National Cancer Institute®
Last Modified: March 1, 2002
UI - 11805588
AU - Vachon CM; Mink PJ; Janney CA; Sellers TA; Cerhan JR; Hartmann L; Folsom
TI - AR Association of parity and ovarian cancer risk by family history of breast or ovarian cancer in a population-based study of postmenopausal women.
SO - Epidemiology 2002 Jan;13(1):66-71
AD - Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. email@example.com
Although parity is associated with a decreased risk of ovarian cancer in the general population, this association among women with a family history is less clear. We examined this question in a prospective cohort of 31,377 Iowa women 55-69 years of age at baseline. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated through Cox regression. We identified 181 incident epithelial ovarian cancers through 13 years of follow-up. At baseline, 14% of the women reported breast or ovarian cancer in a first-degree relative, and an additional 12% reported a family history in a second-degree relative. Among women without a family history of breast or ovarian cancer in a first-degree relative, nulliparous women were at slightly increased risk of ovarian cancer (RR = 1.4, 95% CI = 0.9-2.4) compared with parous women, whereas among women with a family history, nulliparous women were at a much higher risk (RR = 2.7, 95% CI = 1.1-6.6) than parous women. Similar results were seen when family history included first- or second-degree relatives with breast or ovarian cancer or a first- or second-degree relative with ovarian cancer only. Nulliparity may be more strongly associated with an increased risk of ovarian cancer among women with a family history of breast or ovarian cancer, compared with women who do not have a family history of those cancers.
UI - 11793480
AU - Tereschenko IV; Basham VM; Ponder BA; Pharoah PD
TI - BRCA1 and BRCA2 mutations in Russian familial breast cancer.
SO - Hum Mutat 2002 Feb;19(2):184
AD - Department of Prevention, Cancer Research Institute, Tomsk Scientific Centre, Tomsk, Russia. firstname.lastname@example.org
We have screened index cases from 25 Russian breast/ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using multiplex heteroduplex analysis. In addition we tested 22 patients with breast cancer diagnosed before age 40 without family history and 6 patients with bilateral breast cancer. The frequency of families with germline mutations in BRCA was 16% (4/25). One BRCA1 mutation, 5382insC, was found in three families. The results of present study, and those of a separate study of 19 breast-ovarian cancer families, suggest that BRCA1 5382insC is a founder mutation in the Russian population. Three BRCA2 mutations were found in patients with breast cancer without family history: two in young patients and one in patients with bilateral breast cancer. Four novel BRCA2 mutations were identified: three frameshift (695insT, 1528del4, 9318del4) and one nonsense (S1099X). Copyright 2002 Wiley-Liss, Inc.
UI - 11748848
AU - Machackova E; Damborsky J; Valik D; Foretova L
TI - Novel germline BRCA1 and BRCA2 mutations in breast and breast/ovarian cancer families from the Czech Republic.
SO - Hum Mutat 2001 Dec;18(6):545
AD - Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 656 53, Czech Republic.
Germline mutations in breast cancer susceptibility genes, BRCA1 and BRCA2, are responsible for a substantial proportion of high-risk breast and breast/ovarian cancer families. To characterize the spectrum of BRCA1 and BRCA2 mutations, we screened Czech families with breast/ovarian cancer using the non-radioactive protein truncation test, heteroduplex analysis and direct sequencing. In a group of 100 high-risk breast and breast/ovarian cancer families, four novel frame shift mutations were identified in BRCA1 and BRCA2 genes. In BRCA1, two novel frame shift mutations were identified as 3761-3762delGA and 2616-2617ins10; in BRCA2, two novel frame shift mutations were identified as 5073-5074delCT and 6866delC. Furthermore, a novel missense substitution M18K in BRCA1 gene in a breast/ovarian cancer family was identified which lies adjacent just upstream of the most highly conserved C3HC4 RING zinc finger motif. To examine the tertiary structure of the RING zinc finger domain and possible effects of M18K substitution on its stability, we used threading techniques according to the crystal structure of RAG1 dimerization domain of the DNA-binding protein. Copyright 2000 Wiley-Liss, Inc.
UI - 11773283
AU - Geisler JP; Hatterman-Zogg MA; Rathe JA; Buller RE
TI - Frequency of BRCA1 dysfunction in ovarian cancer.
SO - J Natl Cancer Inst 2002 Jan 2;94(1):61-7
AD - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City 52242, USA.
BACKGROUND: Ovarian cancer is one of the most common hereditary cancers in women. Mutations in the BRCA1 gene increase a woman's risk of ovarian cancer. Testing for BRCA1 mutations is cumbersome and impractical for large populations. Therefore, we developed an efficient strategy to detect various types of BRCA1 dysfunction and also determined the relative frequency of BRCA1 dysfunction in ovarian cancer. METHODS: Tumors from 221 patients with epithelial ovarian cancer were screened for loss of heterozygosity (LOH) at the BRCA1 locus. BRCA1 complementary DNA (cDNA) and genomic DNA from all cancers with BRCA1 LOH (106 tumors) or noninformative status (15 tumors) were polymerase chain reaction (PCR) amplified and analyzed for protein truncation in a coupled transcription/translation test. When truncated BRCA1 protein was detected, the BRCA1 gene from both the tumor and a paired blood sample was sequenced. When BRCA1 expression in tumor cDNA was not detected with a protein truncation test, a methylation-specific PCR was used to determine whether the promoter region of BRCA1 was methylated and thus inactivated. All statistical tests were two-sided. RESULTS: Fifty-one (23.1%) of 221 tumors had BRCA1 dysfunction, including 18 with germline mutations, 15 with somatic mutations, and 18 with monoallelic or biallelic hypermethylated promoters. By the consideration of only tumors with LOH or that were noninformative, the efficiency for detecting BRCA1 dysfunction improved to 45 (37.2%) of 121 tumors. Therefore, LOH/noninformative was a strong predictor of mutation status (Fisher's exact test, P<.001). However, this subset of tumors did not include those with BRCA1 missense mutations (estimated at six [2.7%] of 221 not detected by our method) or biallelic promoter methylation (estimated at six [2.7%] of 221). CONCLUSIONS: BRCA1 dysfunction in ovarian cancer is common and occurs via multiple mechanisms. The use of LOH, rather than a family history of ovarian cancer, as a first step in a screening strategy, followed by protein truncation testing, appears to increase the chance of identifying tumors with BRCA1 dysfunction.
UI - 11832208
AU - Venkitaraman AR
TI - Cancer susceptibility and the functions of BRCA1 and BRCA2.
SO - Cell 2002 Jan 25;108(2):171-82
AD - University of Cambridge, CRC Department of Oncology, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, United Kingdom. email@example.com
Inherited mutations in BRCA1 or BRCA2 predispose to breast, ovarian, and other cancers. Their ubiquitously expressed protein products are implicated in processes fundamental to all cells, including DNA repair and recombination, checkpoint control of cell cycle, and transcription. Here, I examine what is known about the biological functions of the BRCA proteins and ask how their disruption can induce susceptibility to specific types of cancer.
UI - 11857010
AU - Bish A; Sutton S; Jacobs C; Levene S; Ramirez A; Hodgson S
TI - Changes in psychological distress after cancer genetic counselling: a comparison of affected and unaffected women.
SO - Br J Cancer 2002 Jan 7;86(1):43-50
AD - Department of Clinical Genetics, Guy's Hospital, St Thomas's Street, London SE1 9RT, UK. firstname.lastname@example.org
This study sought to examine changes in psychological distress following cancer genetic counselling. Women attending a family cancer clinic completed questionnaires before their appointment and at 2 weeks, 6 months and 12 months after their appointment. Twenty-six women were at low risk of developing breast or ovarian cancer, 76 were at moderate risk, 46 were at high risk and 46 women had previously had breast or ovarian cancer. All groups were compared with regard to measures of anxiety, depression, general psychological distress, worry about developing breast and ovarian cancer, and perceived risk of developing breast/ovarian cancer and perceived likelihood of carrying a genetic mutation. General psychological distress did not change over the course of the study and the groups did not differ on these measures. Worry about developing breast cancer and perceptions of the likelihood of carrying a genetic mutation significantly reduced following genetic counselling. On the whole women who had already had breast/ovarian cancer showed more concerns about ovarian cancer and raised perceptions of risk in comparison with the other groups, indicating the need for sensitive counselling of such women.
UI - 11852993
AU - Pieretti M; Hopenhayn-Rich C; Khattar NH; Cao Y; Huang B; Tucker TC
TI - Heterogeneity of ovarian cancer: relationships among histological group, stage of disease, tumor markers, patient characteristics, and survival.
SO - Cancer Invest 2002;20(1):11-23
AD - Department of Pathology and Laboratory Medicine, University of Kentucky Medical Center, Lexington, USA. email@example.com
Epidemiological studies have established associations between various reproductive factors and risk of ovarian cancer; it has also been observed that some of these risk factors are only associated with specific histological subgroups. To investigate the correlation of genetic alterations with these risk factors, we examined a consecutive series of 158 ovarian cancer cases treated at the University of Kentucky (1990-96). Common molecular genetic alterations (LOH on chromosome 17, P53 alterations, K-RAS mutations), histological and clinical characteristics of the disease, demographic patient information and survival were evaluated. These latter data were from the Kentucky Cancer Registry. Univariate analysis showed higher frequencies of chromosome 17 loss and P53 mutations in tumors of advanced stage and grade, and in older and post-menopausal women. Non-mucinous tumors were more likely to be classified as late stage, high-grade cancers, and to have chromosome 17 loss and P53 mutations. Survival analysis indicated that stage was the only independent significant variable. When stage was the outcome variable in multiple logistic regression analysis, histology and chromosome 17 loss were significantly associated with poor survival. This case-case study provides evidence that ovarian cancers of mucinous and non-mucinous histology are significantly different with respect to clinical characteristics, survival and molecular alterations. It also lends support to the hypothesis that ovarian cancer is a heterogeneous disease with distinct etiological factors and clinical outcomes, which may require different approaches to treatment.
UI - 11812076
AU - Kigawa J; Sato S; Shimada M; Kanamori Y; Itamochi H; Terakawa N
TI - Effect of p53 gene transfer and cisplatin in a peritonitis carcinomatosa model with p53-deficient ovarian cancer cells.
SO - Gynecol Oncol 2002 Feb;84(2):210-5
AD - Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan. firstname.lastname@example.org
OBJECTIVE: To determine whether combination treatment consisting of p53 gene transfer and cisplatin (CDDP) improves prognosis of ovarian cancer patients with peritonitis carcinomatosa, we tried this therapy in a peritonitis carcinomatosa model that we developed. METHODS: A human ovarian adenocarcinoma cell line, HRA, which has homozygous deletion of the p53 gene, was used. For p53 gene transfection, we used a recombinant adenovirus carrying a wild-type p53 gene (AxCAp53). To determine the efficiency of the recombinant adenovirus to transduce HRA cells, the cells were infected with AxCALacZ, and the transduced cells were detected by beta-galactosidase staining. The expression of the p53 protein was monitored by Western blot analysis up to 15 days after infection of 50 MOI AxCAp53. The combination effect of AxCAp53 and CDDP was evaluated by 3-(4, 5-dimethelthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Apoptotic cells were assessed morphologically by staining with Hoechst 33258. For the peritonitis carcinomatosa model in this study, we used severe combined immunodeficiency mice with an intraperitoneal injection of HRA cells. RESULTS: The p53 protein was expressed at 24 h after infection with AxCAp53 and disappeared on the 14th day. The present in vitro study showed that wild-type p53 gene transduction significantly enhanced sensitivity to CDDP and the apoptotic index in HRA cells. A significant survival advantage was observed in the combination treatment of AxCAp53 and CDDP compared with single treatments. However, the repetitious treatment did not show significant survival advantage in the long term. CONCLUSION: The present study suggests that intraperitoneal treatment with AxCAp53 and CDDP is potentially useful as an adjuvant therapeutic modality for peritonitis carcinomatosa, although further study is needed to improve the long-term survival for those patients. B)2001 Elsevier Science.
UI - 11812079
AU - Bao R; Selvakumaran M; Hamilton TC
TI - Targeted gene therapy of ovarian cancer using an ovarian-specific promoter.
SO - Gynecol Oncol 2002 Feb;84(2):228-34
AD - Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
OBJECTIVES: The "suicide" gene therapy of cancer using promoters such as cytomegalovirus could cause severe toxicity to normal tissues due to a lack of specificity of prodrug activation. Therefore, we investigated gene therapy of ovarian cancer using ovarian-specific promoter (OSP1) to limit the synthesis of the prodrug activating enzyme HSVtk to ovarian cancer cells. METHODS: The HSVtk expressing plasmid pOSP1-HSVtk was created and transfected into an ovarian cancer cell line OVCAR3. The ganciclovir (GCV) sensitivity of the stable transfectants was evaluated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Tissue specificity of this promoter was evaluated by comparing the sensitivity to GCV between ovarian and nonovarian cancer cell lines after they were transfected with pOSP1-HSVtk. One transfectant sensitive to GCV was implanted intraperitoneally to immunocompromised mice which were treated subsequently with GCV. Furthermore, this ovarian cancer survival model was used to evaluate the in vivo efficacy of cationic lipid mediated pOSP1-HSVtk gene delivery followed by GCV treatment. RESULTS: Stable transfectants of OVCAR3 cells bearing OSP1-HSVtk became more sensitive to GCV treatment compared to the parental cell line and vector transfected OVCAR3 cell line. OSP1-HSVtk could specifically sensitize the OVCAR3 ovarian cancer cell line to GCV. SCID mice transplanted with the OVCAR3 transfectant and treated with GCV survived longer than the mice without GCV treatment (P = 0.032). In vivo gene delivery mediated by a cationic lipid (GL67) followed by GCV treatment yielded a longer survival in the OVCAR3 survival model (P = 0.016). CONCLUSIONS: The OSP1 promoter can selectively direct suicide gene therapy of ovarian cancer and the in vivo efficacy is improved by using a cationic lipid GL67 as delivery vehicle as opposed to the direct injection of plasmid. B)2001 Elsevier Science.
UI - 11848480
AU - Walt H; Hornung R; Fink D; Dobler-Girdziunaite D; Stallmach T; Spycher
TI - MA; Maly F; Haller U; Burki N Hypercalcemic-type of small cell carcinoma of the ovary: characterization of a new tumor line.
SO - Anticancer Res 2001 Sep-Oct;21(5):3253-9
AD - Department of Obstetrics and Gynecology, University Hospital, Zurich, Switzerland. email@example.com
BACKGROUND: The aim of this study was to develop and characterize a mouse xenograft model for the hypercalcemic-type of small cell carcinoma of the ovary (HTSCCO). PATIENTS AND METHODS: Tumor fragments were removed from a patient and cultured in six subsequent generations of nude mice. Histology, comparative genomic hybridization (CGH), electron microscopy and serum calcium levels were investigated. RESULTS: Morphology remained the same from the primary tumor of the patient through the 6th passage in the mouse. Serum calcium levels were significantly higher in the tumor-bearing mice compared to controls. CGH of the HTSCCO did not show evidence of a close relationship to either a germ cell tumor or an epithelial ovarian cancer. CONCLUSION: Some evidence was provided that the HTSCCO is an inhomogeneous tumor that is neither related to a germ cell tumor nor to an epithelial ovarian cancer, but is a distinct tumor entity.
UI - 11848511
AU - Szary J; Kalita K; Przybyszewska M; Dus D; Kieda C; Janik P; Szala S
TI - KDR promoter can transcriptionally target cytosine deaminase suicide gene to cancer cells of nonendothelial origin.
SO - Anticancer Res 2001 Sep-Oct;21(5):3471-5
AD - Department of Molecular Biology, Center of Oncology, Maria Sklodowska-Curie Memorial Institute, Gliwice, Poland.
The KDR/flk-1 gene promoter is considered to be endothelial cell-specific. We show its activity in two cancer cell lines of non-endothelial origin: in murine L1 sarcoma and OVP-10 human ovarian carcinoma cell lines. KDR promoter-driven cytosine deaminase gene can be efficiently expressed in these cells leading to sensitization to 5-fluorocytosine, as demonstrated both in vitro and in vivo. Our results indicated that KDR promoter activity is not endothelial cell-exclusive and that this promoter can also be used to obtain specific expression of therapeutic genes in certain cancer cells.
UI - 11870520
AU - O'Doherty AM; Church SW; Russell SE; Nelson J; Hickey I
TI - Methylation status of oestrogen receptor-alpha gene promoter sequences in human ovarian epithelial cell lines.
SO - Br J Cancer 2002 Jan 21;86(2):282-4
AD - School of Biology and Biochemistry, The Queen's University of Belfast, Lisburn Road, Belfast, Northern Ireland, UK.
We have determined the methylation status of the CpG island of the oestrogen receptor alpha gene in seven human ovarian cell lines. Cell lines expressing oestrogen receptor alpha showed no evidence of hypermethylation. In three of four cell lines that produced no detectable oestrogen receptor alpha protein, hypermethylation was observed at the NotI site of the CpG island. These results indicate that aberrant hypermethylation may be responsible for a significant proportion of epithelial ovarian tumours in which oestrogen receptor alpha expression is lost. Copyright 2002 The Cancer Research Campaign
UI - 11815406
AU - Bonadona V; Saltel P; Desseigne F; Mignotte H; Saurin JC; Wang Q;
TI - Sinilnikova O; Giraud S; Freyer G; Plauchu H; Puisieux A; Lasset C Cancer patients who experienced diagnostic genetic testing for cancer susceptibility: reactions and behavior after the disclosure of a positive test result.
SO - Cancer Epidemiol Biomarkers Prev 2002 Jan;11(1):97-104
AD - Unit of Prevention and Genetic Epidemiology, Comprehensive Cancer Center Leon Berard, 28 rue Laennec, 69008 Lyon, France.
The aim of this prospective study was to evaluate the consequences of the disclosure of a positive genetic test result to patients affected with cancer. Personal repercussions and patients' behavior with the transmission of their results to relatives were considered. We conducted semistructured interviews with 23 cancer patients identified as carriers of a cancer-predisposing mutation for hereditary breast ovarian or nonpolyposis colorectal cancers, 1 month after the disclosure of the test result. Eight patients spontaneously expressed distressed reactions ("you no longer feel cured"), and 14 patients reported at least one negative feeling (dissatisfied, discouraged, unhappy, or worried), despite expecting to be a carrier. Sixteen patients expressed concerns about the risk of developing another cancer, and 18 were concerned for their children's future, in that they may carry the mutation and develop a cancer. Although 8 patients found that disadvantages of knowing their genetic status outweighed the advantages, all but 1 did not regret having undergone genetic testing. All of the patients transmitted their results to at least one close relative. Although 6 of them expressed difficulties in being the only person who could transmit the information and 9 said it was a heavy responsibility, all except 1 did not want someone else to have to inform their families. Our results illustrate the potential negative impact of diagnostic genetic testing in patients with cancer. This includes distressed reactions and difficulties in transmitting their results to relatives. Future large-scale studies are warranted to confirm our findings.
UI - 11772280
AU - Harries M; Kaye SB
TI - Recent advances in the treatment of epithelial ovarian cancer.
SO - Expert Opin Investig Drugs 2001 Sep;10(9):1715-24
AD - CRC Department of Medical Oncology, The Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK. firstname.lastname@example.org
Ovarian cancer leads to more fatalities than any other form of gynaecological cancer in North America and Europe. Over the last 30 years survival figures have improved somewhat due to improvements in diagnosis, surgery and chemotherapy. Despite these advances, the majority of patients will die from their disease, with the overall 5-year survival being just 30%. The majority of patients with this disease will require treatment with cytotoxic chemotherapy. It is now well established that the platinum agents (cisplatin or carboplatin) are the most important drugs to be included in first-line regimens. More recently, randomised trials have confirmed the benefit of the addition of taxanes to platinum-containing regimens and the standard of care has become the combination of carboplatin and paclitaxel. Several unanswered questions remain regarding the optimal schedule, the optimum duration of treatment, possible benefits to be gained from the addition of other drugs and whether paclitaxel the best taxane. Despite high response rates to first line chemotherapy, the majority of patients with advanced ovarian cancer will relapse and will be candidates for further chemotherapy, which can palliate symptoms and improve survival even in recurrent disease. For a patient relapsing within six months of first-line treatment, studies have shown that there is little point in rechallenge with the same drugs. However, for patients who have a longer treatment-free interval the response rates to rechallenge with platinum is significant. A number of drugs have been shown to have activity in platinum- and taxane-refractory disease and are approved for this and/or other applications. These include topotecan, etoposide, pegylated liposomal doxorubicin, epirubicin, gemcitabine, altretamine, oxaliplatin and vinorelbine. Anti-oestrogens such as tamoxifen have a small but significant response rate. Recurrent ovarian cancer is a good setting to test investigational agents and compounds with promising activity including new platinums and taxoids, as well as a range of new compounds. Non-cytotoxic approaches that are showing promise include therapies designed to overcome drug resistance, signal transduction inhibitors, immunotherapy and gene therapy.
UI - 11857368
AU - Rogers PM; Beale PJ; Al-Moundhri M; Boxall F; Patterson L; Valenti M;
TI - Raynaud F; Hobbs S; Johnston S; Kelland LR Overexpression of BclXL in a human ovarian carcinoma cell line: paradoxic effects on chemosensitivity in vitro versus in vivo.
SO - Int J Cancer 2002 Feb 20;97(6):858-63
AD - CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
The effect of overexpressing the antiapoptotic protein BclXL in a human ovarian carcinoma cell line has been investigated in terms of sensitivity to the 2 major drugs used to treat this disease, paclitaxel and cisplatin. Stable transfection of BclXL into CH1 cells, which are relatively sensitive to cisplatin, resulted in around 2.7-fold higher expression in comparison with empty vector controls. However, this level of overexpression did not result in significant resistance in vitro to paclitaxel or cisplatin at the 50% inhibition level, using either short-term (4-day) growth inhibition or longer term colony-forming assays. By contrast, parallel subcutaneous xenograft models of these isogenic ovarian carcinoma cells in vivo, differing only in BclXL status, showed that this low-level BclXL overexpression conferred significant resistance to both paclitaxel and cisplatin in comparison with parent, nontransfected tumours. Whereas parent non-BclXL transfected tumours were highly responsive, with the disappearance of tumours for at least 50 days post treatment, tumours overexpressing BclXL grew back after 30 and 20 days after treatment with paclitaxel and cisplatin, respectively. These differences in responsiveness to paclitaxel in vivo were not attributable to any significant changes in the delivery of drug to the tumour. These data suggest that the responsiveness of ovarian cancer to paclitaxel and cisplatin in vivo, and therefore perhaps clinically, is influenced by levels of the antiapoptotic protein BclXL. Such effects may be missed in vitro when using short-term growth inhibition or clonogenic assays. Copyright 2001 Wiley-Liss, Inc.
UI - 11786575
AU - Ben David Y; Chetrit A; Hirsh-Yechezkel G; Friedman E; Beck BD; Beller
TI - U; Ben-Baruch G; Fishman A; Levavi H; Lubin F; Menczer J; Piura B; Struewing JP; Modan B; National Israeli Study of Ovarian Cancer Effect of BRCA mutations on the length of survival in epithelial ovarian tumors.
SO - J Clin Oncol 2002 Jan 15;20(2):463-6
AD - Department of Gynecology, Haemek Medical Center, Afula.
PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v. 37.8 months; 3-year survival, 65.8% v. 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.
UI - 11829379
AU - Leeson S; Iredale R; Stansfield K; Evans A; Gray J
TI - Developing a cancer genetics service in Wales: opinions of gynaecologists on the management of women at risk of familial ovarian cancer.
SO - Eur J Cancer Care (Engl) 2001 Sep;10(3):172-8
AD - Department of Obstetrics and Gynaecology, Ysbyty Gwynedd, North Wales, UK.
In Wales, a cancer genetics service has been developing since 1998. Gynaecologists play an integral role in the management of women with a family history of ovarian cancer and we were interested in investigating referral practice and management for relatives of patients with ovarian cancer among gynaecologists in Wales. In 1999, a postal questionnaire was sent to all gynaecologists. The response rate was 51%. The questionnaire contained structured questions about current provision and a number of hypothetical scenarios to explore referral patterns to the cancer genetics service. The results of this study showed that referrals varied widely among specialists, as did the numbers who required onward referral to cancer genetics. The offer of screening to women at high risk of ovarian cancer was consistent, although there were variations in how often it was offered and the age at which it was offered. Most gynaecologists were easily able to establish when it was appropriate to refer onwards to cancer genetics, differentiating between women at high or low risk. There was some confusion about women at moderate risk of ovarian cancer. This study demonstrated the need for clear referral guidelines in Wales. Guidelines have since been distributed to all general practitioners and specialists; however, continued monitoring and further evaluation of referral practices will be necessary.
UI - 11844822
AU - Shih HA; Couch FJ; Nathanson KL; Blackwood MA; Rebbeck TR; Armstrong KA;
TI - Calzone K; Stopfer J; Seal S; Stratton MR; Weber BL BRCA1 and BRCA2 mutation frequency in women evaluated in a breast cancer risk evaluation clinic.
SO - J Clin Oncol 2002 Feb 15;20(4):994-9
AD - Abramson Family Cancer Research Institute and Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
PURPOSE: To determine the prevalence of BRCA1 and BRCA2 mutations in families identified in a breast cancer risk evaluation clinic. PATIENTS AND METHODS: One hundred sixty-four families seeking breast cancer risk evaluation were screened for coding region mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis and DNA sequencing. RESULTS: Mutations were identified in 37 families (22.6%); 28 (17.1%) had BRCA1 mutations and nine (5.5%) had BRCA2 mutations. The Ashkenazi Jewish founder mutations 185delAG and 5382insC (BRCA1) were found in 10 families (6.1%). However, 6174delT (BRCA2) was found in only one family (0.6%) despite estimates of equal frequency in the Ashkenazi population. In contrast to other series, the average age of breast cancer diagnosis was earlier in BRCA2 mutation carriers (32.1 years) than in women with BRCA1 mutations (37.6 years, P =.028). BRCA1 mutations were detected in 20 (45.5%) of 44 families with ovarian cancer and 12 (75%) of 16 families with both breast and ovarian cancer in a single individual. Significantly fewer BRCA2 mutations (two [4.5%] of 44) were detected in families with ovarian cancer (P =.01). Eight families had male breast cancer; one had a BRCA1 mutation and three had BRCA2 mutations. CONCLUSION: BRCA1 mutations were three times more prevalent than BRCA2 mutations. Breast cancer diagnosis before 50 years of age, ovarian cancer, breast and ovarian cancer in a single individual, and male breast cancer were all significantly more common in families with BRCA1 and BRCA2 mutations, but none of these factors distinguished between BRCA1 and BRCA2 mutations. Evidence for reduced breast cancer penetrance associated with the BRCA2 mutation 6174delT was noted.
UI - 11855879
AU - Leitao M; Boyd J
TI - Preoperative CA-125 levels in patients with hereditary compared to sporadic epithelial ovarian carcinoma.
SO - Gynecol Oncol 2002 Mar;84(3):413-5
AD - Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
OBJECTIVE: The aim of this study was to determine whether a significant difference in preoperative CA-125 levels exists between patients with BRCA-associated hereditary ovarian carcinoma and those with sporadic ovarian carcinoma and whether the CA-125 level predicts the probability of optimal cytoreductive surgery. METHODS: From a retrospective cohort of 189 consecutive ovarian cancer patients genotyped for BRCA mutation status, data on preoperative CA-125 levels were available for 49/88 (56%) hereditary cases and 43/101 (43%) sporadic cases. Data on the extent of surgical cytoreduction were obtained for all 92 patients with available CA-125 data. Comparison of preoperative CA-125 levels between hereditary and sporadic groups was assessed using the Kruskal-Wallis chi(2) test. Correlation of surgical cytoreduction with preoperative CA-125 level was assessed using Fisher's exact test. RESULTS: Mean preoperative CA-125 levels were not significantly different among BRCA1 (2289 U/ml), BRCA2 (2586 U/ml), and sporadic (3307 U/ml) cases (P = 0.5). For hereditary cases, optimal cytoreduction was achieved in 59% of patients with preoperative CA-125 levels of <500 U/ml and in 52% of patients with preoperative levels >500 U/ml. For sporadic cases, optimal cytoreduction was achieved in 62% of patients with CA-125 levels of <500 U/ml and in 20% of patients with levels >500 U/ml (P = 0.01). CONCLUSIONS: Preoperative CA-125 levels are not significantly different for patients with hereditary compared to sporadic ovarian carcinoma. The probability of optimal cytoreduction is independent of the preoperative CA-125 level for hereditary cases, but optimal cytoreduction is significantly less likely for sporadic cases with CA-125 levels of >500 U/ml.
UI - 11850083
AU - Schmid-Braz AT; Cavalli LR; Cornelio DA; Wuicik L; Ribeiro EM;
TI - Bleggi-Torres LF; Lima RS; de Andrade Urban C; Haddad BR; Cavalli IJ Comprehensive cytogenetic evaluation of a mature ovarian teratoma case.
SO - Cancer Genet Cytogenet 2002 Jan 15;132(2):165-8
AD - Departamento de Genetica, Universidade Federal do Parana, Caixa Postal 19071, CEP 81531-970, Curitiba, Parana, Brazil.
Mature ovarian teratomas are benign ovarian germ cell tumors that usually present with a normal karyotype. There are very few reports describing chromosomal abnormalities in these tumors, none of which are recurrent. In this study we report on a mature teratoma case with clonal chromosomal alterations which include monosomies of chromosomes 6, 14, 16, and 21; trisomies of chromosomes 14 and 21; and deletions of Xq, 5p, 16p, and 17p. Comparative genomic hybridization evaluation of the sample revealed a normal profile. These findings are discussed together with the cytogenetic reports on other cases of ovarian teratomas described in the literature.
UI - 11857748
AU - Llort G; Munoz CY; Tuser MP; Guillermo IB; Lluch JR; Bale AE; Franco MA
TI - Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain.
SO - Hum Mutat 2002 Mar;19(3):307
AD - Unidad de Consejo Genetico. Servicio de Prevencion y Control del Cancer, Instituto Catalonian National Cancer Institute, Barcelona, Spain.
BRCA1 and BRCA2 mutations underlie a substantial proportion of all hereditary breast cancer. The mutational spectrum in these genes is very broad, with hundreds of different BRCA mutations reported worldwide. However, high frequency founder mutations make up a substantial fraction of all mutations in some ethnic groups. We directly sequenced BRCA1 and BRCA2 in 35 Spanish breast/ovarian cancer families and found 13 mutations of which 3 had been reported previously in Spain. The ten novel mutations are: IVS5+1 G>A, 1491delA, Leu1086Ter, and Gln895Ter in BRCA1; Glu49Ter, 5373delGTAT, 5947delCTCT, 6672delTA, 8281insA, and Pro3039Leu (which also involves a splice site) in BRCA2. Our data, in combination with previous reports, indicate that 14 mutations have been seen recurrently in Spanish families. Analyzing these 14 mutations in 42 previously untested breast/ovarian cancer families revealed only two families testing positive, one for BRCA1 185delAG and one for BRCA2 9254delATCAT. While several mutations have been found recurrently in Spain, none appear to be high frequency founder mutations based on studies of breast and ovarian cancer families. Copyright 2002 Wiley-Liss, Inc.
UI - 11857749
AU - Khoo US; Chan KY; Cheung AN; Xue WC; Shen DH; Fung KY; Ngan HY; Choy KW;
TI - Pang CP; Poon CS; Poon AY; Ozcelik H Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: a founder mutation of BRCA1 identified in the Chinese population.
SO - Hum Mutat 2002 Mar;19(3):307-8
AD - Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Previous mutational analysis for BRCA gene mutations in sporadic ovarian cancer occurring in Chinese patients in Hong Kong identified six germline BRCA1 mutations and one germline BRCA2 mutation, six of which were novel (Khoo et al., 2000). Knowledge of BRCA gene mutations in the Chinese population is relatively scant. In this study, we focussed on whether any of these mutations could be recurrent in our Chinese population, making use of archival paraffin embedded tissue. A consecutive series of 214 ovarian cancer cases, half of Southern Chinese origin from Hong Kong whilst the other half of Northern Chinese origin from Beijing were used for the study. We identified one further novel mutation, 1081delG, in BRCA1. This was found to occur in two unrelated individuals with shared haplotype as revealed by allelotype analysis, thus demonstrating founder effect. Two other recurrent mutations were also identified, the 2371-2372delTG mutation in BRCA1 and the 3337C>T mutation in BRCA2 recurring in two and three unrelated individuals respectively, giving an overall prevalence 4.7% of recurrent BRCA mutations in ovarian cancer in the Southern Chinese population. Most importantly, all our recurrent mutation carriers were identified from Southern Chinese patients from Hong Kong whilst such mutations were absent in samples from the Northern Chinese. Our findings indicate possible heterogeneity in the BRCA genotype between Northern and Southern Chinese. The identification of a founder mutation and two recurrent mutations moreover, has important implications towards screening strategies for breast and ovarian cancer among Chinese of southern ancestral origin who are now dispersed throughout the world. Copyright 2002 Wiley-Liss, Inc.
UI - 11867510
AU - Baxter SW; Choong DY; Eccles DM; Campbell IG
TI - Transforming growth factor beta receptor 1 polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer.
SO - Cancer Epidemiol Biomarkers Prev 2002 Feb;11(2):211-4
AD - Cancer Genetics Laboratory, Victorian Breast Cancer Research Consortium, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria 3002, Australia.
UI - 11715007
AU - Kauff ND; Scheuer L; Robson ME; Glogowski E; Kelly B; Barakat R; Heerdt
TI - A; Borgen PI; Davis JG; Offit K Insurance reimbursement for risk-reducing mastectomy and oophorectomy in women with BRCA1 or BRCA2 mutations.
SO - Genet Med 2001 Nov-Dec;3(6):422-5
AD - Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
PURPOSE: Risk-reducing surgery is an important option for women with BRCA1 and BRCA2 mutations. There are reports in the literature that insurance reimbursement for these procedures varies greatly. Because health insurance coverage significantly affects medical decision-making, current information regarding reimbursement practices of third-party payers is needed. METHODS: Retrospective study of hospital billing records of 38 women with documented BRCA1 or BRCA2 mutations who underwent either a risk-reducing mastectomy or a risk-reducing oophorectomy between March 1, 1997, and July 30, 2000. RESULTS: Complete billing and reimbursement information was available for 35 women undergoing a total of 39 risk-reducing surgeries. A total of 38 of 39 (97%) risk-reducing surgeries were covered in full, less applicable coinsurance and deductibles. The rate of insurance reimbursement did not vary with type of insurance, personal history of cancer, or type of procedure. CONCLUSION: Insurance carriers reimbursed the vast majority of BRCA mutation carriers undergoing risk-reducing surgery.
UI - 11811029
AU - Castex MP; Bertozzi AI; Rubie H; Domenech B; Duchayne E; Selves J;
TI - Dastugue N; Danjoux M; Kulhein E; Galinier P; Robert A [Testicular feminization, germinal tumor, NK lymphoma: what is the relationship?]
SO - Arch Pediatr 2001 Dec;8(12):1337-40
AD - Unite d'hemato-oncologie, hopital des enfants, BP 3119, 31026 Toulouse, France.
CASE REPORT: The authors report the case of a ten-year-old girl, who had been treated for a malignant germinal tumour five years before, presenting with a leukaemia-like syndrome associating bone pain, liver and spleen nodules and bone marrow involvement. The cyto-pathological analysis showed undifferentiated cells and CD56 and protein S100 were found as the only positive markers. The child received several subsequent lines of chemotherapy and ultimately died of the disease. COMMENTS: Particular cytogenetic abnormalities were observed (iso1q10, iso6p10) and were in favor of an unusual NK cell lymphoma. CONCLUSION: This analysis revealed a XY genotype (testicular feminization syndrome).
UI - 11852357
AU - Gancberg D; Scourneau M; Verdebout JM; Larsimont D; Verhest A
TI - [Detection of extra chromosomes 12 by fluorescent in situ hybridization (FISH) in ovarian stromal tumors. Study of 12 cases and review of the literature]
SO - Ann Pathol 2001 Oct;21(5):393-8
AD - Laboratoire d'Anatomie Pathologique, Institut Jules Bordet, 1, rue Heger-Bordet, 1000 Bruxelles, Belgique, France.
Chromosomic aberrations play a major role in the initiation and the progression of benign as well as malignant tumors. In particular, trisomy 12 is frequently observed in female genitourinary tract tumors and constitutes a recurrent and often unique anomaly in stromal ovarian tumors such as fibrothecomas. Today, the genetic analysis of fresh or fixed solid tumors is enabled by the fluorescent in situ hybridization method (FISH). Using FISH and/or conventional cytogenetics, we analysed 12 ovarian stromal tumors (6 fibromas, 3 fibro thecomas and 3 thecomas). All of these tumors were benign and trisomy 12 was observed in all cases. Moreover, 3 cases presented trisomy and tetrasomy for chromosome 12 simultaneously. The high frequency of trisomy 12 in this tumor type suggests that this abnormality might be implicated in ovarian tumorigenesis.
UI - 11751530
AU - Gregoire L; Rabah R; Schmelz EM; Munkarah A; Roberts PC; Lancaster WD
TI - Spontaneous malignant transformation of human ovarian surface epithelial cells in vitro.
SO - Clin Cancer Res 2001 Dec;7(12):4280-7
AD - Department of Immunology and Microbiology, Karmanos Cancer Institute, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA.
PURPOSE: Epithelial ovarian cancer has no reliable marker for early detection and no known specific premalignant changes. Human ovarian surface epithelial (HOSE) cells expressing human papillomavirus type 16 (HPV-16) E6/E7 genes undergo crisis, and surviving cells exhibit an immortalized phenotype. Cells show an increasingly invasive phenotype on collagen rafts over time. To ascertain the nature of this aberrant growth, we characterized this spontaneous progression of HOSE cells from a benign to an invasive phenotype using histopathology, immunophenotyping, and tumorigenesis assays. EXPERIMENTAL DESIGN: At various passages, cells were monitored for growth on collagen, response to tumor necrosis factor alpha and daunorubicin, immunohistochemistry and Western blot analysis of E-cadherin and beta-catenin, growth in soft agar, and tumor formation in immunodeficient mice. RESULTS: As passage number increased, cells became increasingly aggressive on collagen, with more pronounced focal stratification and invasion. Furthermore, late-passage cells were more resistant to the apoptotic effects of TNF-alpha and daunorubicin than earlier-passage cells. E-cadherin expression was limited to early-passage cells, whereas beta-catenin was expressed regardless of passage. Cells invading collagen formed colonies in soft agar at low efficiency but were not tumorigenic in immunodeficient mice. Some cultures recovered from colonies grew in soft agar at high efficiencies, and one was tumorigenic. CONCLUSIONS: HOSE cells expressing E6/E7, over time, develop characteristics of malignant cells and produce tumors consistent with an ovarian surface epithelium lineage. Progression of HOSE cells from a benign to an invasive phenotype in vitro may provide a model to dissect the progression of ovarian cancer.
UI - 11879576
AU - Roberts D; Williams SJ; Cvetkovic D; Weinstein JK; Godwin AK; Johnson
TI - SW; Hamilton TC Decreased expression of retinol-binding proteins is associated with malignant transformation of the ovarian surface epithelium.
SO - DNA Cell Biol 2002 Jan;21(1):11-9
AD - Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
We have developed a modified form of suppression subtractive hybridization (SSH) that allows multiple specimens of distinct phenotypic groups to be compared for consistent differences in gene expression. We applied this system to identify genes that were expressed in normal rat ovarian surface epithelial (ROSE) cells but whose expression was lost/downregulated in four independently transformed rat ovarian cancer cell lines. Northern blot analysis using 14 of 28 nonredundant cDNA fragments from this difference library showed that the mRNA transcripts were present in normal ROSE cells but lost or markedly downregulated in four related transformed cell lines. Of particular interest, cellular retinol-binding protein 1 (CRBP1) and retinol-binding protein (RBP), two genes whose products are involved in retinol transport and metabolism, were found to be downregulated in this ovarian cancer model system. To determine if this change had relevance to human ovarian cancer, we evaluated a series of human ovarian cancer cell lines and a limited number of frozen human ovarian tumors and found lost or decreased expression of CRBP1 and RBP relative to expression in human ovarian surface epithelial (HOSE) cells. We hypothesize that the loss of CRBP1 and RBP expression disrupts retinol metabolism and retinoic acid production, which may facilitate the occurrence of genetic damage leading to the malignant transformation of the ovarian surface epithelium, the cells from which ovarian cancer arises.
UI - 11890988
AU - Sham JS; Tang TC; Fang Y; Sun L; Qin LX; Wu QL; Xie D; Guan XY
TI - Recurrent chromosome alterations in primary ovarian carcinoma in Chinese women.
SO - Cancer Genet Cytogenet 2002 Feb;133(1):39-44
AD - Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.
Ovarian cancer is one of the most frequent gynecological malignancies worldwide with a poor prognosis. Comparative genomic hybridiza