National Cancer Institute®
Last Modified: February 1, 2002
UI - 11745676
AU - Evans MF; Herrington CS
TI - Allelic imbalance is not restricted to numerically abnormal chromosomes in epithelial ovarian tumours.
SO - J Pathol 2001 Nov;195(4):443-50
AD - Department of Pathology, Duncan Building, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, Merseyside, UK.
In this study, 23 low malignant potential (LMP) and 27 invasive epithelial ovarian tumours have been examined by microdissection and microsatellite polymerase chain reaction (PCR) for allelic imbalance (AI) at loci on the p and q arms of chromosomes 1, 11, 17, and X, and the data have been compared with interphase cytogenetics for numerical abnormalities (aneusomy) of these chromosomes. AI was uncommon in LMP tumours (5 of 23 at 9 of 146 informative loci) but was significantly more common (p<0.001) in invasive carcinomas (21 of 27 at 47 of 168 informative loci). This difference remained when LMP tumours were compared specifically with stage I carcinomas (p<0.001). A greater number of loci were involved in AI amongst serous than amongst mucinous carcinomas (p=0.015). AI was present at significantly more loci in carcinomas showing aneusomy by interphase cytogenetics than in those showing no numerical chromosome abnormalities (p<0.001). However, amongst the carcinomas showing aneusomy, AI was as frequent at loci on chromosomes with no numerical abnormality as at those with the numerical changes. These data demonstrate that aneusomy and AI are interrelated phenomena but that AI does not occur simply as a consequence of numerical chromosome changes. Copyright 2001 John Wiley & Sons, Ltd.
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 - 11751427
AU - Riva F; Zuco V; Vink AA; Supino R; Prosperi E
TI - UV-induced DNA incision and proliferating cell nuclear antigen recruitment to repair sites occur independently of p53-replication protein A interaction in p53 wild type and mutant ovarian carcinoma cells.
SO - Carcinogenesis 2001 Dec;22(12):1971-8
AD - Centro di Studio per l'Istochimica del CNR, Piazza Botta 10, 27100 Pavia, Italy.
The tumour suppressor gene TP53 plays an important role in the regulation of DNA repair, and particularly of nucleotide excision repair. The influence of p53 status on the efficiency of the principal steps of this repair pathway was investigated after UV-C irradiation in the human ovarian carcinoma cell line IGROV-1 (expressing wild-type p53) and in the derived clone IGROV-1/Pt1 (with p53 mutations at codons 270 and 282). Clonogenic survival after UV-C irradiation showed that IGROV-1/Pt1 cells were approximately 2-fold more resistant to DNA damage than parental cells. Modulation of p53 protein levels, cell cycle arrest and apoptosis were induced in UV-irradiated IGROV-1 cells, but not in the p53-mutant cell line. Exposure to UV or cisplatin induced down-regulation of p53-replication protein A (RPA) interaction in parental, but not in IGROV-1/Pt1 cells. However, persistent binding of p53 to RPA did not affect the early steps of DNA repair. In fact, both UV-induced DNA incision and the recruitment of proliferating cell nuclear antigen (PCNA) to DNA repair sites occurred to a comparable extent in p53-wild type and -mutant cell lines, although PCNA remained associated with chromatin for a longer period of time in IGROV-1/Pt1 cells. Global genome repair, as detected by immunoblot analysis of cyclobutane pyrimidine dimers, was not significantly different in the two cell lines at 3 h after UV irradiation. In contrast, lesion removal at 24 h was markedly reduced in IGROV-1/Pt1 cells, being approximately 25% of the initial amount of damage, as compared with approximately 50% repair in parental cells. These results indicate that the presence of mutant p53 protein and its persistent interaction with RPA do not affect the early steps of nucleotide excision repair in IGROV-1/Pt1 cells. Thus, repair defects in p53-mutant ovarian carcinoma cells may be attributed to late events, possibly related to a reduced removal/recycling of PCNA at repair sites.
UI - 11786728
AU - Hovig E; Rye PD; Warren DJ; Nustad K
TI - CA 125: the end of the beginning.
SO - Tumour Biol 2001 Nov-Dec;22(6):345-7
AD - Central Laboratory, Norwegian Radium Hospital, Oslo, Norway.
CA 125, a high-molecular-weight mucin, was first defined in 1981 by the monoclonal antibody OC125. Until recently, it has defied many attempts to purify it from a variety of sources, although many research groups have successfully raised antibodies that bind to CA 125. Nevertheless, CA 125 has demonstrated its considerable value as a marker in monitoring patients with ovarian cancer. This year, two research groups have succeeded in cloning the high-molecular-weight mucin CA 125. Their findings are summarized and the significance discussed in light of existing data from the human genome. Copyright 2001 S. Karger AG, Basel
UI - 11786729
AU - O'Brien TJ; Beard JB; Underwood LJ; Dennis RA; Santin AD; York L
TI - The CA 125 gene: an extracellular superstructure dominated by repeat sequences.
SO - Tumour Biol 2001 Nov-Dec;22(6):348-66
AD - Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. firstname.lastname@example.org
CA 125 has long presented problems to both clinicians and investigators because there was no definitive information on its structure and function. Here, we describe our work on cloning the CA 125 gene with the anticipation that such information will provide the basis for understanding its structure and its physiologic role in both normal and malignant tissues. The CA 125 protein core is composed of a short cytoplasmic tail, a transmembrane domain and an extraordinarily large glycosylated extracellular structure. This structure is dominated by a repeat domain composed of 156 amino acid repeat units which encompass the epitope binding sites. The molecule also includes an amino terminal domain of serine/threonine-rich sequences which would account for most of the O-glycosylation known to be present in CA 125. CA 125 is an unusually large transmembrane glycoprotein. Its release from the surface of the cell is most probably dependent on cytoplasmic phosphorylation followed by proteolytic cleavage. The extracellular domain is characterized by a large number of repeat units (probably 60+) which encompass an interactive disulfide bridged cysteine-loop and the site of OC125 and M11 binding. Sequencing the gene provides us with the ability to initiate the quest to understand the biological function of CA 125. Copyright 2001 S. Karger AG, Basel
UI - 11780384
AU - Pan L; Tong Y; Jin Y; Zhou S; Zhang Y; Yang X; Mao N
TI - Reversing drug resistance in the ovarian carcinoma cell line SKOV3/mdr1 in vitro by antisense oligodeoxynucleotides.
SO - Chin Med J (Engl) 2001 Sep;114(9):929-32
AD - Department of Obstetrics and Gynecology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing 100730, China.
OBJECTIVE: To investigate the effect of multidrug resistance gene 1 (mdr1) antisense oligodeoxynucleotides (ODNs) on reversing multidrug resistance in the drug resistant ovarian carcinoma cell line SKOV3/mdr1. METHODS: The ovarian carcinoma cell line SKOV3 transducted with a human multidrug resistance gene (mdr1) served as the drug resistant model (SKOV3/mdr1). The mdr1 antisense ODNs was transfected into SKOV3/mdr1 cells while mediated by lipofectamine. Reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the expression and the amount of the mdr1 mRNA in the cells. The positive rate and function of the mdr1 gene product P-glycoprotein (Pgp) in the mdr1 antisense ODNs treated SKOV3/mdr1 cells were determined by flow cytometry and rhodamine 123 efflux. Drug resistance in the SKOV3/mdr1 cell line was observed by MTT assay and cell colony culture. RESULTS: The mdr1 mRNA level was decreased to about 60% of that of beta-actin after mdr1 antisense ODNs treatment. The Pgp positive rate of mdr1 antisense ODNs treated SKOV3/mdr1 cells decreased from 100% to 52.6% (P < 0.01). The intracellular rhodamine 123 retention was increased from 9.1% to 33.8% (P < 0.01). The chemoresistance to taxol decreased to 58% of SKOV3/mdr1 with mdr1 antisense ODN treatment. Compared with SKOV3/mdr1 cells in the control group, under a certain range of drug concentrations, the number of drug resistance colonies in mdr1 antisense ODNs treated SKOV3/mdr1 cells for taxol and doxorubicin decreased by 8.6 +/- 0.8 fold and 3.1 +/- 0.6 fold, respectively. Some non-specific functions during oligodeoxyncleotide treatment was also detected. CONCLUSION: mdr1 expression in the SKOV1/mdr1 cell line was partially inhibited after mdr1 antisense ODNs treatment at the mRNA and protein level, increasing the chemotherapy sensitivity of this drug resistant ovarian carcinoma cell line.
UI - 10885351
AU - Meijers-Heijboer EJ; Verhoog LC; Brekelmans CT; Seynaeve C;
TI - Tilanus-Linthorst MM; Wagner A; Dukel L; Devilee P; van den Ouweland AM; van Geel AN; Klijn JG Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation.
SO - Lancet 2000 Jun 10;355(9220):2015-20
AD - Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancer. In families with BRCA1 or BRCA2 mutations, identification of mutation carriers is clinically relevant in view of the options for surveillance and prevention. METHODS: We assessed presymptomatic DNA testing and prophylactic surgery in 53 consecutive families presenting to the Rotterdam Family Cancer Clinic with a known BRCA1 or BRCA2 mutation. We identified predictors for DNA testing and prophylactic surgery with univariate and multivariate analysis. FINDINGS: 682 unaffected individuals with a 50% risk (275 women and 271 men) or with a 25% risk (136 women) for carrying a mutation were identified and offered a DNA test. Presymptomatic DNA testing was requested by 48% (198 of 411) of women and 22% (59 of 271) of men (odds ratio for difference between sexes 3.21 [95% CI 2.27-4.51]; p<0.001). In women, DNA testing was significantly more frequent at young age, in the presence of children, and at high pre-test genetic risk for a mutation. Of the unaffected women with an identified mutation who were eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral mastectomy and 64% (29 of 45) for oophorectomy. Parenthood was a predictor for prophylactic mastectomy but not for prophylactic oophorectomy. Age was significantly associated with prophylactic oophorectomy, but not with prophylactic mastectomy, although there was a tendency towards mastectomy at younger ages. INTERPRETATION: In a clinical setting, we show a high demand for BRCA1 and BRCA2 testing by unaffected women at risk, and of prophylactic surgery by unaffected women with the mutation. Young women with children especially opt for DNA testing and prophylactic mastectomy.
UI - 11499060
AU - Frank TS; Critchfield GC
TI - Identifying and managing hereditary risk of breast and ovarian cancer.
SO - Clin Perinatol 2001 Jun;28(2):395-406
AD - Myriad Genetic Laboratories, Salt Lake City, Utah, USA. email@example.com
In the past, all women with a family history of breast or ovarian cancer were considered to be at increased risk of cancer themselves. The discovery of BRCA1 and BRCA2 demonstrated that susceptibility to breast and ovarian cancer can be inherited by women as a single-gene autosomal dominant disorder. For such women, evaluation of family history is an important screening tool to identify the possibility of hereditary cancer risk but only genetic testing can provide definitive, individualized risk assessment. Women who have inherited mutations in BRCA1 or BRCA2 now have several medical management options to address their increased risk of cancer. A well-educated community of health care providers and patients can use hereditary risk assessment, including genetic testing, to improve health care.
UI - 11791119
AU - Ueno NT; Yu D; Hung MC
TI - E1A: tumor suppressor or oncogene? Preclinical and clinical investigations of E1A gene therapy.
SO - Breast Cancer 2001;8(4):285-93
AD - Department of Molecualr and Cellular Oncology, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 448, Houston, TX 77030, USA. firstname.lastname@example.org
In the late 1980s, we have shown that the E1A gene can downregulate HER-2/neu overexpression, thus reversing the tumorigenic and metastatic phenotype. Further, E1A can function as a tumor suppressor gene by inducing apoptosis and inhibiting metastasis. At The University of Texas M. D. Anderson Cancer Center, we have been investigating the adenovirus type 5 E1A gene as a potential therapeutic gene in breast and ovarian cancer since 1995 by using cationic liposome as gene delivery system. In this chapter, we recount our development of E1A as a therapeutic gene.
UI - 11781689
AU - Barkardottir RB; Sarantaus L; Arason A; Vehmanen P; Bendahl PO; Kainu T;
TI - Syrjakoski K; Krahe R; Huusko P; Pyrhonen S; Holli K; Kallioniemi OP; Egilsson V; Kere J; Nevanlinna H Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.
SO - Eur J Hum Genet 2001 Oct;9(10):773-9
AD - Department of Pathology, University Hospital of Iceland, Iceland. email@example.com
The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.
UI - 11774736
AU - Kigawa J; Sato S; Shimada M; Takahashi M; Itamochi H; Kanamori Y;
TI - Terakawa N p53 gene status and chemosensitivity in ovarian cancer.
SO - Hum Cell 2001 Sep;14(3):165-71
AD - Department of Obstetrics and Gynecology, Tottori University, School of Medicine.
Recent studies suggest that drug induced apoptosis relates to the sensitivity. p53 gene, which has a pivotal role in inducing apoptosis, frequently mutates in ovarian cancer. Therefore, p53 gene status and chemosensitivity in epithelial ovarian cancer is discussed. Nonresponders to chemotherapy had mutations of the p53 gene more frequently (83% for nonresponders vs. 16% for responders) in patients with epithelial ovarian cancer undergoing platinum-base chemotherapy. Apoptotic index was significantly greater in tumors with wild-type p53 gene than those without the gene. p53 gene transduction markedly enhanced the sensitivity to cisplatin (CDDP) and CDDP-induced apoptosis, but did not affect the sensitivity to paclitaxel (PTX) nor PTX-induced apoptosis in ovarian cancer cells without p53 gene. The combination treatment with a recombinant adenovirus carrying a wild-type p53 gene (AxCAp53) and CDDP significantly suppressed tumor growth of ovarian cancer cells with and without p53 gene, compared with a single treatment of either AxCAp53 or CDDP in ovarian cancer xenograft. Apoptotic index was significantly higher and proliferating cell nuclear antigen labeling index was relatively lower in an ovarian cancer xenograft without p53 gene receiving combination treatment, compared with a single treatment of either CDDP or AxCAp53, suggesting that the transduction of p53 gene induces apoptosis, but does not enhance the DNA repair system. A significant survival advantage was observed in the combination treatment compared with other treatments in carcinoma peritonitis models. In conclusion, p53 gene status contributes the sensitivity to CDDP in ovarian cancer. Additionally, combination treatment of p53 gene transduction and CDDP may be an effective therapeutic modality for ovarian cancer without wild-type p53 gene.
UI - 11807777
AU - Buchholz TA; Wu X; Hussain A; Tucker SL; Mills GB; Haffty B; Bergh S;
TI - Story M; Geara FB; Brock WA Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2.
SO - Int J Cancer 2002 Feb 10;97(5):557-61
AD - Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. firstname.lastname@example.org
The BRCA1 and BRCA2 gene products are thought to play important roles in the processing of DNA damage. To assess whether heterozygous mutations in these genes are associated with cellular radiosensitivity, we performed an in vitro radiation clonogenic survival assay on dermal fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1, 2 BRCA2). These data were compared to results obtained from a previous set of 17 prospectively studied cancer patients who had a negligible risk for a BRCA mutation. In addition, results from radiation-induced chromatid break assay performed on lymphocytes obtained from 9 BRCA heterozygotes (8 BRCA1, 1 BRCA2) were compared to results from a control group of 18 women with no cancer history. Results from both assays suggested that cells containing a heterozygous mutation in BRCA1 or BRCA2 were more radiosensitive than controls. For the fibroblast studies, the mean surviving fraction at 2 Gy (SF2) for carriers was 0.279 vs. 0.348 for the control set (p = 0.007). For the lymphocyte studies, the mean number of chromatid breaks after 125 cGy of radiation was 0.79 breaks per cell for the carriers vs. 0.45 for the controls (p = 0.0005). There was no apparent difference in the radiosensitivity between cells with BRCA1 vs. BRCA2 mutations (p = 0.769), although the small sample size minimizes the certainty of this observation. These preliminary results are consistent with a relationship between a germline mutation in BRCA1 or BRCA2 and a hypersensitivity to radiation. This phenotype could possibly predispose to an increased risk of radiation-induced mutagenesis and carcinogenesis. Copyright 2001 Wiley-Liss, Inc.
UI - 11782386
AU - Shridhar V; Sen A; Chien J; Staub J; Avula R; Kovats S; Lee J; Lillie J;
TI - Smith DI Identification of underexpressed genes in early- and late-stage primary ovarian tumors by suppression subtraction hybridization.
SO - Cancer Res 2002 Jan 1;62(1):262-70
AD - Department of Experimental Pathology, Division of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. email@example.com
To identify novel tumor suppressor genes involved in ovarian carcinogenesis, we generated four down-regulated suppression subtraction cDNA libraries from two early-stage (stage I/II) and two late-stage (stage III) primary ovarian tumors, each subtracted against cDNAs derived from normal ovarian epithelial cell brushings. Approximately 600-700 distinct clones were sequenced from each library. Comparison of down-regulated clones obtained from early- and late-stage tumors revealed genes that were unique to each library which suggested tumor-specific differences. We found 45 down-regulated genes that were common in all four libraries. We also identified several genes, the role of which in tumor development has yet to be elucidated, in addition to several under expressed genes, the potential role of which in carcinogenesis has been described previously (Bagnoli et al., Oncogene, 19: 4754-4763, 2000; Yu et al., Proc. Natl. Acad. Sci. USA, 96: 214-219, 1999; Mok et al., Oncogene, 12: 1895-1901, 1996). The differential expression of a subset of these genes was confirmed by semiquantitative reverse transcription-PCR using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as control in a panel of 15 stage I and 15 stage III tumors of mixed histological subtypes. Chromosomal sorting of library sequences revealed that several of the genes mapped to known regions of deletion in ovarian cancer. Loss of heterozygosity (LOH) analysis revealed multiple genomic regions with a high frequency of loss in both early- and late-stage tumors. To determine whether loss of expression of some of the genes corresponds to loss of an allele by LOH, we used a microsatellite marker for one of the novel genes on 8q and have shown that loss of expression of this novel gene correlates with loss of an allele by LOH. In conclusion, our analysis has identified down-regulated genes, which map to known as well as novel regions of deletions and may represent potential candidate tumor suppressor genes involved in ovarian cancer.
UI - 11802208
AU - de la Hoya M; Osorio A; Godino J; Sulleiro S; Tosar A; Perez-Segura P;
TI - Fernandez C; Rodriguez R; Diaz-Rubio E; Benitez J; Devilee P; Caldes T Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing.
SO - Int J Cancer 2002 Feb 1;97(4):466-71
AD - Laboratory of Molecular Oncology, Hospital Universitario San Carlos, Madrid, Spain.
Index cases from a clinically relevant cohort of 102 Spanish families with at least 3 cases of breast and/or ovarian cancer (at least 1 case diagnosed before age 50) in the same lineage were screened for germline mutations in the entire coding sequence and intron boundaries of the breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the prevalence of mutations was 43% in female breast/ovarian cancer families, 15% in female breast cancer families and 100% in male breast cancer families. Three recurrent mutations (185delAG, 589delCT and A1708E) explained 63% of BRCA1-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer, concomitant breast/ovarian cancer in a single patient and prostate cancer but not unilateral breast cancer were associated with BRCA1 and BRCA2 mutations. Male breast cancer was associated with BRCA2 mutations. The presence of male breast cancer was the only cancer phenotype that distinguished BRCA2- from BRCA1-related families. We have developed a logistic regression model for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The predictive positive and negative values of this model were 77.4% and 79%, respectively (probability cutoff of 30%). The findings of our work may be a useful tool for increasing the cost-effectiveness of genetic testing in familial cancer clinics. Copyright 2001 Wiley-Liss, Inc.
UI - 11802209
AU - Meindl A; German Consortium for Hereditary Breast and Ovarian Cancer
TI - Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.
SO - Int J Cancer 2002 Feb 1;97(4):472-80
AD - Department of Medical Genetics, Ludwig-Maximilians University, Munich, Germany. firstname.lastname@example.org
The main focus of this German-wide multi-center study was to establish a BRCA1/2 mutation profile and to determine family types with high frequencies of mutations in these genes. In a comprehensive study, the entire coding sequences of the breast cancer genes BRCA1 and BRCA2 were analyzed in 989 unrelated patients from German breast/ovarian cancer families. A total of 77 BRCA1 and 63 BRCA2 distinct deleterious mutations were found in 302 patients. More than (1/3) of these mutations are novel and might be specific for the German population. Eighteen common mutations were found in 68% of cases in BRCA1 and 13 recurrent mutations in 44% of cases in BRCA2, facilitating prescreening approaches. Haplotype analysis indicate that 14 out of 20 recurrent mutations are likely originating from a common founder. An additional 50 different rare sequence variants with unknown relevance for tumorigenesis were found in 72 families. Correlation of BRCA1/BRCA2 detection rates with family history identified families with both breast and ovarian cancer to be at highest risk for BRCA1/BRCA2 mutations (43% and 10%, respectively), followed by families with at least 2 premenopausal cases of breast cancer (24% BRCA1 and 13% BRCA2 mutations). These data provide strong evidence for further predisposing genes in the German population. In breast cancer families with 2 or 3 affected females but only a single or no premenopausal case, mutations were detected with low frequencies (about 10% or less for both genes). The decision for or against molecular diagnosis is now aided by considering the expected mutation detection rates that greatly depend on family history and structure. Copyright 2001 Wiley-Liss, Inc.
UI - 11826460
AU - Levin T; Reichelt J; Heimdal K; Moller P
TI - [Information to families with hereditary breast and ovarian cancer]
SO - Tidsskr Nor Laegeforen 2001 Nov 20;121(28):3292-4
AD - Seksjon for genetisk veiledning Avdeling for kreftgenetikk Det Norske Radiumhospital 0310 Oslo. email@example.com
BACKGROUND: Under Norwegian legislation, persons at risk should make the initial contact with the proper health personnel, and not vice versa. It may be argued that the physician should be allowed to make contact with persons at risk of preventable or curable disorders. MATERIAL AND METHODS: We identified all first-degree relatives of all 75 BRCA1 mutation carriers diagnosed within a given period of time and asked them whether or not they had been informed by their relatives. RESULTS: After two years, 60/63 (95%) adult sisters and daughters had made contact with us; the remaining three (5%) had been informed. In comparison, 18/45 (40%) adult brothers and sons had contacted us. INTERPRETATION: The legislation constituted no barrier to offering health services to the target group. Information on our services had reached all close relatives who could benefit from them. This may be representative for curable inherited disorders. We examined inherited cancer limited to females; similar studies on inherited cancers in males and on other curable inherited disorders should be performed. Outside the framework of the present study, we are aware of rare examples of distant cousins who have not been properly informed through their families. One legally acceptable way of identifying mutation carrier families is to test all patients with breast or ovarian cancer for causative mutations. Health services should be monitored to make future decisions based on empirical evidence.
UI - 11810077
AU - Walker GR; Schlesselman JJ; Ness RB
TI - Family history of cancer, oral contraceptive use, and ovarian cancer risk.
SO - Am J Obstet Gynecol 2002 Jan;186(1):8-14
AD - Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Florida, USA.
OBJECTIVE: The purpose of this study was to determine whether women with a family history of ovarian cancer are at reduced risk of ovarian cancer from the use of oral contraceptives and to compare their risk with that of women with no family history of ovarian cancer. STUDY DESIGN: A diagnosis of epithelial ovarian cancer were ascertained from 39 hospitals in 3 northeastern states. Personal interviews with the women and 1367 control subjects provided data that allowed us to estimate the relative risk of ovarian cancer in relation to a family history of cancer and total duration of oral contraception. RESULTS: Among the 33 case patients and 24 control subjects with a first-degree family history of ovarian cancer, risk of ovarian cancer declined with increasing duration of oral contraception (P =.01). Risk reduction from short-term use of oral contraceptives (< or = 48 months) did not differ significantly by family history (combined estimate of odds ratio, 0.72; 90% CI, 0.59%-0.87%). Risk reduction from long-term use of oral contraceptives (>48 months) was greater in women with a positive family history of ovarian cancer (odds ratio, 0.12) than in women with a negative family history of ovarian cancer (odds ratio, 0.51; test of interaction, P =.04; 692 case patients, 1279 control subjects). CONCLUSION: Four to 8 years of oral contraception may substantially reduce the risk of ovarian cancer by age 70 years in women with a family history of the disease, from approximately 4 women per 100 women who did not use oral contraceptives to only 2 women per 100 women who did use oral contraceptives.
UI - 10746681
AU - Huang LW; Garrett AP; Muto MG; Colitti CV; Bell DA; Welch WR; Berkowitz
TI - RS; Mok SC Identification of a novel 9 cM deletion unit on chromosome 6q23-24 in papillary serous carcinoma of the peritoneum.
SO - Hum Pathol 2000 Mar;31(3):367-73
AD - Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
To define regions of deletion on chromosome 6q in papillary serous carcinoma of the peritoneum (PSCP), we analyzed 103 tumor tissues from 53 patients by using 11 polymorphic microsatellite markers spanning loci from 6q23 to 6q27. Allelic losses on 6q were observed in 42 of 53 (79.2%) cases. We identified 3 distinct regions with a high percentage (>40%) of loss of heterozygosity. The first region is located at 6q23-24 and defined by D6S311 (15 of 35 informative cases, 42.9%). Detailed deletion mapping of chromosome 6q23-24 in these tumor samples identified a novel 9 cM minimal deletion region flanked by D6S250 and ESR. The second one is located at 6q25.1-25.2 and defined by D6S448 (17 of 36 informative cases, 47.2%). A second minimal deletion region of 4 cM was flanked by D6S420 and D6S442. The third region is located at 6q27 and defined by D6S297 (9 of 19 informative cases, 47.4%). Comparing these results with our cases of advanced staged invasive serous epithelial ovarian carcinoma (SEOC), we observed that allelic losses at D6S311 (6q23) and D6S149 (6q27) were significantly higher for PSCP than for SEOC. The pattern of allelic loss at each tumor site within an individual patient was also studied. A total of 36 cases displayed allelic loss for at least 1 of multiple tumor sites, and 35 of these patients exhibited nonidentical patterns of allelic loss at various tumor sites of the same patient. Furthermore, an alternating pattern of allelic loss in the same patient was identified in 3 of 53 patients studied. These results show that allelic losses on 6q are very frequent in PSCP, and we show 2 discrete minimal deletion regions on 6q, suggesting the existence of at least 2 tumor suppressor genes within 6q that may be involved in the pathogenesis of PSCP. In addition, the finding of different patterns of allelic loss at different tumor sites within the same patient indicate a mutifocal origin in some PSCP cases. These results provide strong evidence to support our previous reports that PSCP is a multifocal disease entity.
UI - 11526715
AU - Greggi S; Legge F; Mancuso S
TI - [Familial ovarian carcinoma]
SO - Minerva Ginecol 2001 Feb;53(1 Suppl 1):3-5
AD - Istituto di Clinica Ostetrica e Ginecologica, Universita Cattolica del Sacro Cuore, Roma.
UI - 11526718
AU - Ferrandina G; Legge F; Fagotti A; Fanfani F; Mancuso S; Scambia G
TI - [Biological factors with prognostic significance in ovarian cancer]
SO - Minerva Ginecol 2001 Feb;53(1 Suppl 1):40-5
AD - Istituto di Clinica Ostetrica e Ginecologica, Universita Cattolica del Sacro Cuore, Roma.
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 - 11743636
AU - Herrera CA; Xu L; Bucana CD; Silva el VG; Hess KR; Gershenson DM; Fidler
TI - IJ Expression of metastasis-related genes in human epithelial ovarian tumors.
SO - Int J Oncol 2002 Jan;20(1):5-13
AD - Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
We examined the expression level of several genes that regulate distinct steps of metastasis in 55 formalin-fixed, paraffin-embedded, archival specimens of primary human ovarian carcinoma from patients undergoing curative surgery. The expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), basic fibroblast growth factor (bFGF), E-cadherin, type IV collagenase, matrix metalloproteinase (MMP-2 and MMP-9), and interleukin 8 (IL-8) was examined by a colorimetric in situ mRNA hybridization technique. The expression level of E-cadherin, MMP-2, MMP-9, VEGF, and IL-8 mRNA correlated with disease stages. The ratio of type IV collagenase expression (mean of the expression of MMP-2 and MMP-9) to E-cadherin expression (MMP:E-cadherin ratio) increased with increasing stage of disease (p<0.0001). Death rates significantly increased with high MMP:E-cadherin ratio (p=0.0005). Multivariate analysis of overall survival showed that the MMP:E-cadherin ratio was a significant independent prognostic factor, even after adjustment for known prognostic factors, such as histology, stage, and age.
UI - 11780319
AU - Ye D; Xie X; Lu W; Chen H; Cheng B
TI - Growth inhibition of interleukin-2 receptor gene-transduced peripheral blood lymphocytes on human ovarian cancer cells.
SO - Chin Med J (Engl) 2001 Mar;114(3):303-7
AD - Department of Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
OBJECTIVE: To investigate the growth inhibition of interleukin-2 receptor (IL-2R) gene-transduced peripheral blood lymphocytes (PBLs) on human ovarian cancer cells. METHODS: Interleukin-2 (IL-2) and IL-2R genes were transfected into human ovarian cancer cell line 3AO and PBLs, respectively, using the same Fugene vector. Twenty-four hours later transfected and nontransfected PBLs were cocultured with transfected and nontransfected 3AO for 48 hours. cytotoxicity of PBLs on 3AO was detected by the MTT assay. RESULTS: The morphology of IL-2-transduced 3AO and IL-2R-transduced PBLs remained unchanged. 3AO cells could be transfected with the IL-2 gene and expressed IL-2 mRNA, and PBLs could be transfected with the IL-2R gene and expressed IL-2R mRNA. IL-2 transduced 3AO cells enhanced their response to the cytotoxicity of PBLs. Furthermore, growth inhibition of PBLs to 3AO cells increased significantly when the IL-2R was transfected into PBLs and when the IL-2 gene was transfected into 3AO cells and the two were combined. CONCLUSIONS: IL-2R gene transduced PBLs are able to enhance their cytotoxicity on IL-2 gene transduced ovarian cancer cells. This method may be a new way to investigate IL-2 gene therapy for ovarian cancer.
UI - 11780195
AU - Guan J; Ma L; Wei L
TI - Characteristics of ovarian cancer cells transduced by the bicistronic retroviral vector containing GM-CSF and HSV-TK genes.
SO - Chin Med J (Engl) 2001 Feb;114(2):147-51
AD - Department of Gynecology and Obstetrics, People's Hospital, Peking University, Beijing 100044, China.
OBJECTIVES: To explore whether HSV-TK (herpes simplex virus thymidine kinase) and GM-CSF (granulocyte-macrophage colony-stimulating factor) genes could be linked by internal ribosome entry site (IRES) in one retroviral vector and expressed by ovarian cancer cells following transfection, and to observe the characteristics of the transduced cells. METHODS: Retroviral vector pLGM-I-TK was constructed by linking the HSV-TK gene and GM-CSF gene with the IRES sequence. By using the "ping-pong" technique, pLGM-I-TK was transfected into the packaging cell line, PA317, to produce a PA317/TK-GM cell line. Using the resulting viral supernatant to infect the ovarian cancer cell line SKOV3, PCR and RT-PCR were used to explore the integration and transcription of HSV-TK and GM-CSF genes. The cytotoxicity of GCV (gancyclovir) on SKOV3/TK-GM was determined by MTT assay and the bystander effect of the HSV-TK/GCV system was also assessed. ELISA was used to measure the expression of GM-CSF by the transgene cells. RESULTS: The bicistronic retroviral vector constructed could be successfully transduced into PA317 and the titer of the retroviral vector was about 8.6 x 10(5) cfu/ml. PCR and RT-PCR demonstrated the successful integration and transcription of HSV-TK and GM-CSF genes transduced into the SKOV3 cell. SKOV3/TK-GM cells could be killed by GCV, and the IC50 was 0.7 microgram/ml. The bystander effect was demonstrated. The expression level of GM-CSF in SKOV3/TK-GM was 60.4 ng.ml-1 x 10(6) cells-1 x 2 days-1. CONCLUSION: The IRES sequence can be used to construct retroviral vectors to facilitate co-transfection of two genes. SKOV3/TK-GM cells can simultaneously express the HSV-TK and GM-CSF genes with biological activities which could be useful for enhancing the function of immune cells on the basis of suicide gene therapy.
UI - 11779836
AU - Manderson EN; Mes-Masson AM; Novak J; Lee PD; Provencher D; Hudson TJ;
TI - Tonin PN Expression profiles of 290 ESTs mapped to chromosome 3 in human epithelial ovarian cancer cell lines using DNA expression oligonucleotide microarrays.
SO - Genome Res 2002 Jan;12(1):112-21
AD - Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada.
We have investigated previously the utility of oligonucleotide expression microarray technology in an analysis of four spontaneously transformed epithelial ovarian cancer (EOC) cell lines, TOV-21G, TOV-81D, OV-90, and TOV-112D. Here, we examine the expression of 290 expressed sequence tags (ESTs) that map to human chromosome 3 in a primary culture derived from normal ovarian surface epithelium (NOSE), NOV-31, and the four spontaneously transformed EOC cell lines. One of these cell lines, OV-90, harbors a deletion of an entire chromosome 3p arm. Whereas the most aggressive cell lines (OV-90, TOV-112D, and TOV-21G) exhibited the highest levels of expression, assessed by the mean of expression values of all ESTs, OV-90 showed the lowest mean of expression of ESTs that map to the 3p arm in comparison with TOV-112D and TOV-21G. This difference in expression profile of 3p ESTs in OV-90 is also reflected in the ratio of expression of ESTs on 3p versus the 3q arm and in that the expression values of ESTs that map to 3p were more often lower than higher in OV-90 in two-way comparisons with NOV-31, TOV-21G, and TOV-112D. The loss of a 3p arm does not affect the pattern of differential expression in analyses based on the range of numeric expression values of each EST or fold differences in expression for each EST in comparison with NOV-31. However, 25 differentially expressed ESTs were identified on the basis of threefold differences in expression values between NOV-31 and any EOC cell line; and six of these ESTs were differentially expressed uniquely in OV-90. The investigation of these ESTs could facilitate the identification of novel chromosome 3 genes implicated in ovarian tumorigenesis.
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 - 11821951
AU - Liu Y; Emilion G; Mungall AJ; Dunham I; Beck S; Le Meuth-Metzinger VG;
TI - Shelling AN; Charnock FM; Ganesan TS Physical and transcript map of the region between D6S264 and D6S149 on chromosome 6q27, the minimal region of allele loss in sporadic epithelial ovarian cancer.
SO - Oncogene 2002 Jan 17;21(3):387-99
AD - ICRF Molecular Oncology Laboratories, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.
We have previously shown a high frequency of allele loss at D6S193 (62%) on chromosomal arm 6q27 in ovarian tumours and mapped the minimal region of allele loss between D6S297 and D6S264 (3 cM). We isolated and mapped a single non-chimaeric YAC (17IA12, 260-280 kb) containing D6S193 and D6S297. A further extended bacterial contig (between D6S264 and D6S149) has been established using PACs and BACs and a transcript map has been established. We have mapped six new markers to the YAC; three of them are ESTs (WI-15078, WI-8751, and TCP10). We have isolated three cDNA clones of EST WI-15078 and one clone contains a complete open reading frame. The sequence shows homo