Last Modified: November 1, 2001
Table of Contents
CancerMail from the National Cancer Institute
UI - 21198524
AU - Goodman MT; McDuffie K; Kolonel LN; Terada K; Donlon TA; Wilkens LR; Guo C; Le Marchand L
TI - Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism.
SO - Cancer Epidemiol Biomarkers Prev 2001 Mar;10(3):209-16
AD - Cancer Etiology Program, Cancer Research Center, University of Hawaii, Honolulu 96813, USA. firstname.lastname@example.org
Steroid hormones, such as estrogens, appear to be associated with ovarian carcinogenesis, but the precise biological mechanisms are unclear. Polymorphisms in genes that regulate the concentration of estrogens and their metabolites may contribute directly to the individual variation in ovarian cancer risk through a mechanism involving oxidative stress or indirectly by influencing ovarian cancer susceptibility associated with ovulation and reproduction. We conducted a population-based, case-control study of primary ovarian cancer between 1993 and 1999 in Hawaii to test several genetic and related hypotheses. A personal interview and blood specimen were obtained in the subjects' homes. In a sample of 129 epithelial ovarian cancer cases and 144 controls, we compared the frequencies of several polymorphisms in genes that regulate steroid hormone metabolism and catecholestrogen formation. Multivariate unconditional logistic regression was used to model the association of each genetic polymorphism separately after adjusting for age, ethnicity, and other covariates. The high-activity Val432 allele of the CYP1B1 gene, which may be linked to oxidative stress through elevated 4-hydroxylated catecholestrogen formation, was associated with an increased risk of ovarian cancer. The Val/Leu genotype for CYP1B1 was associated with an odds ratio of 1.8 (95% confidence interval, 1.0-3.3) and the Val/Val genotype with an odds ratio of 3.8 (95% confidence interval, 1.2-11.4) compared with the Leu/Leu genotype (P = 0.005). Tobacco smokers with at least one CYP1A1 (MspI) m2 allele, one CYP1B1 Val allele, one COMT Met allele, or two CYP1A2 A alleles were at significantly increased risk of ovarian cancer compared to never-smokers with CYP1A1 (MspI) ml/ml, CYP1B1 Leu/Leu, COMT Val/Val, or CYP1A2 A/A genotypes, respectively. We found a positive statistical interaction (P = 0.03) between tobacco smoking and the CYP1A1 (MspI) polymorphism on the risk of ovarian cancer. None of the other gene-environment (pregnancy, oral contraceptive pill use) or gene-gene interactions were statistically significant. Although not significant, there was a suggestion that the effect of the CYP1B1 Val allele was reduced substantially in the presence of the high-activity COMT Met allele. These findings suggest that the CYP1B1-Val allele and perhaps other genetic polymorphisms in combination with environmental or hormonal exposures are susceptibility factors for ovarian cancer.
UI - 21227879
AU - La Vecchia C
TI - Epidemiology of ovarian cancer: a summary review.
SO - Eur J Cancer Prev 2001 Apr;10(2):125-9
AD - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Ovarian cancer is among the five leading sites for cancer incidence and mortality in women from developed countries. Its incidence and mortality rates have, however, been declining over the last few decades following the introduction of oral contraceptives, which - together with parity - are the best recognized protective factor for the disease. Late menopause and irregular menstrual cycles may also reduce the risk, while the role of hormone replacement therapy in menopause and fertility treatments is still unclear. Cosmetic talc use and some aspect of diet (i.e. saturated fats, refined carbohydrates) have been associated with increased risk, in some--though not all--studies), while vegetable consumption appears to be inversely related to risk. These issues remain open to debate. Women with a family history of ovarian and breast cancer in first-degree relatives are also at increased risk, but family history accounts for only 4-5% of cases. Most ovarian cancers are therefore environmental in origin and consequently, at least in principle, avoidable.
UI - 21317174
AU - Moritani S; Moriya T; Kushima R; Sugihara H; Harada M; Hattori T
TI - Ovarian carcinoma recurring as carcinosarcoma.
SO - Pathol Int 2001 May;51(5):380-4
AD - Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga, Japan. email@example.com
Malignant mixed mesodermal tumor is a rare tumor of the ovary and its histogenesis is controversial. We report the case of an ovarian tumor that seemed to be a pure carcinoma and recurred as a carcinosarcoma, and suggest a possible histogenesis for this kind of tumor. The patient was a 62-year-old Japanese woman. The primary tumor was confined to the right ovary and was a histologically poorly differentiated endometrioid adenocarcinoma with focal squamous differentiation. The tumor recurred as peritoneal dissemination 9 months later showing a histological appearance of carcinosarcoma of heterologous type. The recurrent tumor also contained intermingled foci of similar histology as the primary tumor. The carcinomatous component of the recurrent tumor showed more obvious differentiation to adenocarcinoma with increased expression of epithelial markers compared to the primary tumor. Epithelial membrane antigen was positive also in a few cells of the sarcomatous component, which implies that this tumor had features of metaplastic carcinoma. The DNA ploidy pattern of the primary ovarian tumor was diploid, while an additional aneuploid subpopulation appeared in the recurrent tumor. These findings suggest the possible histogenesis of carcinosarcoma of the ovary as progression and clonal evolution of endometrioid adenocarcinoma.
UI - 21319025
AU - Parazzini F; Pelucchi C; Negri E; Franceschi S; Talamini R; Montella M; La Vecchia C
TI - Use of fertility drugs and risk of ovarian cancer.
SO - Hum Reprod 2001 Jul;16(7):1372-5
AD - Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62-20157 Milan, Italy. firstname.lastname@example.org
BACKGROUND: The potential association between fertility drugs and risk of ovarian cancer has been analysed using data from a case-control study conducted between January 1992 and September 1999 in four Italian areas. METHODS: Cases were 1031 women (median age 56, range 18-79 years) with incident, histologically confirmed epithelial ovarian cancer. Controls were 2411 women (median age 57, range 17-79 years) residing in the same geographical areas and admitted to the same network of hospitals for cases for a wide spectrum of acute, non neoplastic, non hormone-related conditions. RESULTS: A total of 15 cases and 26 controls reported use of fertility drugs. The corresponding odds ratio (OR) was 1.3 (95% confidence interval 0.7-2.5). The OR was 1.2 for women reporting last use <25 years before interview and 1.3 for >25 years. CONCLUSIONS: Considering calendar year at use, the OR was non-significantly above unity for women reporting fertility drug use after 1970. The OR was 0.6 among nulliparous women and 1.9 among parous ones.
UI - 21345309
AU - Kozlowski P; Krzyzosiak WJ
TI - Combined SSCP/duplex analysis by capillary electrophoresis for more efficient mutation detection.
SO - Nucleic Acids Res 2001 Jul 15;29(14):E71
AD - Laboratory of Cancer Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.
SSCP and heteroduplex analysis (HA) continue to be the most popular methods of mutation detection due to their simplicity, high sensitivity and low cost. The advantages of these methods are most clearly visible when large genes, such as BRCA1 and BRCA2, are scanned for scattered unknown mutations and/or when a large number of DNA samples is screened for specific mutations. Here we describe a novel combined SSCP/duplex analysis adapted to the modern capillary electrophoresis (CE) system, which takes advantage of multicolor labeling of DNA fragments and laser-induced fluorescence detection. In developing this method, we first established the optimum conditions for homoduplex and heteroduplex analysis by CE. These were determined based on comprehensive analysis of representative Tamra-500 markers and BRCA1 fragments at different concentrations of sieving polymer and temperatures in the presence or absence of glycerol. The intrinsic features of DNA duplex structures are discussed in detail to explain differences in the migration rates between various types of duplexes. When combined SSCP/duplex analysis was carried out in single conditions, those found to be optimal for analysis of duplexes, all 31 BRCA1 and BRCA2 mutations, polymorphisms and variants tested were detected. It is worth noting that the panel of analyzed sequence variants was enriched in base substitutions, which are usually more difficult to detect. The sensitivity of mutation detection in the SSCP portion alone was 90%, and that in the duplex portion was 81% in the single conditions of electrophoresis. As is also shown here, the proposed combined SSCP/duplex analysis by CE has the potential of being applied to the analysis of pooled genomic DNA samples, and to multiplex analysis of amplicons from different gene fragments. These modifications may further reduce the costs of analysis, making the method attractive for large scale application in SNP scanning and screening.
UI - 21385714
AU - Unoki M; Nakamura Y
TI - Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway.
SO - Oncogene 2001 Jul 27;20(33):4457-65
AD - Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). Expression of six of them (PINK1, EGR2, HCLS1, DUSP1, BPOZ, and NFIL3) was decreased in ovarian tumors compared with corresponding normal tissues. Colony-formation assays using plasmid clones designed to express each gene indicated that EGR2 and BPOZ were able to suppress growth of cancer cells significantly; in particular, cancer-cell lines stably expressing BPOZ grew more slowly than control cells containing mock vector. Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G(1)/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. Therefore both genes appear to be novel candidates as mediators of the PTEN growth-suppressive signaling pathway.
UI - 21395051
AU - Sachs L; Taube A; Tishelman C
TI - Risk in numbers--difficulties in the transformation of genetic knowledge from research to people--the case of hereditary cancer.
SO - Acta Oncol 2001;40(4):445-53
AD - Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
Difficulties in communicating diagnostic information are exacerbated when the 'diagnosis' is a 'genetic risk' for cancer. The risk estimation demanded in this situation differs from other types of probability estimations. Observations of participants in 45 consultation sessions between physicians and potential patients were conducted at a clinic for hereditary cancer to explore the communication of genetic information. Thirty-three sessions were audiotaped, transcribed verbatim and analyzed, along with notes from the other sessions. A dominant theme was found to be numerical discussion of risk. Further analysis resulted in the description of problems for practitioners in the process of translating scientific knowledge into clinical management. Problems in providing information include unclear aims of the consultation sessions, mixing various types of background information and probabilities, recognizing how low the predictive values are, and difficulties in communicating the relationship between probability and conclusions. Problems in communicating information about the genetic risk for cancer are of at least two types: dilemmas arising from uncertainties implicit in the nature of the information itself and difficulties in communicating information in a manner that those concerned can interpret. These issues need clarification, so that information with far-reaching consequences can be made as clear and comprehensible as possible for those involved.
UI - 21397936
AU - Liu VW; Shi HH; Cheung AN; Chiu PM; Leung TW; Nagley P; Wong LC; Ngan HY
TI - High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas.
SO - Cancer Res 2001 Aug 15;61(16):5998-6001
AD - Department of Obstetrics and Gynecology, University of Hong Kong, Queen Mary Hospital, Hong Kong.
To investigate the potential role of somatic mitochondrial DNA (mtDNA) mutations in tumorigenesis, the occurrence of mutations in mtDNA of ovarian carcinomas was studied. We sequenced the D-loop region of mtDNA of 15 primary ovarian carcinomas and their matched normal controls. Somatic mtDNA mutations were detected in 20% (3 of 15) tumor samples carrying single or multiple changes. Complete sequence analysis of the mtDNA genomes of another 10 pairs of primary ovarian carcinomas and control tissues revealed somatic mtDNA mutations in 60% (6 of 10) of tumor samples. Most of these mutations were homoplasmic, and most were T-->C or G-->A transitions, but one represented a differential length within a run of identical C residues. A region of mtDNA sequence including the 16S and 12S rRNA genes, the D-loop and the cytochrome b gene, may represent the zone of preferred mtDNA mutation in ovarian cancer. The high incidence of mtDNA mutations found in ovarian carcinomas and other human cancers suggests that genetic instability of mtDNA might play a significant role in tumorigenesis.
UI - 21411563
AU - Pribill I; Speiser P; Leary J; Leodolter S; Hacker NF; Friedlander ML; Birnbaum D; Zeillinger R; Krainer M
TI - High frequency of allelic imbalance at regions of chromosome arm 8p in ovarian carcinoma.
SO - Cancer Genet Cytogenet 2001 Aug;129(1):23-9
AD - Department of Medicine I, Clinical Division of Oncology, University Hospital, Molecular Oncology Group, Wahringergurtel 18-20, A-1090 Vienna, Austria.
Progressive genetic changes such as the inactivation of tumor suppressor genes (TSG) are thought to play an important role in the initiation and progression of ovarian cancer. Frequent nonrandom allelic imbalance (AI) at 8p11-p21 and 8p22-pter suggests the existence of TSGs that may be involved in the carcinogenesis of several human malignancies. We investigated 70 ovarian tumors with 11 highly polymorphic markers spanning 8p12-p21 and 8p22-pter to produce an AI map of 8p in epithelial ovarian cancer. Allelic imbalance was demonstrated in 54 tumors (77%), most frequently occurring at D8S136 (54%) and at D8S1992 (55%). Poorly differentiated and advanced stage cancers were more often affected by AI (G1+G2 vs. G3; 20% vs. 66%; stage I+II vs. III+IV, 36% vs. 54%, P<.001; Kruskal-Wallis test) than well differentiated and early stage tumors. There was no relationship between histological subtype and AI. Smallest regions of overlap (SRO) were delineated by analyzing 38 tumors with partial AI. This study provides compelling evidence for the involvement of TSGs on the short arm of chromosome 8, at 8p12-p21 and at 8p23 in the development and progression of epithelial ovarian cancer.
UI - 21319740
AU - Lodder L; Frets PG; Trijsburg RW; Meijers-Heijboer EJ; Klijn JG; Duivenvoorden HJ; Tibben A; Wagner A; van der Meer CA; van den Ouweland AM; Niermeijer MF
TI - Psychological impact of receiving a BRCA1/BRCA2 test result.
SO - Am J Med Genet 2001 Jan 1;98(1):15-24
AD - Department of Medical Psychology and Psychotherapy, Erasmus University Rotterdam/Netherlands Institute for Health Sciences.
Mutation analysis for autosomal dominant hereditary breast/ovarian cancer genes (BRCA1/BRCA2) became an important technique for women at risk of carrying these mutations. Healthy female mutation carriers have a high lifetime risk for breast and/or ovarian cancer and may opt for frequent breast and ovary surveillance or prophylactic surgery (mastectomy and/or oophorectomy). Psychological distress was assessed in 78 healthy women at risk of having inherited a BRCA1/BRCA2 mutation opting for genetic testing and 56 partners several weeks prior to ("pre-test") and after ("post-test") learning about their DNA test result. Twenty-five women were found to be mutation carriers, and 53 were non-mutation carriers. One goal of the study was to identify individuals at risk for high distress in the weeks following disclosure of the test result. Interview transcripts were used to give a fuller picture of pre- and post-test distress. High post-test anxiety was reported by 20% of the mutation carrier women and by 35% of their partners. Eleven percent of women without the mutation and 13% of their partners reported high post-test anxiety levels. High post-test anxiety in women was significantly related to 1) a high level of pre-test anxiety and 2) being a mutation carrier. Women without a mutation who had a sister identified as a mutation carrier recently had higher post-test levels of depression than the other non-mutation carriers. It is suggested to consider seriously the need for psychological support in mutation carriers who had been anxious at pre-test already. For most non-mutation carriers, psychological follow-up might be of lesser importance, but those having a sister receiving an unfavorable test result should be informed about the possibility that they might not feel relief.
UI - 21345032
AU - Piura B; Rabinovich A; Yanai-Inbar I
TI - Three primary malignancies related to BRCA mutation successively occurring in a BRCA1 185delAG mutation carrier.
SO - Eur J Obstet Gynecol Reprod Biol 2001 Aug;97(2):241-4
AD - Unit of Gynecologic Oncology, Department of Obstetrics and Gynecology, Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 151, 84101, Beer-Sheva, Israel. email@example.com
The 185delAG and 5382insC mutations in the BRCA1 gene and the 6174delT mutation in the BRCA2 gene (the Ashkenazi mutations) have been found to be significantly more common among Jews of eastern European ancestry (1 in 40, 2.5%) in comparison to the general population (1 in 800 to 1 in 300, 0.12-0.33%). Carriers of these mutations, especially the BRCA1 185delAG mutation, have a significantly increased lifetime risk of breast and ovarian carcinoma and other carcinomas as compared to non-carriers. A case of three primary malignancies related to the BRCA1 185delAG mutation successively occurring in a carrier of this mutation, is described. The patient successively developed breast carcinoma, ovarian micropapillary serous carcinoma and peritoneal papillary serous carcinoma. Immunohistochemical staining results have indicated that these tumors are three separate primary malignancies. This case illustrates that ovarian serous borderline tumors (including micropapillary serous carcinoma) and peritoneal papillary serous carcinomas should be considered, like breast and ovarian carcinomas, tumors expressed in BRCA mutation carriers.
UI - 21372035
AU - Galmozzi E; Tomassetti A; Sforzini S; Mangiarotti F; Mazzi M; Nachmanoff K; Elwood PC; Canevari S
TI - Exon 3 of the alpha folate receptor gene contains a 5' splice site which confers enhanced ovarian carcinoma specific expression.
SO - FEBS Lett 2001 Jul 27;502(1-2):31-4
AD - Unit of Molecular Therapies, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
The human folate receptor (FR) is overexpressed in ovarian carcinoma. FR transcripts are heterogeneous due to the use of two promoters, P1 and P4, and alternative splicing of exon 3. RNase protection assay and RT-PCR revealed higher levels of the transcripts that include exon 3 in lines and specimens from ovarian carcinoma. A P1-chloramphenicol acetyltransferase (CAT) construct containing exon 3 demonstrated efficient reporter expression only in ovarian carcinoma. 5' and 3' deleted variants of the P1-CAT construct were analyzed by RT-PCR of the exogenous transcripts and reporter activity. A 5' splice site and 35 bp downstream intronic region of exon 3 appeared to regulate enhanced FR expression in ovarian carcinoma.
UI - 21375958
AU - Neyns B; De Rijcke M; Vermeij J; Teugels E; Zeinoun Z; De Greve J
TI - Contaminants within bacterial plasmid preparations trigger apoptosis in liposome transfected OVCAR3, but not in SKOV3 or AZ224 human ovarian cancer cells.
SO - Cell Biol Int 2001;25(8):715-23
AD - Laboratory of Medical Oncology and Department of Medical Oncology, Oncologisch Centrum, Akademisch Ziekenhuis Vrije Universiteit Brussel, Belgium.
Toxicity associated with plasmid/liposome transfection of eucaryote cells has been attributed to the inherent toxicity of cationic lipid formulations and also to bacterial contaminants of plasmid DNA preparations, such as lipopolysaccharides (LPS). Certain plasmid preparations were observed to trigger apoptosis in DNA/liposome transfected OVCAR3 human epithelial ovarian cancer cells. In contrast, AZ224 and SKOV3 cells were unaffected under the same conditions. Agarose gel electrophoresis with recovery of the plasmid DNA removed the toxic component, but not purification by phenol/chloroform extraction or isopicnic CsCl ultracentrifugation. The toxicity of individual preparations correlated with the concentration of bacterial LPS. However, polymixin B could not neutralise the toxicity and neither could the effect be reproduced by the addition of bacterial LPS to non-toxic plasmid preparations. Surprisingly, the conditioned medium of OVCAR3 cells undergoing apoptosis was found to kill non-transfected OVCAR3 cells but not AZ224 or SKOV3 cells. This observation illustrates the possibility that unpredictable contaminants of bacterial plasmid preparations are able to cause cell death in the context of plasmid/liposome transfection in a cell-type specific way. It emphasizes the importance of achieving maximal plasmid DNA purity when performing DNA transfection experiments that focus on cell survival. Copyright 2001 Academic Press.
UI - 21423687
AU - Lu KH; Broaddus RR
TI - Gynecological tumors in hereditary nonpolyposis colorectal cancer: We know they are common--now what?
SO - Gynecol Oncol 2001 Aug;82(2):221-2
UI - 21423688
AU - Watson P; Butzow R; Lynch HT; Mecklin JP; Jarvinen HJ; Vasen HF; Madlensky L; Fidalgo P; Bernstein I; International Collaborative Group on HNPCC
TI - The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.
SO - Gynecol Oncol 2001 Aug;82(2):223-8
AD - Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS:. Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage. Copyright 2001 Academic Press.
UI - 21423689
AU - Casado E; Nettelbeck DM; Gomez-Navarro J; Hemminki A; Gonzalez Baron M; Siegal GP; Barnes MN; Alvarez RD; Curiel DT
TI - Transcriptional targeting for ovarian cancer gene therapy.
SO - Gynecol Oncol 2001 Aug;82(2):229-37
AD - Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Ovarian carcinoma is a leading cause of cancer death in women. Though advances in conventional therapies have been achieved, long-term survival rates for most patients diagnosed with ovarian cancer are still low. Therefore, novel molecular therapeutic strategies such as gene therapy are being intensively pursued. Such approaches are based on the enormous progress that has been achieved in the elucidation of the molecular foundations of ovarian cancer. In this regard transcriptional control elements (promoters) of genes frequently upregulated or specifically expressed in tumors can be applied in a heterologous context to drive expression of therapeutic genes in targeted gene therapy strategies. This review discusses transcriptional targeting strategies in ovarian cancer gene therapy and gives an overview of tumor-specific promoters (TSPs) that have been applied for this purpose. Copyright 2001 Academic Press.
UI - 21423694
AU - Ahluwalia A; Yan P; Hurteau JA; Bigsby RM; Jung SH; Huang TH; Nephew KP
TI - DNA methylation and ovarian cancer. I. Analysis of CpG island hypermethylation in human ovarian cancer using differential methylation hybridization.
SO - Gynecol Oncol 2001 Aug;82(2):261-8
AD - Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana 47405, USA.
OBJECTIVE: The aim of this study was to examine CpG island methylation patterns in ovarian cancer and determine whether epigenetic information can be related to clinical data of patients. CpG island (CpGI) hypermethylation is commonly associated with cancer progression, but little is currently known about the role of methylation in ovarian cancer. METHODS: Differential methylation hybridization (DMH) analysis at 742 loci was performed to determine methylation signatures for 20 primary epithelial ovarian carcinomas (Stages II, III, and IV adenocarcinomas, serous papillary), 6 ovarian cancer cell lines, and normal ovarian surface epithelial cells. RESULTS: Between 23 and 108 methylated CpGIs were seen in the ovarian carcinomas. Fewer (P < 0.05) methylated CpGIs were observed in the ovarian cancer cell lines; however, a number of CpGIs were commonly hypermethylated in both the cell lines and the tumor samples. A methylation signature, consisting of frequently (P < 0.05) methylated CpGIs, was determined for the samples. The observed pattern of methylation in ovarian cancers included several (11) CpGI tags that were previously reported to be hypermethylated in human breast cancer. CONCLUSIONS: Epigenetic signatures in ovarian cancer were determined using DMH. This proof-of-concept study lays the foundation for genome-wide screening of methylation to examine epigenotype-phenotype relationships in ovarian cancer. Copyright 2001 Academic Press.
UI - 21423696
AU - Alvarez AA; Axelrod JR; Whitaker RS; Isner PD; Bentley RC; Dodge RK; Rodriguez GC
TI - Thrombospondin-1 expression in epithelial ovarian carcinoma: association with p53 status, tumor angiogenesis, and survival in platinum-treated patients.
SO - Gynecol Oncol 2001 Aug;82(2):273-8
AD - Division of Gynecologic Oncology, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
OBJECTIVE: The regulation of the metastatic process in epithelial ovarian cancer has not been well defined. Similar to other tumor types, the angiogenic phenotype in ovarian cancer strongly influences clinical outcome, suggesting that the acquisition of a pro-angiogenic environment is essential to the process of ovarian cancer proliferation and metastasis. Thrombospondin-1 (TSP-1) is a potent peptide shown in other tumor systems to be associated with angiogenesis and possibly regulated by p53, a gene which is mutated in as high as 50% of advanced ovarian cancers. The purpose of this study was to investigate TSP-1 expression in invasive epithelial ovarian cancer and to examine the relationship between TSP-1 expression and the degree of angiogenesis. In addition, we examined whether TSP-1 expression was associated with overexpression of p53. METHODS: Frozen sections obtained from 85 patients with invasive epithelial ovarian cancer were examined immunohistochemically for expression of TSP-1 and p53. The sections were examined microscopically by two investigators, who were blinded to the clinicopathologic variables. Outcome variables included the correlation among TSP-1, angiogenesis, and p53, as well as the association between TSP-1 expression and survival. RESULTS: The majority (62%) of cases demonstrated high levels (3+) of TSP-1 expression; 7% demonstrated no TSP-1 expression. p53 was overexpressed in 55% of cases, and expression was inversely correlated with TSP-1 staining. Thirteen cancers had 0 or 1+ TSP-1 staining; 12 (92%) of these overexpressed the p53 protein. In contrast, only 49% of tumors with high expression of TSP-1 have overexpression of p53 (P = 0.02). TSP-1 was suggestive for improved survival in patients with advanced disease; high TSP-1 expression was associated with a median survival of 2.4 years compared to 1.5 years for patients with tumors having a lower degree of TSP-1 expression (P = 0.06). CONCLUSION: These data suggest that TSP-1 may possess a tumor inhibitory function in patients with advanced epithelial ovarian carcinoma. The reduction of TSP-1 expression associated with overexpression of p53 may be coupled with the development of a pro-angiogenic environment and malignant phenotype. Copyright 2001 Academic Press.
UI - 21423700
AU - Ahluwalia A; Hurteau JA; Bigsby RM; Nephew KP
TI - DNA methylation in ovarian cancer. II. Expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells.
SO - Gynecol Oncol 2001 Aug;82(2):299-304
AD - Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana 47405, USA.
OBJECTIVE: The aim of this study was to investigate whether expression of the enzymes that catalyze cytosine CpG island methylation, DNA methyltransferases, DNMT1, DNMT3a, and DNMT3b is altered in human ovarian cancer. Aberrations in DNA methylation are common in cancer and have important roles in tumor initiation and progression. Tumors that display frequent and concurrent inactivation of multiple genes by methylation are designated as having a CpG Island methylator phenotype, or CIMP. To date, colon, gastric, and most recently ovarian cancers meet the CIMP criteria for cancer. We hypothesized that altered expression of DNA methyltransferases can result in hypermethylation events seen in CIMP cancers. METHODS: DNMT1, DNMT3a, and DNMT3b mRNA levels in eight ovarian cancer cells lines (Hey, HeyA8, HeyC2, OVCAR-3, SK-OV-3, PA-1, A2780, and A2780-P5) were compared to DNMT expression in normal ovarian surface epithelial cells using semi-quantitative reverse transcription-polymerase chain reaction. RESULTS: In HeyA8 and HeyC2 ovarian cancer cells, DNMT1 expression levels were up to threefold higher (P < 0.05) than in normal ovarian surface epithelial cells. SK-OV-3 and PA-1 displayed increased DNMT3b expression (P < 0.05) compared to normal ovarian surface epithelial cells. Transcript levels for DNMT3a, however, were similar in cancer and normal ovarian cells. CONCLUSIONS: We observed differential expression of the DNMT genes in some ovarian cancer cell lines and conclude that alterations in DNMT expression might contribute to the CIMP phenotype in ovarian cancer. However, based on the lack of aberrant DNMT expression in some of the cancer cell lines examined, we further suggest that another mechanism(s), in addition to DNMT overexpression, accounts for methylation anomalies commonly observed in ovarian cancer. Copyright 2001 Academic Press.
UI - 97294417
AU - Gayther SA; Harrington P; Russell P; Kharkevich G; Garkavtseva RF; Ponder BA
TI - Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia.
SO - Am J Hum Genet 1997 May;60(5):1239-42
UI - 21060593
AU - Gorski B; Byrski T; Huzarski T; Jakubowska A; Menkiszak J; Gronwald J; Pluzanska A; Bebenek M; Fischer-Maliszewska L; Grzybowska E; Narod SA; Lubinski J
TI - Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.
SO - Am J Hum Genet 2000 Jun;66(6):1963-8
AD - Department of Genetics and Pathology, Hereditary Cancer Center, 70-115 Szczecin, Poland.
We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age <50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities-5382insC, C61G, and 4153delA-accounted for 51%, 20%, and 11% of the identified mutations, respectively.
UI - 21230827
AU - Chiaffarino F; Pelucchi C; Parazzini F; Negri E; Franceschi S; Talamini R; Conti E; Montella M; La Vecchia C
TI - Reproductive and hormonal factors and ovarian cancer.
SO - Ann Oncol 2001 Mar;12(3):337-41
AD - Istituto di Ricerche Farmacologiche Mario Negri, Universita degli Studi di Milano, Milan, Italy.
BACKGROUND: Menstrual, reproductive and hormonal factors have been related to ovarian cancer risk, but further quantification of their role in various populations is required. PATIENTS AND METHODS: Cases were 1031 women, below age 79, with incident, histologically confirmed epithelial ovarian cancer, and controls 2411 women, admitted between 1992 and 1999 to a network of hospitals in 4 Italian areas for acute, non-neoplastic, diseases. Odds ratios (OR) were obtained using multiple logistic regression. RESULTS: Multiparity was associated with a significant reduction in risk of ovarian cancer (OR = 0.6 for 3, and 0.5 for > or = 4 births). No consistent association was observed with time since first or last birth, nor with spontaneous or induced abortions. Late age at menarche (OR = 0.8), and early menopause (OR = 0.6) were inversely related to risk, as did long-term oral contraceptive use (OR = 0.5, for > or = 5 years). Hormone replacement therapy in menopause was associated with a non-significantly elevated risk (OR = 1.4). The pattern of risk was similar for women with and for those without family history of breast or ovarian cancer. CONCLUSIONS: This uniquely large study confirms and further quantities the relation between hormonal and reproductive factors and ovarian cancer. The pattern of risk observed cannot be totally explained by a role of ovulation in ovarian carcinogenesis.
UI - 21249655
AU - Newman LA; Kuerer HM; Hunt KK; Vlastos G; Ames FC; Ross MI; Singletary SE
TI - Educational review: role of the surgeon in hereditary breast cancer.
SO - Ann Surg Oncol 2001 May;8(4):368-78
AD - Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Up to 10% of the breast cancers detected in the United States are related to an inherited germline mutation, usually in the BRCA1 or BRCA2 genes, and the majority of these patients will at some point require surgical evaluation and/or treatment. Women who harbor a genetic predisposition for breast cancer face an increased risk for early onset disease, bilateral tumors, and other non-breast malignancies, such as ovarian cancer. These issues raise questions regarding the appropriate surveillance regimen, and the potential efficacy of risk reduction strategies that should be considered. Once a breast cancer diagnosis has been established, the prognosis appears to be similar to stage-controlled sporadic breast cancer, despite an increased prevalence of adverse primary tumor features. However, the role of breast conservation therapy for these patients and the optimal means of addressing the substantially increased risk for contralateral tumors is not yet defined. The reported literature in this area, including a discussion of the value of genetic counseling and genetic testing, is reviewed.
UI - 21303185
AU - Ricevuto E; Sobol H; Stoppa-Lyonnet D; Gulino A; Marchetti P; Ficorella C; Martinotti S; Meo T; Tosi M
TI - Diagnostic strategy for analytical scanning of BRCA1 gene by fluorescence-assisted mismatch analysis using large, bifluorescently labeled amplicons.
SO - Clin Cancer Res 2001 Jun;7(6):1638-46
AD - Unite Immunogenetique et Unite/Institut National de la Sante et de la Recherche Medicale (INSERM) 276, Institut Pasteur, Paris, France. firstname.lastname@example.org
The aim of this study was to develop a protocol for reliable, sensitive, and cost-effective mutation scanning of the BRCA1 gene, based on a modification of fluorescence-assisted mismatch analysis. The main features of this method are: (a) robust PCR amplification and strandspecific labeling of 25 large amplicons using uniform conditions and universal fluorescent primers; and (b) sensitive characterization of the position of sequence changes. The diagnostic accuracy of this method was tested by scanning the large exon 11 in 12 DNA samples with reported mutations. In a blind test, specific patterns of fluorescence profiles were obtained, and all were attributed correctly, without sequencing, to each mutation or polymorphism. Seven breast/ovarian cancer families with high probability of BRCA1-related predisposition were screened. Three truncating mutations (of which one was novel and three were missense changes, including two novel ones) were detected. The three missense mutations affect the highly conserved BRCT domain. Scanning by FAMA appears to be free of biases for particular types of sequence changes-except for exon deletions/duplications, which cannot be detected by conventional PCR-based methods-and allows substantial savings in the number of sequencing reactions and in the time invested in their interpretation. Therefore, it lends itself to screening structurally complex loci in the diagnostic context and in other fields of genetic analysis.
UI - 21303202
AU - Modesitt SC; Ramirez P; Zu Z; Bodurka-Bevers D; Gershenson D; Wolf JK
TI - In vitro and in vivo adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer.
SO - Clin Cancer Res 2001 Jun;7(6):1765-72
AD - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
PURPOSE: The objectives of this study were to determine the effects of adenovirus-mediated p16 and p53 on growth and apoptosis in ovarian cancer cells and on survival in nude mice implanted with human ovarian cancer cells. EXPERIMENTAL DESIGN: SKOV-3 ip1 (p53 and p16 null), 2774 (p53 and p16 mutant), and OVCA 420 (p53 and p16 wild-type) cells were used for in vitro studies. SKOV-3 ip1, 2774, and Hey A8 (p53 and p16 wild-type) cells were used in the nude mouse studies. The E1-deleted adenoviruses containing p53, p16, or beta-galactosidase cDNA were transfected into the different cell types or inoculated into the nude mice after injection with ovarian cancer cells. RESULTS: Cell counting, microtetrazolium, and anchorage-independent growth assays on transfected cells demonstrated that p16 and the p16/p53 combination suppressed growth, whereas p53 did not (except in the anchorage-independent growth assay). Although cells infected with the p16/p53 combination had decreased growth compared with cells infected with either tumor suppressor alone, the difference was only statistically significant compared with p53. p16, p53, and the p16/p53 combination all increased apoptosis in the cells. In the nude mice, p16 treatment resulted in the longest survival for all three models, although it only reached statistical significance for the 2774 and SKOV-3 ip1 groups. CONCLUSIONS: Overall, p16 demonstrated greater growth inhibition than p53 both in vivo and in vitro. The p16/p53 combination demonstrated a consistent trend toward increased growth suppression and apoptosis over p16 or p53 alone. Adenovirus-mediated p16 may be a viable future treatment for ovarian cancer.
UI - 21396251
AU - Berry DA
TI - Role of population-based studies in assessing genetic cancer risk.
SO - J Natl Cancer Inst 2001 Aug 15;93(16):1188-9
UI - 21396264
AU - Loman N; Johannsson O; Kristoffersson U; Olsson H; Borg A
TI - Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer.
SO - J Natl Cancer Inst 2001 Aug 15;93(16):1215-23
AD - Department of Oncology, Lund University Hospital, Sweden. Niklas.Loman@onk.lu.se
BACKGROUND: BRCA1 and BRCA2 are the two major susceptibility genes involved in hereditary breast cancer. This study was undertaken to provide reliable population-based estimates of genetic influence and to characterize the nature and prevalence of BRCA1 and BRCA2 germline mutations in early-onset breast cancer. METHODS: In a series comprising all women diagnosed with breast cancer under the age of 41 years in southern Sweden during 1990 through 1995 (n = 262), family history of cancer was evaluated in 95% (n = 250) of the case subjects and germline mutations in BRCA1 and BRCA2 were analyzed in 89% (n = 234). All statistical tests were two-sided. RESULTS: A total of 97 case subjects had at least one first- or second-degree relative with breast or ovarian cancer; 34 (14%; 95% confidence interval [CI] = 9.6% to 18%) cases had at least two first- or second-degree relatives, 22 (8.8%; 95%CI = 5.3% to 12%) had one first-degree relative, and 41 (16%; 95% CI = 12% to 21%) had one second-degree relative with either cancer. If two females affected with breast or ovarian cancer who were related through an unaffected male were also defined as first-degree relatives, then a higher number of case subjects, 120 (48%; 95% CI = 42% to 54%), had at least one first-degree or second-degree relative with breast or ovarian cancer. Sixteen (6.8%; 95% CI = 4.0% to 11%) BRCA1 mutation carriers and five (2.1%; 95% CI = 0.70% to 4.9%) BRCA2 mutation carriers were identified. Among case subjects with one first- or more than one first- or second-degree relative with breast or ovarian cancer, BRCA mutations were more frequent (P<.001) than among the case subjects without this degree of family history. BRCA mutations were also statistically significantly more common among women with bilateral breast cancer than among women with unilateral breast cancer (P =.002). BRCA mutations were more common among younger case subjects than among older ones (P =.0027). CONCLUSIONS: Almost half (48%) of women in southern Sweden with early-onset breast cancer have some family history of breast or ovarian cancer, and 9.0% of early-onset breast cancer cases are associated with a germline mutation in BRCA1 or BRCA2. Mutation carriers were more prevalent among young women, women with at least one first- or second-degree relative with breast or ovarian cancer, and women with bilateral breast cancer.
UI - 21382085
AU - Bingham C; Roberts D; Hamilton TC
TI - The role of molecular biology in understanding ovarian cancer initiation and progression.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():7-11
AD - Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
In this review, we will present clinical and experimental data that the surface epithelial cells of the ovary are the most likely cell of origin of ovarian cancer. Using a rat model of the disease, we demonstrate the utility of the molecular techniques of Differential Display Genome Scanning and Suppression Subtractive Hybridization to detect gene expression and genetic differences between normal rat surface epithelial cells and their transformed counterpart. Lastly, we provide examples of how molecular techniques can be used to predict which tumors will respond to chemotherapy.
UI - 21411799
AU - Klein M; Graf AH; Rosen A; Hacker GW
TI - Re: Aziz S, et al. A genetic epidemiological study of carcinoma of the Fallopian tube. Gynecol Oncol 2001;80:341-5.
SO - Gynecol Oncol 2001 Sep;82(3):590
UI - 21433637
AU - Gras E; Cortes J; Diez O; Alonso C; Matias-Guiu X; Baiget M; Prat J
TI - Loss of heterozygosity on chromosome 13q12-q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors.
SO - Cancer 2001 Aug 15;92(4):787-95
AD - Department of Pathology, Hospital Santa Creu i Sant Pau, Autonomous University of Barcelona, 08025 Barcelona, Spain.
BACKGROUND: BRCA-1 and BRCA-2 are tumor suppressor genes in familial breast-ovarian carcinoma syndrome. BRCA-1 is also a tumor suppressor gene in sporadic ovarian carcinomas. However, the role of BRCA-2 in sporadic ovarian tumors remains unclear. METHODS: DNA from 52 patients with clinically apparent sporadic ovarian tumors was extracted from blood and from fresh-frozen tumor tissue and normal tissue (10 benign, 7 borderline, and 35 malignant). Loss of heterozygosity (LOH) was analyzed in six microsatellite loci on chromosome 13q. BRCA-2 mutations were detected by single-strand conformation polymorphism analysis and the protein truncation test. BRCA-2 promoter methylation was evaluated by methylation specific polymerase chain reaction analysis. RESULTS: LOH on chromosome 13q12-q14 was identified in 16 tumors (30.8%): Fifteen of these tumors were carcinomas (15 of 35 tumors; 42.8%) and one was a borderline tumor. LOH was frequent in carcinomas with serous differentiation (12 of 16 tumors; 75%). LOH on chromosome 13q12-q14 coexisted with LOH on chromosome 17q in 10 carcinomas. BRCA-2 methylation was not detected in any tumor. BRCA-2 mutations were found in three tumors (one somatic nonsense and two germline frameshift). BRCA-2 fulfilled the two hits for a tumor suppressor gene in these three tumors; in one of them, a BRCA-1 tumor suppressor role had been demonstrated previously. CONCLUSIONS: The results suggest that BRCA-1 and BRCA-2 may act synergically in sporadic ovarian carcinomas with serous differentiation. The demonstration of BRCA-2 germline mutations in patients with ovarian carcinoma with LOH on chromosome 13q12-q14 and lack of a remarkable family history of cancer suggest that the proportion of ovarian carcinomas that result from hereditary predisposition may be higher than previously estimated. Copyright 2001 American Cancer Society.
UI - 21433659
AU - Julian-Reynier CM; Bouchard LJ; Evans DG; Eisinger FA; Foulkes WD; Kerr B; Blancquaert IR; Moatti JP; Sobol HH
TI - Women's attitudes toward preventive strategies for hereditary breast or ovarian carcinoma differ from one country to another: differences among English, French, and Canadian women.
SO - Cancer 2001 Aug 15;92(4):959-68
AD - INSERM U379, Epidemiology and Social Sciences Applied to Medical Innovation, Paoli-Calmettes Institute, 232 Boulevard Sainte Marguerite, 13273 Marseilles cedex 9, France. email@example.com
BACKGROUND: The authors investigated the acceptability to women of the preventive strategies available for dealing with hereditary breast/ovarian carcinoma in France, the United Kingdom, and Canada, countries selected because of their cultural differences. The authors aimed to discover the existence of specific factors that may affect acceptability of these preventative measures. METHODS: A cross-sectional, multicenter survey was conducted in Marseilles, France (n = 141), in Manchester, England (n = 130), and in Montreal, Quebec (n = 84). All of the women attending cancer genetic clinics for the first time because of a family history of breast-ovarian carcinoma completed a self-administered questionnaire before their clinic consulta