National Cancer Institute®
Last Modified: October 1, 2002
UI - 11936875
AU - Li QQ; Yunmbam MK; Zhong X; Yu JJ; Mimnaugh EG; Neckers L; Reed E
TI - Lactacystin enhances cisplatin sensitivity in resistant human ovarian cancer cell lines via inhibition of DNA repair and ERCC-1 expression.
SO - Cell Mol Biol (Noisy-le-grand) 2001;47 Online Pub():OL61-72
AD - Medical Ovarian Cancer Section, Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, MD 20892, USA. firstname.lastname@example.org
Cisplatin is among the most effective chemotherapeutic agents in the treatment of human ovarian cancer. The cytotoxicity of cisplatin results primarily from its ability to bind covalently to DNA and prevent DNA replication and transcription. The ubiquitin-proteasome pathway plays important roles in a broad array of basic cellular processes. Lactacystin is a selective inhibitor of the proteasome that can inhibit the ubiquitin pathway. However, the effect of lactacystin on DNA repair and the antitumor activity of cisplatin in ovarian cancer have not been evaluated. We report in this work that lactacystin, at concentrations that do not appear harmful, increased cisplatin toxicity in three resistant human ovarian carcinoma cell lines. In addition, lactacystin significantly enhanced DNA platination and decreased DNA repair of cisplatin-DNA adducts in these cell lines, as measured by atomic absorption spectrometry. Furthermore, Northem blot analysis and in vitro nuclear transcript elongation assay demonstrated that lactacystin dramatically reduced the steady-state mRNA expression and the rate of transcription of the DNA repair gene ERCC-1 in these cells. These observations indicate that proteasome inhibition has impact on nucleotide excision repair in several ways: i/ the normal ERCC-1 message upregulation is suppressed; ii/ cisplatin-DNA adduct repair is inhibited, and iii/ DNA platination, as well as cisplatin cytotoxicity, is enhanced.
UI - 11954756
AU - Shimoyama H; Nakajima M; Naka H; Park YD; Hori K; Morikawa H; Yoshioka A
TI - A girl with bilateral ovarian tumours: Frasier syndrome.
SO - Eur J Pediatr 2002 Feb;161(2):81-3
AD - Department of Paediatrics, Nara Medical University, Kashihara City, Japan. email@example.com
Frasier syndrome (FS) is characterised by male pseudohermaphroditism, slowly progressing nephropathy and frequent development of gonadoblastoma. The Wilms' tumour suppressor gene (WT1 gene) plays an important role in the development of the urogenital system and the gonads. A splice mutation in intron 9 of the WT1 gene was recently described in patients with FS. We analysed the WT1 gene of a Japanese patient with male pseudohermaphroditism, steroid resistant-nephr-opathy and gonadoblastoma by the polymerase chain reaction and direct sequencing and detected a heterozygous point mutation in intron 9. CONCLUSION: analysis of the Wilms' tumour suppressor gene in a patient with Frasier syndrome by the polymerase chain reaction and direct sequencing detected a + 5G -->A transition at a position of the second alternative splice region of exon 9, important for predicting the risk of the occurrence of Wilms' tumour.
UI - 12203782
AU - Arcellana-Panlilio MY; Egeler RM; Ujack E; Magliocco A; Stuart GC;
TI - Robbins SM; Coppes MJ Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors.
SO - Genes Chromosomes Cancer 2002 Oct;35(2):176-81
AD - Department of Oncology, University of Calgary, Calgary, Canada.
Granulosa cell tumors (GCTs) of the ovary are relatively rare and account for <5% of all ovarian cancers. The molecular pathogenesis of these tumors is not well understood. We tested the hypothesis that cyclin-dependent kinase inhibitors, specifically the inhibitors of the cyclin-dependent kinase 4 (INK4) family, are targets for altered gene expression in GCTs. The status of RB1, INK4A, INK4B, INK4C, INK4D, and ARF in 13 adult and 2 juvenile ovarian GCTs was determined by reverse transcription-polymerase chain reaction of total RNA and exon-specific sequencing of genomic DNA. Tumors showing loss of INK4A expression were assayed further by exon-deletion analysis and methylation-specific PCR. None of the juvenile tumors demonstrated altered expression, but 7/12 (58%) adult GCTs lacked expression of INK4A, INK4B, or both. In one of these cases, we noted a homozygous deletion of the INK4A locus, and in the remaining tumors we found hypermethylation of the promoter region, a mechanism that can lead to gene inactivation. These data support a role for the INK4 family of CDK inhibitors in the biology of GCTs. Copyright 2002 Wiley-Liss, Inc.
UI - 12228708
AU - Wilson JH; Elledge SJ
TI - Cancer. BRCA2 enters the fray.
SO - Science 2002 Sep 13;297(5588):1822-3
AD - Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
UI - 12240546
AU - Thames HD; Petersen C; Petersen S; Nieder C; Baumann M
TI - Immunohistochemically detected p53 mutations in epithelial tumors and results of treatment with chemotherapy and radiotherapy. A treatment-specific overview of the clinical data.
SO - Strahlenther Onkol 2002 Aug;178(8):411-21
AD - Department of Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
BACKGROUND: The aim was to ascertain whether many hundreds of clinical reports over the last decade are consistent with the prediction of a poorer outcome in cancer patients with p53 abnormalities treated with cytotoxic drugs and radiation. MATERIAL AND METHOD: There are 301 studies on the influence of p53 overexpression published through summer 2000, in which chemotherapy or radiotherapy was used alone or in combination with surgery. From 45 reports meeting stringent selection rules, comparison groups are identified in whom the same measure of outcome was reported for the same treatment applied to the same tumor, with results corrected for important prognostic factors. Metaanalysis techniques are then applied to the comparison groups. Attention was limited to reports using immunohistochemical techniques, to form comparison groups of sufficient size. RESULTS: Four comparison groups were identified by treatment and endpoint: 1) Stage I-III breast cancer (surgery and chemotherapy, disease-free survival, seven studies); 2) stage I-III breast cancer (surgery and chemotherapy, overall survival, six studies); 3) stage II-IV head and neck cancer (radiotherapy and chemotherapy, overall survival, five studies); 4) FIGO I-IV ovarian cancer (surgery and chemotherapy, overall survival, six studies). In the breast (disease-free survival) and ovarian (overall survival) comparison groups, the hazard ratio for a deleterious effect of p53 overexpression was significant or marginally significant, depending on assumed ranges for unreported hazard ratios in non-significant studies. CONCLUSIONS: Despite the many caveats related to metaanalysis applied to retrospective data, high variability of immunohistochemical technique, etc., a nearly significant negative effect of p53 overexpression on outcome of treatment with cytotoxic drugs and radiation emerges in the few studies where heterogeneity can be sufficiently reduced or accounted for.
UI - 12237282
AU - Brose MS; Rebbeck TR; Calzone KA; Stopfer JE; Nathanson KL; Weber BL
TI - Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.
SO - J Natl Cancer Inst 2002 Sep 18;94(18):1365-72
AD - Department of Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia 19104, USA.
BACKGROUND: Increasing numbers of BRCA1 mutation carriers are being identified in cancer risk evaluation programs. However, no estimates of cancer risk specific to a clinic-based population of mutation carriers are available. These data are clinically relevant, because estimates based on families ascertained for linkage studies may overestimate cancer risk in mutation carriers, and population-based series may underestimate it. Wide variation in risk estimates from these disparate ascertainment groups makes counseling in risk evaluation programs difficult. The purpose of this study was to estimate BRCA1-related cancer risks for individuals ascertained in a breast cancer risk evaluation clinic. METHODS: Cumulative observed and age-adjusted cancer risk estimates were determined by analyzing 483 BRCA1 mutation carriers in 147 families identified in two academic breast and ovarian cancer risk evaluation clinics. Cancer risks were computed from the proportion of individuals diagnosed with cancer during a 10-year age interval from among the total number of individuals alive and cancer-free at the beginning of that interval. Age-of-diagnosis comparisons were made using two-sided Student's t tests. RESULTS: By age 70, female breast cancer risk was 72.8% (95% confidence interval [CI] = 67.9% to 77.7%) and ovarian cancer risk was 40.7% (95% CI = 35.7% to 45.6%). The risk for a second primary breast cancer by age 70 was 40.5% (95% CI = 34.1% to 47.0%). We also identified an increased risk of cancer of the colon (twofold), pancreas (threefold), stomach (fourfold), and fallopian tube (120-fold) in BRCA1 mutation carriers as compared with Surveillance, Epidemiology, and End Results (SEER) Program population-based estimates. CONCLUSION: The estimates for breast and ovarian cancer risk in BRCA1 mutation carriers is higher than population-based estimates but lower than estimates based on families ascertained for linkage studies. These cancer risk estimates may most closely approximate those faced by BRCA1 mutation carriers identified in risk evaluation clinics.
UI - 12237285
AU - Hilton JL; Geisler JP; Rathe JA; Hattermann-Zogg MA; DeYoung B; Buller
TI - RE Inactivation of BRCA1 and BRCA2 in ovarian cancer.
SO - J Natl Cancer Inst 2002 Sep 18;94(18):1396-406
AD - Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA.
BACKGROUND: Although BRCA1 and BRCA2 play important roles in hereditary ovarian cancers, the extent of their role in sporadic ovarian cancers and their mechanisms of inactivation are not yet well understood. Our goal was to characterize BRCA2 mutations and mRNA expression in a group of ovarian tumors previously evaluated for BRCA1 mutations and mRNA expression. METHODS: The tumors of 92 unrelated women with "ovarian" cancer (i.e., ovarian, peritoneal, or fallopian tube cancer) were screened for BRCA2 null mutations using a protein truncation test. Methylation-specific polymerase chain reaction (PCR) was used to examine the BRCA2 promoter for hypermethylation in tumors that did not express BRCA2 mRNA. All statistical tests were two-sided. RESULTS: Nine tumors had a germline (n = 5) or somatic (n = 4) BRCA2 mutation; each was associated with loss of heterozygosity. All of the somatic (1445delC, E880X, 4286del8, and 5783delT) and one of the germline (5984ins4) mutations were unique to this study. One tumor had somatic mutations in both BRCA1 and BRCA2. Two tumors are, to our knowledge, the first cases of germline BRCA2-associated peritoneal cancer. Twelve additional tumors lacked detectable BRCA2 mRNA, but the BRCA2 promoter was hypermethylated in only one of them, suggesting that other mechanisms effect transcriptional silencing of BRCA2. Tumors lacking BRCA1 mRNA were more likely to lack BRCA2 mRNA than tumors expressing BRCA1 mRNA (P<.001). Overall, 82% (95% confidence interval [CI] = 74% to 90%) of the tumors contained alterations in BRCA1, BRCA2, or both genes. Of 41 informative tumors with some alteration in BRCA2, 36 also had an alteration in BRCA1. The frequency, but not the mechanism, of BRCA1 or BRCA2 dysfunction in ovarian cancer was independent of family history. CONCLUSIONS: Multiple mechanisms cause nearly universal dysfunction of BRCA1 and/or BRCA2 in hereditary and sporadic ovarian carcinoma. Ovarian cancers with BRCA2 dysfunction often have simultaneous BRCA1 dysfunction.
UI - 7304575
AU - Hildreth NG; Kelsey JL; LiVolsi VA; Fischer DB; Holford TR; Mostow ED;
TI - Schwartz PE; White C An epidemiologic study of epithelial carcinoma of the ovary.
SO - Am J Epidemiol 1981 Sep;114(3):398-405
A case-control study to identify risk factors for epithelial ovarian cancer was undertaken among women in the age group 45-74 years who had been admitted to seven hospitals in Connecticut between July, 1977, and March, 1979. Characteristics that were found to increase the risk of epithelial ovarian cancer included being white, never having been pregnant, having a late age at menopause, having a family history of cancer of the ovary or endometrium, and having a long estimated number of years of ovulation. Prior use of post-menopausal estrogens did not alter the risk for epithelial ovarian cancer, but there was some indication that oral contraceptives protect against ovarian cancer. Women with ovarian cancer were somewhat more likely to have had a history of an underactive thyroid and were somewhat less likely to have had a history of an overactive thyroid than controls, although these trends were not statistically significant.
UI - 11956643
AU - Santarosa M; Bidoli E; Gallo A; Steffan A; Boiocchi M; Viel A
TI - Polymorphic CAG repeat length within the androgen receptor gene: identification of a subgroup of patients with increased risk of ovarian cancer.
SO - Oncol Rep 2002 May-Jun;9(3):639-44
AD - Division of Experimental Oncology 1, Centro di Riferimento Oncologico-IRCCS, Aviano, Italy.
The CAG repeat (CAGn) present in the N-terminal region of the androgen receptor (AR) inversely correlates with AR transactivation activity. The aim of this study was to investigate whether polymorphic variation in the CAGn length is associated with the risk of developing ovarian cancer. Using a case-control study design 121 women with histologically confirmed ovarian cancer and 100 controls (healthy women) were genotyped for AR-CAG length. No marked difference in the mean length of CAGn was observed between ovarian cancer patients and controls. However, when considering patients with positive personal or family history of tumor (PPFHT), the mean lengths of the long allele, the short allele and the average of the 2 alleles were longer than in the controls. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were computed after allowance for age. We observed an increase in the risk of ovarian cancer, in terms of OR, in women with CAGn >or=22 (OR=2.17, 95% CI:1.10-4.27). The increase of relative risk was particularly high in women with CAGn >or=22 belonging to the PPFHT group: OR=3.52 (95% CI 1.18-10.47). We also found a statistically significant trend (chi2 trend=4.91; p=0.03) towards an increased risk of ovarian cancer with increasing CAGn length (from
UI - 12219430
AU - MacDonald DJ
TI - Women's decisions regarding management of breast cancer risk.
SO - Medsurg Nurs 2002 Aug;11(4):183-6
AD - City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Twenty-three unaffected women with a family history of breast or ovarian cancer participated in a study to ascertain their cancer-related concerns, beliefs, and preferences for risk management. Their perceptions related to breast cancer risk management options have implications for practicing nurses.
UI - 8061113
AU - Fisk B; Ioannides CG; Aggarwal S; Wharton JT; O'Brian CA; Restifo N;
TI - Glisson BS Enhanced expression of HLA-A,B,C and inducibility of TAP-1, TAP-2, and HLA-A,B,C by interferon-gamma in a multidrug-resistant small cell lung cancer line.
SO - Lymphokine Cytokine Res 1994 Apr;13(2):125-31
AD - Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, TX 77030.
Recent evidence suggests that deficient HLA Class I expression in SCLC lines may be due, in part, to down-regulation of TAP-1 and TAP-2 expression, and, thus, deficient antigen processing. Given the capability of the multidrug transporter mediating MDR, P-gp, to transport peptides, we hypothesized that P-gp may substitute for TAP-1/TAP-2 and enhance antigen processing in SCLC. To investigate this, we studied the H69 line (parent SCLC) and VPR-2 (MDR subline selected in etoposide, P-gp +). HLA-A,B,C expression was significantly increased in VPR-2 cells relative to H69, and was much more inducible with IFN-gamma. TAP-1 and TAP-2 were expressed at low levels in both lines. Differential induction of TAP-1 expression with IFN-gamma exposure was observed, with a dramatic increase in VPR-2 cells, and no change in H69. TAP-2 expression was enhanced in both lines with IFN-gamma, but to a greater degree in VPR-2. VPR-2 cells were resistant to LAK killing relative to H69, and were minimally sensitized with IFN-gamma. In contrast, IFN-gamma enhanced susceptibility of H69 to LAK killing 3-fold. The direct correlation between enhancement of HLA-A,B,C expression by IFN-gamma and the differential inducibility of TAP-1 and TAP-2 expression in P-gp-SCLC lines is novel. Relative LAK sensitivity of H69 and its increase by IFN-gamma may have clinical implications.
UI - 12181777
AU - Liede A; Malik IA; Aziz Z; Rios Pd Pde L; Kwan E; Narod SA
TI - Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan.
SO - Am J Hum Genet 2002 Sep;71(3):595-606
AD - University of Toronto, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, Canada.
The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution that genetic factors make to these high rates, we have conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from two major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7% (95% confidence interval [CI] 4.1%-9.4%), and that among case subjects with ovarian cancer was 15.8% (95% CI 9.2%-22.4%). Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. The majority of detected mutations are unique to Pakistan. Five BRCA1 mutations (2080insA, 3889delAG, 4184del4, 4284delAG, and IVS14-1A-->G) and one BRCA2 mutation (3337C-->T) were found in multiple case subjects and represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 is comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1-mutation-positive case subjects was 48% and was 37% for first-degree relatives of the BRCA2-mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio [OR] 2.1; 95% CI 1.4-3.3; P=.001). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age <40 years) (OR=2.7; 95% CI 1.5-4.9; P=.0008) and case subjects with ovarian cancer (OR=2.4; 95% CI 1.4-4.2; P=.002). These results suggest that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan.
UI - 10639883
AU - Reynolds PP; Benkendorf JL
TI - Genes and generalists: why we need professionals with added competencies.
SO - West J Med 1999 Nov-Dec;171(5-6):375-9
AD - Department of Medicine and History, Johns Hopkins University School of Medicine, Baltimore, MD, USA. firstname.lastname@example.org
UI - 12039933
AU - Berry DA; Iversen ES Jr; Gudbjartsson DF; Hiller EH; Garber JE; Peshkin
TI - BN; Lerman C; Watson P; Lynch HT; Hilsenbeck SG; Rubinstein WS; Hughes KS; Parmigiani G BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
SO - J Clin Oncol 2002 Jun 1;20(11):2701-12
AD - Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA. email@example.com
PURPOSE: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. PATIENTS AND METHODS: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. RESULTS: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. CONCLUSION: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.
UI - 12354469
AU - Bergfeldt K; Rydh B; Granath F; Gronberg H; Thalib L; Adami HO; Hall P
TI - Risk of ovarian cancer in breast-cancer patients with a family history of breast or ovarian cancer: a population-based cohort study.
SO - Lancet 2002 Sep 21;360(9337):891-4
AD - Department of Medical Epidemiology, Karolinska Institutet, S-171 77 Stockholm, Sweden. Kjell.Bergfeldt@mep.ki.se
BACKGROUND: Patients with breast cancer who have mutations in the high penetrance genes BRCA1 and BRCA2, have an increased risk of ovarian cancer. Because these mutations are rare, easily obtained information such as age and family history of breast or ovarian cancer might be preferable for assessment of ovarian cancer risk in clinical practice. METHODS: We linked data from the Swedish Cancer Register to the Swedish Generation Register and generated a cohort of 30552 breast-cancer patients born after 1931, with information on breast and ovarian cancer diagnosis from 146117 first-degree relatives. Standardised incidence ratios (SIRs) with 95% CIs were calculated with nationwide rates of ovarian cancer, adjusted for age and calendar year. FINDINGS: During a mean follow-up of 6 years, 122 incident ovarian cancers were identified in the cohort, yielding an overall SIR of 2.0 (95% CI 1.6-2.4). The risk was higher in breast-cancer patients diagnosed before the age of 40 years, with a family history of breast cancer (5.6; 1.8-13.1) or ovarian cancer (17.0; 3.5-50.0). A consistently increased risk was noted in patients with a relative who was diagnosed before the age of 50 years, with either breast or ovarian cancer. Women with a family history of ovarian cancer have an almost 10% risk of developing ovarian cancer before the age of 70. INTERPRETATION: In young women with breast cancer, the risk of ovarian cancer is greatly raised when a family history of breast or ovarian cancer is present. Close medical surveillance, and perhaps even prophylactic oophorectomy, might be justified in high-risk groups.
UI - 12006538
AU - Buller RE; Shahin MS; Geisler JP; Zogg M; De Young BR; Davis CS
TI - Failure of BRCA1 dysfunction to alter ovarian cancer survival.
SO - Clin Cancer Res 2002 May;8(5):1196-202
AD - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Iowa Hospital and Clinic, Iowa City 52242-1009, USA. firstname.lastname@example.org
PURPOSE: Many factors modify ovarian cancer survival. There are conflicting reports regarding survival of individuals with hereditary BRCA1-related ovarian cancer. None have controlled for other mechanisms of BRCA1 silencing in the control cohort. EXPERIMENTAL DESIGN: Fifty-nine cancers with presumed BRCA1 dysfunction because of mutation (24 germ-line and 16 somatic) or absent BRCA1 mRNA because of promoter hypermethylation (n = 19) were identified among 250 consecutively screened ovarian cancers. Controls were matched from the same population based on p53 mutation type, age at diagnosis, Federation Internationale des Gynaecologistes et Obstetristes surgical stage and histological grade, residual disease, preoperative CA125, disease site, and the presence of BRCA1 mRNA translatable in an in vitro protein expression assay. BRCA1 promoter hypermethylation was determined by the methylation-specific PCR technique. The significance of promoter hypermethylation was confirmed by the absence of detectable BRCA1 mRNA. RESULTS: The median survival for individuals with ovarian cancer BRCA1 dysfunction was 4.1 years versus 3.5 years in the case matched controls (P = 0.98). Grouped on the basis of the mechanism of BRCA1 dysfunction, median survival was 4.5, 2.8, and 2.3 years for germ-line, somatic, and BRCA1 promoter-silenced ovarian cancers. However, for the corresponding matched controls with wild-type BRCA1 sequence, the median survival was virtually identical: 4.6, 2.8, and 3.3 years, respectively. In a Cox proportional hazards analysis, only residual disease (P = 0.0001), age (P = 0.01), and Federation Internationale des Gynaecologistes et Obstetristes stage (P = 0.011) entered the survival model. CONCLUSIONS: In contrast with other published reports, we are unable to detect large survival differences between matched case-control cohorts of ovarian cancers with BRCA1 inactivation by any of three independent mechanisms.
UI - 12060539
AU - Duarte F; Cameselle-Teijeiro JF; Soares R; Seixas C; Cortizo-Torres ME;
TI - Perez-Villanueva J; Schmitt FC [Analysis of mutations in genes BRCA1 and BRCA2 among patients with breast and ovarian cancer in northern Portugal and Galicia]
SO - Rev Clin Esp 2002 May;202(5):259-63
AD - Instituto de Patologia e Inmunologia Molecular, Universidad do Porto (IPATIMUP), Porto, Portugal, Spain.
OBJECTIVE: To detect mutations in the BRCA1 and BRCA2 genes by means of the protein truncation test (PTT) in a population in northern Portugal and Galicia with breast and ovarian cancer. DESIGN: Prospective study. SETTING: Patients in northern Portugal and Galicia with family history of breast and/or ovarian cancer.Patients. A total of 76 women with family history of breast cancer according to the BCLC criteria (Breast Cancer Linkage Consortium) were studied at IPATIMUP. MAIN RESULTS: Five cases (6.5%) with changes in the normal sequence in genes BRCA1 and BRCA2 were identified; three of these mutations occurred in the gene BRCA1 and the other two in the gene BRCA2. Two out of the three mutations found in the gene BRCA1 were de novo mutations. Changes detected in the normal sequence in the gene BRCA2 were mutations reported for the first time among the study population, according to the information obtained through the BCIC database (Breast Cancer Information Core). CONCLUSIONS: This was the first study in detecting individuals carrying mutations in the susceptibility breast cancer genes BRCA1 and BRCA2 among the population of northern Portugal and Galicia.
UI - 12068172
AU - Halabi M; Oliva E; Mazal PR; Breitenecker G; Young RH
TI - Prostatic tissue in mature cystic teratomas of the ovary: a report of four cases, including one with features of prostatic adenocarcinoma, and cytogenetic studies.
SO - Int J Gynecol Pathol 2002 Jul;21(3):261-7
AD - Department of Pathology, General Hospital of Ried, Austria.
Four cases of mature cystic teratoma that contained prostatic tissue are reported. The ovarian tumors occurred in patients from 17 to 38 (mean 31) years of age and had no unusual clinical or gross aspects. The microscopic findings for the most part were typical of a mature cystic teratoma, but they also contained foci of prostatic tissue that ranged from 0.2 to 1.9 cm in greatest dimension. In these areas there was a lobular arrangement of medium-sized acini lined by cuboidal to columnar cells with pale cytoplasm and round nuclei with inconspicuous nucleoli except focally in one case as noted below. Basal cells were seen focally. The prostatic acini lay in a paucicellular fibromuscular stroma. In two cases thick layers of disorganized smooth muscle covered by transitional-like pseudostratified epithelium, resulting in an appearance resembling fetal bladder wall, were present next to the prostatic glands. One tumor also contained prostatic-type acini, which haphazardly infiltrated the stroma over an area approximately 5 mm in maximal dimension. The acini, a few of which contained intraluminal flocculent eosinophilic material, were lined by cells with eosinophilic to amphophilic focally granular cytoplasm and had nuclei that were enlarged compared with the benign-appearing, prostatic-type acini in the four cases and had focally prominent nucleoli. Basal cells were not identified in these infiltrating glands. Grading this focus according to the approach in the prostate, the morphology was that of a Gleason grade 3 of 5 adenocarcinoma. Immunohistochemical stains of the putative prostatic epithelial cells confirmed their nature by showing immunoreactivity for prostatic-specific antigen in the lining epithelial cells in all four cases and for prostatic-specific acid phosphatase in the one case tested. The high molecular cytokeratin stain, 34betaE12, highlighted basal cells to a variable extent in the three cases containing only benign prostatic tissue. Material was not available to immunostain for basal cells in the case with carcinoma. Cytogenetic studies were performed in two cases and showed that the great majority of the nuclei of the nonprostatic and prostatic tissue had an XX karyotype but from 3% to 5% of the nuclei displayed trisomy for the X chromosome. A small number of cases of prostatic tissue in ovarian teratomas have previously been documented but none had morphologic features of carcinoma.
UI - 12068173
AU - Gallardo A; Matias-Guiu X; Lagarda H; Catasus L; Bussaglia E; Gras E;
TI - Suarez D; Prat J Malignant mullerian mixed tumor arising from ovarian serous carcinoma: a clinicopathologic and molecular study of two cases.
SO - Int J Gynecol Pathol 2002 Jul;21(3):268-72
AD - Department of Pathology, Hospital Santa Creu i Sant Pau, Autonomous University of Barcelona, Spain.
The clinical, histologic, and molecular pathologic features of two cases of malignant mullerian mixed tumor (MMMT) arising from ovarian papillary serous carcinoma are presented. Identical p53 mutations were detected in the primary ovarian carcinoma and the subsequent MMMT in each case.
UI - 12360411
AU - Gad S; Caux-Moncoutier V; Pages-Berhouet S; Gauthier-Villars M; Coupier
TI - I; Pujol P; Frenay M; Gilbert B; Maugard C; Bignon YJ; Chevrier A; Rossi A; Fricker JP; Nguyen TD; Demange L; Aurias A; Bensimon A; Stoppa-Lyonnet D Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families.
SO - Oncogene 2002 Oct 3;21(44):6841-7
AD - Service de Genetique Oncologique, Institut Curie, Paris, France.
Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast-ovarian cancers. However, BRCA1 germline mutations are found much less frequently than expected, especially as standard PCR-based mutation detection approaches focus on point and small gene alterations. In order to estimate the contribution of large gene rearrangements to the BRCA1 mutation spectrum, we have extensively analysed a series of 120 French breast-ovarian cancer cases. Thirty-eight were previously found carrier of a BRCA1 point mutation, 14 of a BRCA2 point mutation and one case has previously been reported as carrier of a large BRCA1 deletion. The remaining 67 cases were studied using the BRCA1 bar code approach on combed DNA which allows a panoramic view of the BRCA1 region. Three additional rearrangements were detected: a recurrent 23.8 kb deletion of exons 8-13, a 17.2 kb duplication of exons 3-8 and a 8.6 kb duplication of exons 18-20. Thus, in our series, BRCA1 large rearrangements accounted for 3.3% (4/120) of breast-ovarian cancer cases and 9.5% (4/42) of the BRCA1 gene mutation spectrum, suggesting that their screening is an important step that should be now systematically included in genetic testing surveys.
UI - 12363043
AU - Zaffaroni N; Pennati M; Colella G; Perego P; Supino R; Gatti L; Pilotti
TI - S; Zunino F; Daidone MG Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer.
SO - Cell Mol Life Sci 2002 Aug;59(8):1406-12
AD - Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
Stable transfection of human ovarian carcinoma cells with survivin cDNA caused a four- to sixfold increase in cell resistance to taxotere and taxol (two-sided Student's t test, p < 0.05), with a concomitant reduction in the apoptotic response to taxol, but did not affect cell sensitivity to cisplatin or oxaliplatin. Such findings were indirectly supported by similar observations obtained with clinical tumours. In fact, high levels of survivin protein expression (>30% positive cells), detected by immunohistochemistry in 90/124 (73%) advanced ovarian carcinomas, were significantly associated with clinical resistance to a taxol/platinum-based regimen but unrelated to tumour shrinkage following cisplatin-including combinations (non-taxol based). In the 95 patients receiving a taxol/platinum-based regimen, survivin overexpression correlated with a lower clinical or pathologic complete remission rate than absent/low protein expression (43 vs 75%, p = 0.0058 by logistic regression adjusted for tumour stage, histological grade and p53 expression). Conversely, in the 29 cases treated with cisplatin-containing regimens (not taxol based), survivin expression was unrelated to tumour response. Cellular studies and clinical data suggest a direct link between survivin expression and tumour cell susceptibility to taxol.
UI - 12216079
AU - Nakayama K; Kanzaki A; Ogawa K; Miyazaki K; Neamati N; Takebayashi Y
TI - Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP.
SO - Int J Cancer 2002 Oct 10;101(5):488-95
AD - Department of Pathology Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Intrinsic or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with solid carcinoma. Cisplatin is one of the most effective chemotherapeutic agents for treating ovarian carcinoma. Recently, copper-transporting P-type adenosine triphosphatase (ATP7B) has been demonstrated as one of the genes responsible for cisplatin resistance in vitro. We hypothesized that the expression of ATP7B gene increases resistance to cisplatin in ovarian carcinoma and a priori knowledge of its expression is important for the choice of therapy. The aim of our study was to assess the role of ATP7B gene in ovarian carcinoma and compare its expression with those of multidrug resistance-related transporters such as MDR1, MRP1, MRP2, LRP and BCRP genes. The transporters' gene expression profiles from 82 patients treated with cisplatin-based chemotherapy after surgery were assessed by RT-PCR. We did not observe any significant correlation between ATP7B gene expression and those of MDR1, MRP1, MRP2, LRP or BCRP. The expression level of ATP7B gene was significantly increased (p < 0.05) in patients with moderately-/poorly-differentiated ovarian carcinomas treated with cisplatin-based chemotherapy, thus ATP7B may serve as an independent prognostic factor in these patients. In contrast, the expression level of MDR1, MRP1, MRP2, LRP and BCRP genes were not prognostic indicators of disease. These findings suggest that ATP7B gene may be considered as a novel chemoresistance marker and that inhibitor(s) of ATP7B might be useful, in patients with ovarian carcinoma treated with cisplatin-based chemotherapy. Copyright 2002 Wiley-Liss, Inc.
UI - 9159328
AU - Eltabbakh GH; Belinson JL; Kennedy AW; Biscotti CV; Casey G; Tubbs RR
TI - p53 and HER-2/neu overexpression in ovarian borderline tumors.
SO - Gynecol Oncol 1997 May;65(2):218-24
AD - Department of Gynecology, Cleveland Clinic Foundation, Ohio 44195, USA.
OBJECTIVE: To study p53 and HER-2/neu expression in borderline ovarian tumors (BLOT) by assessing their frequency, coexpression, and relationship to histologic type, FIGO stage, tumor recurrence, and survival. METHODS: Forty-two patients with confirmed BLOT (25 serous, 13 mucinous, and 4 seromucinous) were followed for 1.5 to 14 years (mean, 6.3). Thirty (71%) patients had FIGO stage I and 12 (29%) had FIGO stage III disease. Paraffin-embedded sections from the 42 BLOT, 5 normal ovaries, and 10 benign ovarian cystadenomas were stained using monoclonal antibodies against human p53 (DAKO-p53, DAKO, Denmark) and HER-2/neu (C-erB-2, Triton, Parkway, CA). Positive staining was semiquantitated depending on the number of positively stained tumor cells. p53 and HER-2/neu overexpressions were correlated to each other, to histologic subtype, stage, tumor recurrence, and survival. RESULTS: None of the patients had tumor recurrence. The 5- and 10-year disease-free survival was 100%. None of the normal ovaries or ovarian cystadenomas demonstrated overexpression of p53 or HER-2/neu. Ten (24%) BLOT demonstrated overexpression of p53 and 9 (21%) demonstrated overexpression of HER-2/neu. HER-2/neu overexpression was significantly greater in stage III than in stage I tumors (P = 0.0157). Seromucinous BLOT demonstrated significantly greater p53 overexpression compared with other histologic subtypes (P = 0.030). Coexpression of p53 and HER-2/neu occurred in 4 patients (9.5%). There was no significant correlation between the overexpression of p53 and HER-2/neu (P = 0.180) and no significant relationship between p53 and HER-2/neu overexpression and the presence of microinvasion, ability to perform optimal cytoreductive surgery, tumor recurrence, or survival. CONCLUSIONS: p53 and HER-2/neu overexpression occurred in about 20-25% of BLOT overall and more commonly in seromucinous and advanced stage tumors. Coexpression occurred in 9.5% of the cases with no significant correlation between the expression of p53 and HER-2/neu.
UI - 12070798
AU - Tanner B; Pilch H; Schaffer U; Franzen A; Seufert R; Hengstler JG
TI - [Expression of c-erbB-2 and topoisomerase II alpha in relation to chemoresistance in ovarian cancer]
SO - Zentralbl Gynakol 2002 Mar;124(3):176-83
AD - Universitatsfrauenklinik Mainz, Langenbeckstasse 1, Germany.
In the present study, we examined die role of c-erbB-2 for chemoresistance in ovarian cancer. Overexpression of c-erbB-2 mRNA in tumor tissue was associated with a shorter survival of patients with primary ovarian cancer (P = 0.0001, N = 77) and was an independent prognostic factor in the proportional-hazard model (P = 0.035). A significant association between expression of c-erbB-2 mRNA und survival was obtained for the subgroup of patients who received a standard chemotherapy with carboplatin or cisplatin and cyclophosphamide (P = 0.0003). In addition, the application of a standard chemotherapy improved the survival of patients with relatively low c-erbB-2 expression (P = 0.013), but not of patients with overexpression of c-erbB-2 (P = 0.359). Expression of c-erbB-2 mRNA correlated with expression of topoisomerase IIalpha mRNA determined by a reverse semiquantitative PCR technique (P = 0.009), whereas expression of c-erbB-2 und topoisomerase IIbeta mRNA dit not correlate (P = 0.221). The data suggest that topoisomerase IIalpha, which correlates with c-erbB-2 expression, contributes to the resistance of c-erbB-2-overexpressing carcinomas.
UI - 12096084
AU - Jazaeri AA; Yee CJ; Sotiriou C; Brantley KR; Boyd J; Liu ET
TI - Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers.
SO - J Natl Cancer Inst 2002 Jul 3;94(13):990-1000
AD - Division of Clinical Sciences of the National Cancer Institute, Gaithersburg, MD,USA.
BACKGROUND: Germline mutations in BRCA1 and BRCA2 are responsible for 5%-10% of epithelial ovarian cancers, but the molecular pathways affected by these mutations are unknown. We used complementary DNA (cDNA) microarrays to compare gene expression patterns in ovarian cancers associated with BRCA1 or BRCA2 mutations with gene expression patterns in sporadic epithelial ovarian cancers and to identify patterns common to both hereditary and sporadic tumors. METHODS: Tumor samples from 61 patients with pathologically confirmed epithelial ovarian adenocarcinoma with matched clinicopathologic features were studied, including 18 with BRCA1 founder mutations, 16 with BRCA2 founder mutations, and 27 without either founder mutation (termed sporadic cancers). The cDNA microarrays contained 7651 sequence-verified features. Gene expression data were analyzed with a modified two-sided F test, with P<.0001 considered statistically significant. The expression level of six genes was also studied with reverse transcription-polymerase chain reaction. RESULTS: The greatest contrast in gene expression was observed between tumors with BRCA1 mutations and those with BRCA2 mutations; 110 genes showed statistically significantly different expression levels (P<.0001). This group of genes could segregate sporadic tumors into two subgroups, "BRCA1-like" and "BRCA2-like," suggesting that BRCA1-related and BRCA2-related pathways are also involved in sporadic ovarian cancers. Fifty-three genes were differentially expressed between tumors with BRCA1 mutations and sporadic tumors; six of the 53 mapped to Xp11.23 and were expressed at higher levels in tumors with BRCA1 mutations than in sporadic tumors. Compared with the immortalized ovarian surface epithelial cells used as reference, several interferon-inducible genes were overexpressed in the majority of tumors with a BRCA mutation and in sporadic tumors. CONCLUSIONS: Mutations in BRCA1 and BRCA2 may lead to carcinogenesis through distinct molecular pathways that also appear to be involved in sporadic cancers. Sporadic carcinogenic pathways may result from epigenetic aberrations of BRCA1 and BRCA2 or their downstream effectors.
UI - 12359861
AU - Bertucci F; Eisinger F; Tagett R; Sobol H; Birnbaum D
TI - Re: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers.
SO - J Natl Cancer Inst 2002 Oct 2;94(19):1506-7
UI - 12063435
AU - Rose SL; Buller RE
TI - The role of p53 mutation in BRCA1-associated ovarian cancer.
SO - Minerva Ginecol 2002 Jun;54(3):201-9
AD - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. email@example.com
Ovarian cancer remains the most deadly gynecologic malignancy, resulting in an estimated 23,300 new cases and 13,900 deaths in the United States in the year 2002. The discovery of the BRCA1 gene in 1994 has proven to be of great interest to the study of hereditary ovarian cancer. BRCA1 gene mutation confers a 16-42% lifetime risk of the development of ovarian cancer in those affected. Although BRCA1 functions as a tumor suppressor gene, conflicting studies have shown that BRCA1 dysfunction alone may not be sufficient for tumorigenesis. p53 is a tumor suppressor gene found to be dysfunctional in nearly 50% of all human cancers and in up to 80% of ovarian malignancies. The p53 protein product plays a crucial role in DNA surveillance and repair at the Gap 1-synthesis (G1-S) cell cycle checkpoint. Studies exhibiting the interaction of BRCA1 and p53 and the role of this interaction in DNA damage response led many investigators to suggest that p53 gene mutation is required for BRCA1-associated tumor development. This review explores the evidence for BRCA1 and p53 interplay, and outlines the crucial role p53 may play in BRCA1-related ovarian cancer.
UI - 12370157
AU - Goodman MT; Wu AH; Tung KH; McDuffie K; Cramer DW; Wilkens LR; Terada K;
TI - Reichardt JK; Ng WG Association of galactose-1-phosphate uridyltransferase activity and N314D genotype with the risk of ovarian cancer.
SO - Am J Epidemiol 2002 Oct 15;156(8):693-701
AD - Epidemiology Section, Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813, USA. firstname.lastname@example.org
Deficiency in the galactose-1-phosphate uridyltransferase (GALT) enzyme results in accumulation of galactose and its metabolites in the ovary (Am J Epidemiol 1989;130:904-10). Galactose may raise gonadotropin levels, resulting in proliferation of ovarian epithelium. In 1993-1999, the authors conducted a population-based case-control study of ovarian cancer in Hawaii and Los Angeles, California, to examine the hypothesis that reduced GALT activity is associated with an increased risk of ovarian cancer. A total of 239 ovarian cancer cases and 244 population controls were interviewed. A blood sample was collected to measure levels of GALT and to assay for the N314D (A940G) polymorphism of the GALT gene. Covariate-adjusted mean GALT activity was similar between cases (23.8 micro mol per hour/g hemoglobin (Hb)) and controls (23.7 micro mol per hour/g Hb) (p = 0.83). No evidence was found for a dose-response relation between the odds ratios for ovarian cancer and GALT activity or the ratio of lactose intake to GALT activity. The risk associated with the presence of at least one variant Asp314 allele was 0.77 (95% confidence interval: 0.42, 1.41). This study did not support the hypothesis that reduced galactose metabolism is a risk factor for ovarian cancer, although increased GALT activity attenuated the inverse association of oral contraceptive pill use with risk. <