. All cell lines, except PA-1, showed induction of the p53-targeted genes. Further, inhibitors of p53-dependent apoptosis, mdm2 and Bcl-xL were not overexpressed in A2780 and PA-1 cells. These results suggest that one major defect in PA-1 cells is due to abrogation of induction of the p53-targets which is independent of mdm2 and Bcl-xL. Although A2780 cells showed induction of the p53-targeted genes, the cleavage of caspase-9 was undetectable. Therefore, p53-dependent apoptosis may be blocked upstream or at the caspase-9 level in A2780 cells.
UI - 12014652
AU - Kim NK; An HJ; Kim HJ; Sohn TJ; Roy R; Oh D; Ahn JY; Hwang TS; Cha KY
TI - Altered expression of the DNA repair protein, N-methylpurine-DNA glycosylase (MPG) in human gonads.
SO - Anticancer Res 2002 Mar-Apr;22(2A):793-8
AD - Department of Biochemistry and Institute for Clinical Research, College of Medicine, Pochon CHA University, Sungnam, Korea. firstname.lastname@example.org
BACKGROUND: The multifunctional mammalian MPG is responsible for a damaged DNA base in the nucleus. The DNA repair enzyme is transported from the cytoplasm to nucleus to repair the DNA base when it is damaged. If the enzyme does not work properly, the damaged DNA may lead to carcinogenesis, cell death, aging or infertility. MATERIALS AND METHODS: This study was performed to determine mRNA expression and intracellular localization of the DNA repair protein, N-methylpurine-DNA glycosylase (MPG), in human ovary and testicular tissues, particularly in epithelial ovarian tumor and spermatogenic (maturation) arrest infertile patients, by RT-PCR and immunohistochemical staining using human MPG monoclonal antibody. RESULTS: MPG mRNA expression in epithelial ovarian tumor and spermatogenic arrest testis tissues was slightly higher than in normal ovarian and testicular tissues, respectively. The present study demonstrated new and unexpected patterns of cellular and subcellular localization of this enzyme. In a normal ovary, immunostaining for MPG was observed in the nucleus of oocyte, granulosa and stromal cells. MPG was stained mostly in the nucleus and faintly-stained in the cytoplasm of normal coelomic epithelium as well as in benign epithelial ovarian tumors. However, the MPG expression of the nucleus in malignant epithelial tumors, both serous and mucinous type, disappeared. The spermatocyte and Leydig cells in normal testis were immunostained only in the cytoplasm. The spermatocyte and Leydig cells in spermatogenic arrest testis tissues showed up both in the nucleus and cytoplasm. The subcellular localization of MPG in the tissues tested was heterogeneous, while the altered MPG expression was found in ovarian tumor and spermatogenic arrest testis. CONCLUSION: These results suggest MPG's role in human gonadal tissues and raise the possibility that the altered mRNA level and intracellular localization could be associated with ovarian tumorigenesis and male infertility.
UI - 12014680
AU - Arzimanoglou II; Hansen LL; Chong D; Li Z; Psaroudi MC; Dimitrakakis C;
TI - Jacovina AT; Shevchuk M; Reid L; Hajjar KA; Vassilaros S; Michalas S; Gilbert F; Chervenak FA; Barber HR Frequent LOH at hMLH1, a highly variable SNP in hMSH3, and negligible coding instability in ovarian cancer.
SO - Anticancer Res 2002 Mar-Apr;22(2A):969-75
AD - Department of Obstetrics-Gynecology, Weill Medical College of Cornell University, New York, NY 10021, USA. Arziman@lycosmail.com
BACKGROUND: Molecular alterations such as DNA microsatellite instability (MSI/RER), single nucleotide polymorphism (SNP) and loss of heterozygosity (LOH) can occur throughout the genome and be associated with different types of cancer. In the present study, we aimed at detecting molecular alterations within the mismatch DNA repair genes in ovarian cancer (OC), using a sensitive, accurate and reliable protocol we have developed. MATERIALS AND METHODS: A combination of high-resolution GeneScan software analysis and automated DNA cycle sequencing was used. RESULTS: Negligible coding MSI was observed in selected sequences of mismatch DNA repair genes in our series of sixty-two ovarian tumors and matched blood DNAs. Unlike MSI, loss of one hMLH1 allele was scored in almost half (47%) of the informative cases. In addition, an SNP in hMSH3/intron 5 was found to be highly variable in OC patients. CONCLUSION: 1) Coding DNA instability is likely to be a very rare event in OC and, therefore, may not significantly contribute to the development of OC, and 2) the high frequency of LOH at hMLH1 observed in our ovarian tumors suggests that further investigation is needed to determine if such a trend exists in other mismatch DNA repair and/or critical genes.
UI - 11968083
AU - Oliveira C; Bordin MC; Grehan N; Huntsman D; Suriano G; Machado JC;
TI - Kiviluoto T; Aaltonen L; Jackson CE; Seruca R; Caldas C Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred.
SO - Hum Mutat 2002 May;19(5):510-7
AD - Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Addenbrooke's Hospital, Cambridge, UK.
The International Gastric Cancer Linkage Consortium (IGCLC) predicted that up to 25% of families fulfilling the criteria for hereditary diffuse gastric cancer (HDGC) would harbor CDH1 germline mutations. This was based on observations from the low number of diffuse gastric cancer families described at the time, and its validation would require analysis of larger numbers. Here we report the results of germline CDH1 mutation screening in 39 kindred with familial aggregation of gastric cancer, a subset of which fulfills the criteria defined by the IGCLC for HDGC. CDH1 germline mutations were detected in four of 11 (36.4%) HDGC families. No mutations were identified in 63.6% of HDGC families or in kindred with familial aggregation of gastric cancer not fulfilling criteria for HDGC. These results add support to the evidence that only HDGC families harbor germline mutations in CDH1 and that genes other than CDH1 remain to be identified. Copyright 2002 Wiley-Liss, Inc.
UI - 12052256
AU - Ingvarsson S; Sigbjornsdottir BI; Huiping C; Hafsteinsdottir SH;
TI - Ragnarsson G; Barkardottir RB; Arason A; Egilsson V; Bergthorsson JT Mutation analysis of the CHK2 gene in breast carcinoma and other cancers.
SO - Breast Cancer Res 2002;4(3):R4
AD - Institute for Experimental Pathology, University of Iceland, Reykjavik, Iceland. email@example.com
BACKGROUND: Mutations in the CHK2 gene at chromosome 22q12.1 have been reported in families with Li-Fraumeni syndrome. Chk2 is an effector kinase that is activated in response to DNA damage and is involved in cell-cycle pathways and p53 pathways. METHODS: We screened 139 breast tumors for loss of heterozygosity at chromosome 22q, using seven microsatellite markers, and screened 119 breast tumors with single-strand conformation polymorphism and DNA sequencing for mutations in the CHK2 gene. RESULTS: Seventy-four of 139 sporadic breast tumors (53%) show loss of heterozygosity with at least one marker. These samples and 45 tumors from individuals carrying the BRCA2 999del5 mutation were screened for mutations in the CHK2 gene. In addition to putative polymorphic regions in short mononucleotide repeats in a non-coding exon and intron 2, a germ line variant (T59K) in the first coding exon was detected. On screening 1172 cancer patients for the T59K sequence variant, it was detected in a total of four breast-cancer patients, two colon-cancer patients, one stomach-cancer patient and one ovary-cancer patient, but not in 452 healthy individuals. A tumor-specific 5' splice site mutation at site +3 in intron 8 (TTgt [a --> c]atg) was also detected. CONCLUSION: We conclude that somatic CHK2 mutations are rare in breast cancer, but our results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors. Furthermore, our results suggest that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth.
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