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Cancer Types   /   Gynecologic Cancers   /   Ovarian Cancer   /   NCI Resources

NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of Ovarian Cancer - September 2001

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Last Modified: November 1, 2001

Table of Contents

CancerMail from the National Cancer Institute

1
UI - 21176230
AU - Gramellini D; Rutolo S; Verrotti C; Piantelli G; Fieni S; Vadora E
TI - [Sonographic characterization, Doppler ultrasonography and tumor markers in the diagnosis of malignancy of ovarian masses]
SO - Minerva Ginecol 2001 Feb;53(1):1-11
AD - Istituto di Clinica Ostetrica e Ginecologica, Universita degli Studi, Parma, Italy.
BACKGROUND: The study analyses the diagnostic possibilities regarding ovarian neoplasms offered by different clinical approaches: B-mode morphological ultrasonographic examination, colour Doppler and Doppler pulsed ultrasonography, and lastly the assay of a number of tumour markers. METHODS: A prospective study was carried out in 125 selected patients attending the Ultrasonography unit of the Obstetrics and Gynecology Clinic at Parma University between June 1997 and June 1999 who presented an adnexal mass . All patients underwent transvaginal ultrasonography (multifrequency vaginal probe 5.0-6.5 MHz, Esaote Idea, Genova) to characterise the mass, applying 5 different ultrasonographic scores: Granberg, Sassone, Di Priest, Lerner, Ferrazzi. Colour Doppler imaging was then performed to analyse the vascularisation of the mass, also using pulsed Doppler to study a number of velocimetric parameters: pulsatility index, index of resistance, systolic and diastolic peak velocity, mean velocity. All the patients underwent surgery using laparotomy or video laparoscopy, accompanied by histological analysis. A number of different tumour markers were assayed prior to surgery: Cal25, CA19-9, CEA, beta-HCG, alpha-fetoprotein. RESULTS: Out of 127 pelvic masses examined, histological analysis showed that 19 were malignant and 108 benign. The diagnostic accuracy of malignancy was comparable for the 5 scores studied, with a minimum of 57.48% for Lerner and a maximum of 77.16% for Di Priest. The central importance of vascularisation was the only significant parameter among those analysed using colour Doppler which was useful for the diagnosis of a malignant neoplasm, with a diagnostic accuracy of 82.95%. No indicator obtained using pulsed Doppler was useful for diagnostic purposes. CA125 was the only tumour marker that revealed a statistically significant difference emerged between the benign (21.6 U/ml) and malignant (220.8 U/ml) masses. Its diagnostic accuracy was 75.58%. CONCLUSIONS: This study confirmed that the three methods analysed do not differentiate substantially in their overall diagnostic capacity of malignant ovarian neoplasms. The best performances for ecographic scores (Di Priest) did not exceed a sensitivity of 89.47% with a 21.25% incidence of false positives; this was comparable to CA125 with a sensitivity of 85.71% and false positives in 22.09%. In relation to the central importance of vascularisation, colour Doppler achieved a lower sensitivity (55.55%), but this was confirmed by a low incidence of false positives (7.95%). This revealed its importance as a useful method, especially for excluding the presence of malignant tumours.

2
UI - 21198524
AU - Goodman MT; McDuffie K; Kolonel LN; Terada K; Donlon TA; Wilkens LR; Guo C; Le Marchand L
TI - Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism.
SO - Cancer Epidemiol Biomarkers Prev 2001 Mar;10(3):209-16
AD - Cancer Etiology Program, Cancer Research Center, University of Hawaii, Honolulu 96813, USA. marc@crch.hawaii.edu
Steroid hormones, such as estrogens, appear to be associated with ovarian carcinogenesis, but the precise biological mechanisms are unclear. Polymorphisms in genes that regulate the concentration of estrogens and their metabolites may contribute directly to the individual variation in ovarian cancer risk through a mechanism involving oxidative stress or indirectly by influencing ovarian cancer susceptibility associated with ovulation and reproduction. We conducted a population-based, case-control study of primary ovarian cancer between 1993 and 1999 in Hawaii to test several genetic and related hypotheses. A personal interview and blood specimen were obtained in the subjects' homes. In a sample of 129 epithelial ovarian cancer cases and 144 controls, we compared the frequencies of several polymorphisms in genes that regulate steroid hormone metabolism and catecholestrogen formation. Multivariate unconditional logistic regression was used to model the association of each genetic polymorphism separately after adjusting for age, ethnicity, and other covariates. The high-activity Val432 allele of the CYP1B1 gene, which may be linked to oxidative stress through elevated 4-hydroxylated catecholestrogen formation, was associated with an increased risk of ovarian cancer. The Val/Leu genotype for CYP1B1 was associated with an odds ratio of 1.8 (95% confidence interval, 1.0-3.3) and the Val/Val genotype with an odds ratio of 3.8 (95% confidence interval, 1.2-11.4) compared with the Leu/Leu genotype (P = 0.005). Tobacco smokers with at least one CYP1A1 (MspI) m2 allele, one CYP1B1 Val allele, one COMT Met allele, or two CYP1A2 A alleles were at significantly increased risk of ovarian cancer compared to never-smokers with CYP1A1 (MspI) ml/ml, CYP1B1 Leu/Leu, COMT Val/Val, or CYP1A2 A/A genotypes, respectively. We found a positive statistical interaction (P = 0.03) between tobacco smoking and the CYP1A1 (MspI) polymorphism on the risk of ovarian cancer. None of the other gene-environment (pregnancy, oral contraceptive pill use) or gene-gene interactions were statistically significant. Although not significant, there was a suggestion that the effect of the CYP1B1 Val allele was reduced substantially in the presence of the high-activity COMT Met allele. These findings suggest that the CYP1B1-Val allele and perhaps other genetic polymorphisms in combination with environmental or hormonal exposures are susceptibility factors for ovarian cancer.

3
UI - 21227879
AU - La Vecchia C
TI - Epidemiology of ovarian cancer: a summary review.
SO - Eur J Cancer Prev 2001 Apr;10(2):125-9
AD - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Ovarian cancer is among the five leading sites for cancer incidence and mortality in women from developed countries. Its incidence and mortality rates have, however, been declining over the last few decades following the introduction of oral contraceptives, which - together with parity - are the best recognized protective factor for the disease. Late menopause and irregular menstrual cycles may also reduce the risk, while the role of hormone replacement therapy in menopause and fertility treatments is still unclear. Cosmetic talc use and some aspect of diet (i.e. saturated fats, refined carbohydrates) have been associated with increased risk, in some--though not all--studies), while vegetable consumption appears to be inversely related to risk. These issues remain open to debate. Women with a family history of ovarian and breast cancer in first-degree relatives are also at increased risk, but family history accounts for only 4-5% of cases. Most ovarian cancers are therefore environmental in origin and consequently, at least in principle, avoidable.

4
UI - 21227893
AU - Dal Maso L; Canzonieri V; Talamini R; Franceschi S; La Vecchia C
TI - Origin of ovarian cancer from benign cysts.
SO - Eur J Cancer Prev 2001 Apr;10(2):197-9
AD - Centro di Riferimento Oncologico, Aviano (PN), Italy.
In a case-control study of 1031 epithelial ovarian cancers and 2311 controls conducted in Italy, 56 cases and 116 controls reported history of benign ovarian cysts, corresponding to a relative risk of 1.3 (95% confidence interval = 0.9-1.8). In a subset of 255 histologically reviewed cases, mucinous and endometrioid ovarian neoplasms and neoplasms of stage I or II arose more frequently from cysts, while use of oral contraceptives or parity were not significantly related to history of ovarian cysts.

5
UI - 21221407
AU - Erickson JR; Hasegawa Y; Fang X; Eder A; Mao M; Furui T; Aoki J; Morris A; Mills GB
TI - Lysophosphatidic acid and ovarian cancer: a paradigm for tumorogenesis and patient management.
SO - Prostaglandins Other Lipid Mediat 2001 Apr;64(1-4):63-81
AD - Atairgin Technologies, Irvine, CA 92612 USA.

6
UI - 21236976
AU - Weiss NS; Rossing MA
TI - Non-hormonal contraception and the risk of ovarian cancer.
SO - Epidemiology 2001 May;12(3):300
AD - Department of Epidemiology, School of Public Health and Community Medicine, Box 357236, University of Washington, Seattle, WA 98195-7236, USA.

7
UI - 21236978
AU - Ness RB; Grisso JA; Vergona R; Klapper J; Morgan M; Wheeler JE; Study of Health and Reproduction (SHARE) Study Group
TI - Oral contraceptives, other methods of contraception, and risk reduction for ovarian cancer.
SO - Epidemiology 2001 May;12(3):307-12
AD - Graduate School of Public Health and Pittsburgh Cancer Institute, University of Pittsburgh, USA.
Oral contraceptives reduce the risk of ovarian cancer, but the impact of other methods of contraception has not been fully explored. This population-based, case-control study involved women 20-69 years of age who had ever had intercourse. We compared cases with a recent diagnosis of ovarian cancer (N = 727) with community controls (N = 1,360). All methods of contraception evaluated were associated with a reduced risk for ovarian cancer. After adjustment for age, race, pregnancies, and family history of ovarian cancer, the odds ratios for ever-use of each method as compared with never-use were: oral contraceptives for contraception, 0.6 (95% confidence interval = 0.5-0.8); intrauterine device, 0.8 (95% confidence interval = 0.6-1.0); barrier methods, 0.8 (95% confidence interval = 0.6-0.9); tubal ligation, 0.5 (95% confidence interval 0.4-0.7); and vasectomy, 0.8 (95% confidence interval = 0.6-1.1). Nulligravid women were not protected by any of these contraceptive methods. Multigravid women, however, were protected by all methods. We conclude that various methods of contraception reduce ovarian cancer risk. This effect does not appear to result from contraceptive use being a nonspecific marker of fertility. The results imply mechanisms other than hormonal or ovulatory by which ovarian cancer risk is reduced.

8
UI - 21236981
AU - Weyer PJ; Cerhan JR; Kross BC; Hallberg GR; Kantamneni J; Breuer G; Jones MP; Zheng W; Lynch CF
TI - Municipal drinking water nitrate level and cancer risk in older women: the Iowa Women's Health Study.
SO - Epidemiology 2001 May;12(3):327-38
AD - Center for Health Effects of Environmental Contamination, University of Iowa, USA.
Nitrate contamination of drinking water may increase cancer risk, because nitrate is endogenously reduced to nitrite and subsequent nitrosation reactions give rise to N-nitroso compounds; these compounds are highly carcinogenic and can act systemically. We analyzed cancer incidence in a cohort of 21,977 Iowa women who were 55-69 years of age at baseline in 1986 and had used the same water supply more than 10 years (87% > 20 years); 16,541 of these women were on a municipal supply, and the remainder used a private well. We assessed nitrate exposure from 1955 through 1988 using public databases for municipal water supplies in Iowa (quartile cutpoints: 0.36, 1.01, and 2.46 mg per liter nitrate-nitrogen). As no individual water consumption data were available, we assigned each woman an average level of exposure calculated on a community basis; no nitrate data were available for women using private wells. Cancer incidence (N = 3,150 cases) from 1986 through 1998 was determined by linkage to the Iowa Cancer Registry. For all cancers, there was no association with increasing nitrate in drinking water, nor were there clear and consistent associations for non-Hodgkin lymphoma; leukemia; melanoma; or cancers of the colon, breast, lung, pancreas, or kidney. There were positive associations for bladder cancer [relative risks (RRs) across nitrate quartiles = 1, 1.69, 1.10, and 2.83] and ovarian cancer (RR = 1, 1.52, 1.81, and 1.84), and inverse associations for uterine cancer (RR = 1, 0.86, 0.86, and 0.55) and rectal cancer (RR = 1, 0.72, 0.95, and 0.47) after adjustment for a variety of cancer risk/protective factors, agents that affect nitrosation (smoking, vitamin C, and vitamin E intake), dietary nitrate, and water source. Similar results were obtained when analyses were restricted to nitrate level in drinking water from 1955 through 1964. The positive association for bladder cancer is consistent with some previous data; the associations for ovarian, uterine, and rectal cancer were unexpected.

9
UI - 21319025
AU - Parazzini F; Pelucchi C; Negri E; Franceschi S; Talamini R; Montella M; La Vecchia C
TI - Use of fertility drugs and risk of ovarian cancer.
SO - Hum Reprod 2001 Jul;16(7):1372-5
AD - Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62-20157 Milan, Italy. parazzini@iftmn.mnegri.it
BACKGROUND: The potential association between fertility drugs and risk of ovarian cancer has been analysed using data from a case-control study conducted between January 1992 and September 1999 in four Italian areas. METHODS: Cases were 1031 women (median age 56, range 18-79 years) with incident, histologically confirmed epithelial ovarian cancer. Controls were 2411 women (median age 57, range 17-79 years) residing in the same geographical areas and admitted to the same network of hospitals for cases for a wide spectrum of acute, non neoplastic, non hormone-related conditions. RESULTS: A total of 15 cases and 26 controls reported use of fertility drugs. The corresponding odds ratio (OR) was 1.3 (95% confidence interval 0.7-2.5). The OR was 1.2 for women reporting last use <25 years before interview and 1.3 for >25 years. CONCLUSIONS: Considering calendar year at use, the OR was non-significantly above unity for women reporting fertility drug use after 1970. The OR was 0.6 among nulliparous women and 1.9 among parous ones.

10
UI - 21391376
AU - Vergote I
TI - Prognostic factors in stage I ovarian carcinoma.
SO - Verh K Acad Geneeskd Belg 2001;63(3):257-71; discussion 272-6
AD - Faculty of Medicine, Department of Obstetrics and Gynaecology, Division of Gynaecologic Oncology, KULeuven-U.Z. Gasthuisberg, Herestraat 49-B 3000 Leuven.
Most studies on prognostic factors in stage I ovarian carcinoma have been hampered by a relative small number of patients included. In this study we identified the most important independent clinical and pathological prognostic factors in stage I epithelial invasive ovarian carcinoma in a large data base of 1545 patients with stage I epithelial ovarian carcinoma. The patients were treated in 6 different countries but were analysed in the same way. Because of the increasing use of endoscopy to remove possibly malignant cysts and the reports on rapid spread of ovarian carcinoma in the peritoneal cavity after laparoscopic removal of ovarian cancers, special attention was made to the presence and timing of the cysts before or during surgery. The multivariate analyses identified degree of differentiation as the most powerful prognostic indicator of disease-free survival, followed by rupture before surgery, rupture during surgery, International Federation of Gynaecology and Obstetrics (FIGO) 1973 stage and age. When the effects of these factors were accounted for, none of the following were of prognostic value for disease-free survival: histological type, dense adhesions, extracapsular growth, ascites, FIGO stage 1988, and size of tumour. In conclusion, degree of differentiation was the most powerful prognostic indicator in Stage I ovarian cancer and should be used when deciding therapy in clinical practice. We also strongly advocate the inclusion of degree of differentiation in a new FIGO classification of stage I ovarian carcinoma. In addition, rupture before and during surgery, FIGO Stage 1973 (Ib versus Ia) and age were shown to be independent prognostic factors. Hence, every effort should be made to avoid rupture during primary surgery of malignant ovarian tumours confined to the ovaries.

11
UI - 21385714
AU - Unoki M; Nakamura Y
TI - Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway.
SO - Oncogene 2001 Jul 27;20(33):4457-65
AD - Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). Expression of six of them (PINK1, EGR2, HCLS1, DUSP1, BPOZ, and NFIL3) was decreased in ovarian tumors compared with corresponding normal tissues. Colony-formation assays using plasmid clones designed to express each gene indicated that EGR2 and BPOZ were able to suppress growth of cancer cells significantly; in particular, cancer-cell lines stably expressing BPOZ grew more slowly than control cells containing mock vector. Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G(1)/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. Therefore both genes appear to be novel candidates as mediators of the PTEN growth-suppressive signaling pathway.

12
UI - 21398855
AU - Olson SH; Mignone L; Nakraseive C; Caputo TA; Barakat RR; Harlap S
TI - Symptoms of ovarian cancer.
SO - Obstet Gynecol 2001 Aug;98(2):212-7
AD - Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. olsons@mskcc.org
OBJECTIVE: To examine the symptoms of ovarian cancer in patients compared with symptoms experienced by healthy women using a case-control design. METHODS: Cases (n = 168) were women with ovarian cancer diagnosed at two hospitals in New York between 1994 and 1997 who were interviewed shortly after diagnosis. They were compared with healthy women (n = 251 controls) from the community. Women were asked about the prevalence, duration, and constancy of eight symptoms and about use of three types of medications in the 6 to 12 months before diagnosis (cases) or interview (controls). RESULTS: Nearly all the cases (93%) reported at least one symptom, compared with 42% of controls. The most common symptoms among cases were: unusual bloating, fullness, and pressure in the abdomen (71%); unusual abdominal pain or lower back pain (52%); and lack of energy (43%). The proportions of controls reporting these symptoms were 9, 15, and 16%, respectively, resulting in odds ratios and 95% confidence intervals of 25.3 (15.6, 40.9), 6.2 (4.0, 9.6), and 3.9 (2.5, 6.1), respectively, for these symptoms. Bloating, fullness, and pressure was of more recent onset among cases than controls (4.9 months compared with 7.6 months, P =.01). There were only minor differences in reported symptoms between cases with early and later stage disease. CONCLUSION: Unusual bloating, fullness, and pressure, abdominal or back pain, and lack of energy are prominent symptoms in women with ovarian cancer and distinguish them from controls. Information on symptoms may make women and physicians more aware of changes associated with ovarian cancer.

13
UI - 21378017
AU - Yiu GK; Chan WY; Ng SW; Chan PS; Cheung KK; Berkowitz RS; Mok SC
TI - SPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells.
SO - Am J Pathol 2001 Aug;159(2):609-22
AD - Department of Obstetrics, Gynecology, and Reproductive Biology, Laboratory of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., Boston, MA 02115, USA.
Secreted protein acidic and rich in cysteine (SPARC) is an extracellular Ca(2+)-binding matricellular glycoprotein that associates with cell populations undergoing migration, morphogenesis, and differentiation. Studies on endothelial cells have established that its principal functions in vitro are counteradhesion and antiproliferation. The mechanism(s) underlying these antitumor effects is unknown. In this study, we showed that SPARC expression in ovarian cancer cells is inversely correlated with the degree of malignancy. The immunohistochemical data presented here confirmed the importance of diminished SPARC expression in ovarian cancer development. Treating human ovarian surface epithelial cells and ovarian cancer cells with SPARC revealed that as SPARC inhibits the proliferation of both normal and cancer cells, it induces apoptosis only in cancer cells. This observation indicates that down-regulation of SPARC is essential for ovarian carcinogenesis as cancer cells become sensitized to the apoptotic activity of SPARC during malignant transformation. We also showed here the first direct evidence that putative SPARC receptors are present on ovarian epithelial cells. Their levels are higher in human ovarian surface epithelial cells than cancer cells. Binding of SPARC to its receptor is likely to trigger tissue-specific signaling pathways that mediate its tumor suppressing functions. Decrease in ligand-receptor interaction by the down-regulation of SPARC and/or its receptor is essential for ovarian carcinogenesis.

14
UI - 21388246
AU - Fraifeld V; Seidman R; Sagi O; Muradian K; Wolfson M
TI - Aurintricarboxylic acid decreases proliferative potential of SKOV3 and MCF7 human carcinoma cells.
SO - Anticancer Res 2001 May-Jun;21(3B):1975-8
AD - Department of Clinical Pharmacology, Center for the Multidisciplinary Research in Aging, Ben-Gurion University of the Negev, Beer-Sheva, Israel. vadimfra@zahav.net.il
The effect of aurintricarboxylic acid (ATA) on cell growth and proliferative capacity was studied in human ovarian SKOV3 and breast MCF7 carcinoma cells. ATA moderately inhibited cell growth measured by a Neutral red assay after a 24-hour incubation of the cells in the presence of ATA. The ATA-treated cells displayed a markedly decreased capacity to proliferate, as was evident from a colony formation assay. The initial and delayed anti-proliferative effects of ATA were dose-dependent. Together, the results indicated that ATA offers the potential of being recognized as an anti-tumor drug, at least in certain types of cancers.

15
UI - 21403961
AU - Chua IS; Tan KT; Lim-Tan SK; Ho TH
TI - A clinical review of granulosa cell tumours of the ovary cases in KKH.
SO - Singapore Med J 2001 May;42(5):203-7
AD - Department of General Obstetrics & Gynaecology, KK Women's and Children's Hospital.
INTRODUCTION: Granulosa cell tumour (GCT) represents the largest group of sex-cord stromal tumours and comprises 1.5-3% of ovarian malignancy. The aim is to determine the incidence of the disease, study the profile of local patients, and assess the use of imaging studies in the diagnosis of the tumour. MATERIAL AND METHODS: Clinical records of 19 patients diagnosed with GCT between October 1988 and July 1997 in Kandang Kerbau Hospital (KKH) were reviewed. RESULTS: GCT accounts for 3.5% of ovarian malignancy (54 out of 1552) in Singapore, of which 94.7% are adult GCT. In our study, patients are mainly peri/postmenopausal women (63.2%) in their 50s who experience post-menopausal bleeding. There is a high incidence of association with endometrial hyperplasia (40%). Ultrasound scans are able to predict the size and involvement of the tumour rather accurately. In our study sample, 13 patients (68.4%) presented with Stage 1 of the disease, none with Stage 2, 1 with Stage 3 (5.3%) and none with Stage 4. The other 5 patients (26.3%) were unstaged. Only one patient required adjuvant chemotherapy. CONCLUSION: The local data with regards to GCT is congruent with those found in foreign literature. However, in our study, there were no patients with recurrence whereas GCTs are known to be late recurring in up to 20% of patients 10-20 years after diagnosis.This is probably attributed to the relatively short period of follow-up in this study. Thus, despite the fact that there is no evidence of recurrence of disease in our current study, we still recommend a vigilant follow-up protocol on all patients as literature has proven that with early detection of recurrences, it is possible to achieve complete cure.

16
UI - 21397936
AU - Liu VW; Shi HH; Cheung AN; Chiu PM; Leung TW; Nagley P; Wong LC; Ngan HY
TI - High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas.
SO - Cancer Res 2001 Aug 15;61(16):5998-6001
AD - Department of Obstetrics and Gynecology, University of Hong Kong, Queen Mary Hospital, Hong Kong.
To investigate the potential role of somatic mitochondrial DNA (mtDNA) mutations in tumorigenesis, the occurrence of mutations in mtDNA of ovarian carcinomas was studied. We sequenced the D-loop region of mtDNA of 15 primary ovarian carcinomas and their matched normal controls. Somatic mtDNA mutations were detected in 20% (3 of 15) tumor samples carrying single or multiple changes. Complete sequence analysis of the mtDNA genomes of another 10 pairs of primary ovarian carcinomas and control tissues revealed somatic mtDNA mutations in 60% (6 of 10) of tumor samples. Most of these mutations were homoplasmic, and most were T-->C or G-->A transitions, but one represented a differential length within a run of identical C residues. A region of mtDNA sequence including the 16S and 12S rRNA genes, the D-loop and the cytochrome b gene, may represent the zone of preferred mtDNA mutation in ovarian cancer. The high incidence of mtDNA mutations found in ovarian carcinomas and other human cancers suggests that genetic instability of mtDNA might play a significant role in tumorigenesis.

17
UI - 21411563
AU - Pribill I; Speiser P; Leary J; Leodolter S; Hacker NF; Friedlander ML; Birnbaum D; Zeillinger R; Krainer M
TI - High frequency of allelic imbalance at regions of chromosome arm 8p in ovarian carcinoma.
SO - Cancer Genet Cytogenet 2001 Aug;129(1):23-9
AD - Department of Medicine I, Clinical Division of Oncology, University Hospital, Molecular Oncology Group, Wahringergurtel 18-20, A-1090 Vienna, Austria.
Progressive genetic changes such as the inactivation of tumor suppressor genes (TSG) are thought to play an important role in the initiation and progression of ovarian cancer. Frequent nonrandom allelic imbalance (AI) at 8p11-p21 and 8p22-pter suggests the existence of TSGs that may be involved in the carcinogenesis of several human malignancies. We investigated 70 ovarian tumors with 11 highly polymorphic markers spanning 8p12-p21 and 8p22-pter to produce an AI map of 8p in epithelial ovarian cancer. Allelic imbalance was demonstrated in 54 tumors (77%), most frequently occurring at D8S136 (54%) and at D8S1992 (55%). Poorly differentiated and advanced stage cancers were more often affected by AI (G1+G2 vs. G3; 20% vs. 66%; stage I+II vs. III+IV, 36% vs. 54%, P<.001; Kruskal-Wallis test) than well differentiated and early stage tumors. There was no relationship between histological subtype and AI. Smallest regions of overlap (SRO) were delineated by analyzing 38 tumors with partial AI. This study provides compelling evidence for the involvement of TSGs on the short arm of chromosome 8, at 8p12-p21 and at 8p23 in the development and progression of epithelial ovarian cancer.

18
UI - 21118887
AU - Bertone ER; Hankinson SE; Newcomb PA; Rosner B; Willet WC; Stampfer MJ; Egan KM
TI - A population-based case-control study of carotenoid and vitamin A intake and ovarian cancer (United States).
SO - Cancer Causes Control 2001 Jan;12(1):83-90
AD - Department of Boistatistics and Epidemiology, University of Massachusetts, Amherst 01003-9304, USA. elizabeth.bertone@channing.harvard.edu
OBJECTIVE: To evaluate the association between dietary intake of carotenoids and vitamin A and the incidence of ovarian cancer. METHODS: We conducted a population-based case-control study of ovarian cancer in Massachusetts and Wisconsin. Incident cases diagnosed between 1991 and 1994 were identified through statewide tumor registries. We selected community controls at random from lists of licensed drivers and Medicare recipients; 327 cases and 3129 controls were included in the analysis. Data were collected by telephone interview, which included an abbreviated food and supplement list to quantify typical consumption of carotenoids (lutein/zeaxanthin, alpha-carotene, beta-carotene), retinol and total vitamin A at 5 years prior to diagnosis in cases, or to a comparable reference date in controls. Results were adjusted for age, state, and other risk factors. RESULTS: Participants with the highest dietary intake of lutein/zeaxanthin (> or =24,000 microg/week) experienced a 40% lower risk of ovarian cancer (95% CI = 0.36-0.99) compared to those with the lowest intake. Intake of alpha-carotene, beta-carotene, retinol and total vitamin A was unrelated to risk. Among foods, we observed non-significantly lower risks with high consumption of spinach, carrots, skim/lowfat milk and liver. CONCLUSION: These results support previous findings suggesting an inverse relationship between carotenoid intake and ovarian cancer risk.

19
UI - 21372035
AU - Galmozzi E; Tomassetti A; Sforzini S; Mangiarotti F; Mazzi M; Nachmanoff K; Elwood PC; Canevari S
TI - Exon 3 of the alpha folate receptor gene contains a 5' splice site which confers enhanced ovarian carcinoma specific expression.
SO - FEBS Lett 2001 Jul 27;502(1-2):31-4
AD - Unit of Molecular Therapies, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
The human folate receptor (FR) is overexpressed in ovarian carcinoma. FR transcripts are heterogeneous due to the use of two promoters, P1 and P4, and alternative splicing of exon 3. RNase protection assay and RT-PCR revealed higher levels of the transcripts that include exon 3 in lines and specimens from ovarian carcinoma. A P1-chloramphenicol acetyltransferase (CAT) construct containing exon 3 demonstrated efficient reporter expression only in ovarian carcinoma. 5' and 3' deleted variants of the P1-CAT construct were analyzed by RT-PCR of the exogenous transcripts and reporter activity. A 5' splice site and 35 bp downstream intronic region of exon 3 appeared to regulate enhanced FR expression in ovarian carcinoma.

20
UI - 21375958
AU - Neyns B; De Rijcke M; Vermeij J; Teugels E; Zeinoun Z; De Greve J
TI - Contaminants within bacterial plasmid preparations trigger apoptosis in liposome transfected OVCAR3, but not in SKOV3 or AZ224 human ovarian cancer cells.
SO - Cell Biol Int 2001;25(8):715-23
AD - Laboratory of Medical Oncology and Department of Medical Oncology, Oncologisch Centrum, Akademisch Ziekenhuis Vrije Universiteit Brussel, Belgium.
Toxicity associated with plasmid/liposome transfection of eucaryote cells has been attributed to the inherent toxicity of cationic lipid formulations and also to bacterial contaminants of plasmid DNA preparations, such as lipopolysaccharides (LPS). Certain plasmid preparations were observed to trigger apoptosis in DNA/liposome transfected OVCAR3 human epithelial ovarian cancer cells. In contrast, AZ224 and SKOV3 cells were unaffected under the same conditions. Agarose gel electrophoresis with recovery of the plasmid DNA removed the toxic component, but not purification by phenol/chloroform extraction or isopicnic CsCl ultracentrifugation. The toxicity of individual preparations correlated with the concentration of bacterial LPS. However, polymixin B could not neutralise the toxicity and neither could the effect be reproduced by the addition of bacterial LPS to non-toxic plasmid preparations. Surprisingly, the conditioned medium of OVCAR3 cells undergoing apoptosis was found to kill non-transfected OVCAR3 cells but not AZ224 or SKOV3 cells. This observation illustrates the possibility that unpredictable contaminants of bacterial plasmid preparations are able to cause cell death in the context of plasmid/liposome transfection in a cell-type specific way. It emphasizes the importance of achieving maximal plasmid DNA purity when performing DNA transfection experiments that focus on cell survival. Copyright 2001 Academic Press.

21
UI - 21405923
AU - Weiss NS; Rossing MA
TI - Oestrogen-replacement therapy and risk of ovarian cancer.
SO - Lancet 2001 Aug 11;358(9280):438
AD - Department of Epidemiology, University of Washington, Seattle, WA 98195-7236, USA. nweiss@u.washington.edu

22
UI - 21423687
AU - Lu KH; Broaddus RR
TI - Gynecological tumors in hereditary nonpolyposis colorectal cancer: We know they are common--now what?
SO - Gynecol Oncol 2001 Aug;82(2):221-2

23
UI - 21423688
AU - Watson P; Butzow R; Lynch HT; Mecklin JP; Jarvinen HJ; Vasen HF; Madlensky L; Fidalgo P; Bernstein I; International Collaborative Group on HNPCC
TI - The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.
SO - Gynecol Oncol 2001 Aug;82(2):223-8
AD - Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS:. Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage. Copyright 2001 Academic Press.

24
UI - 21423694
AU - Ahluwalia A; Yan P; Hurteau JA; Bigsby RM; Jung SH; Huang TH; Nephew KP
TI - DNA methylation and ovarian cancer. I. Analysis of CpG island hypermethylation in human ovarian cancer using differential methylation hybridization.
SO - Gynecol Oncol 2001 Aug;82(2):261-8
AD - Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana 47405, USA.
OBJECTIVE: The aim of this study was to examine CpG island methylation patterns in ovarian cancer and determine whether epigenetic information can be related to clinical data of patients. CpG island (CpGI) hypermethylation is commonly associated with cancer progression, but little is currently known about the role of methylation in ovarian cancer. METHODS: Differential methylation hybridization (DMH) analysis at 742 loci was performed to determine methylation signatures for 20 primary epithelial ovarian carcinomas (Stages II, III, and IV adenocarcinomas, serous papillary), 6 ovarian cancer cell lines, and normal ovarian surface epithelial cells. RESULTS: Between 23 and 108 methylated CpGIs were seen in the ovarian carcinomas. Fewer (P < 0.05) methylated CpGIs were observed in the ovarian cancer cell lines; however, a number of CpGIs were commonly hypermethylated in both the cell lines and the tumor samples. A methylation signature, consisting of frequently (P < 0.05) methylated CpGIs, was determined for the samples. The observed pattern of methylation in ovarian cancers included several (11) CpGI tags that were previously reported to be hypermethylated in human breast cancer. CONCLUSIONS: Epigenetic signatures in ovarian cancer were determined using DMH. This proof-of-concept study lays the foundation for genome-wide screening of methylation to examine epigenotype-phenotype relationships in ovarian cancer. Copyright 2001 Academic Press.

25
UI - 21423702
AU - Yamamoto R; Okamoto K; Yukiharu T; Kaneuchi M; Negishi H; Sakuragi N; Fujimoto S
TI - A study of risk factors for ovarian metastases in stage Ib-IIIb cervical carcinoma and analysis of ovarian function after a transposition.
SO - Gynecol Oncol 2001 Aug;82(2):312-6
AD - Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-8638, Japan.
OBJECTIVE: The objective of the present study was to examine the incidence and risk factors of ovarian metastases in cervical carcinoma. The function of transposed ovaries was also studied. METHODS: In order to analyze the risk factors of ovarian metastases, 255 slides of pathological specimens were reassessed by multivariate logistic regression analysis. Fifty-six patients were studied prospectively on the basis of the function of transposed ovaries. Basal body temperature and serum hormone levels were analyzed. RESULTS: Ovarian metastasis was identified in 2 of 485 (0.4%) patients with squamous cell carcinoma and in 12 of 146 (8.2%) patients with nonsquamous tumors of the cervix. Histologic type (P = 0.0014) and blood vessel invasion (P = 0.0433) were significant independent risk factors for ovarian metastases, as revealed by multivariate logistic regression analysis. Cumulative survival curves of preserved ovaries showed a significant (P < 0.005) decline in the group with postoperative radiotherapy. CONCLUSION: Preservation of ovarian function should be pursued in patients with squamous cell carcinoma of the cervix, provided that the patient has no other risk factor (blood vessel invasion) for ovarian metastases. Moreover, sufficient attention should be paid to the proper handling of ovarian blood vessels during surgery, in order to shield and protect them from exposure to scattered radiation administered during postoperative radiotherapy. Copyright 2001 Academic Press.

26
UI - 21423719
AU - Oh C; Kendler A; Hernandez E
TI - Ovarian endodermal sinus tumor in a postmenopausal woman.
SO - Gynecol Oncol 2001 Aug;82(2):392-4
AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Temple University School of Medicine, 3401 N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
BACKGROUND: Ovarian endodermal sinus tumor is rare in postmenopausal women. CASE: We report the case of a 75-year-old woman with a pure endodermal sinus tumor of the ovary. CONCLUSION: We believe this to be the oldest patient reported with an ovarian endodermal sinus tumor. The histogenesis of this entity in older patients may be different than when it occurs in young women. Copyright 2001 Academic Press.

27
UI - 97294417
AU - Gayther SA; Harrington P; Russell P; Kharkevich G; Garkavtseva RF; Ponder BA
TI - Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia.
SO - Am J Hum Genet 1997 May;60(5):1239-42

28
UI - 21060593
AU - Gorski B; Byrski T; Huzarski T; Jakubowska A; Menkiszak J; Gronwald J; Pluzanska A; Bebenek M; Fischer-Maliszewska L; Grzybowska E; Narod SA; Lubinski J
TI - Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.
SO - Am J Hum Genet 2000 Jun;66(6):1963-8
AD - Department of Genetics and Pathology, Hereditary Cancer Center, 70-115 Szczecin, Poland.
We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age <50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities-5382insC, C61G, and 4153delA-accounted for 51%, 20%, and 11% of the identified mutations, respectively.

29
UI - 21230827
AU - Chiaffarino F; Pelucchi C; Parazzini F; Negri E; Franceschi S; Talamini R; Conti E; Montella M; La Vecchia C
TI - Reproductive and hormonal factors and ovarian cancer.
SO - Ann Oncol 2001 Mar;12(3):337-41
AD - Istituto di Ricerche Farmacologiche Mario Negri, Universita degli Studi di Milano, Milan, Italy.
BACKGROUND: Menstrual, reproductive and hormonal factors have been related to ovarian cancer risk, but further quantification of their role in various populations is required. PATIENTS AND METHODS: Cases were 1031 women, below age 79, with incident, histologically confirmed epithelial ovarian cancer, and controls 2411 women, admitted between 1992 and 1999 to a network of hospitals in 4 Italian areas for acute, non-neoplastic, diseases. Odds ratios (OR) were obtained using multiple logistic regression. RESULTS: Multiparity was associated with a significant reduction in risk of ovarian cancer (OR = 0.6 for 3, and 0.5 for > or = 4 births). No consistent association was observed with time since first or last birth, nor with spontaneous or induced abortions. Late age at menarche (OR = 0.8), and early menopause (OR = 0.6) were inversely related to risk, as did long-term oral contraceptive use (OR = 0.5, for > or = 5 years). Hormone replacement therapy in menopause was associated with a non-significantly elevated risk (OR = 1.4). The pattern of risk was similar for women with and for those without family history of breast or ovarian cancer. CONCLUSIONS: This uniquely large study confirms and further quantities the relation between hormonal and reproductive factors and ovarian cancer. The pattern of risk observed cannot be totally explained by a role of ovulation in ovarian carcinogenesis.

30
UI - 21303188
AU - Birner P; Schindl M; Obermair A; Breitenecker G; Oberhuber G
TI - Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy.
SO - Clin Cancer Res 2001 Jun;7(6):1661-8
AD - Institute of Clinical Pathology, University of Vienna, A-1090 Vienna, Austria. peter.birner@akh-wien.ac.at
PURPOSE: To investigate the impact of expression of hypoxia-inducible factor (HIF)-1alpha on prognosis and on response to chemotherapy in epithelial ovarian tumors. EXPERIMENTAL DESIGN: Expression of HIF-1alpha protein was studied by immunohistochemistry in 102 specimens of epithelial ovarian cancers, in 50 borderline tumors, and in 20 cystadenomas. Results were correlated with p53, p21, and bcl-2 expression, microvessel density (MVD), apoptotic rate of tumor cells, and survival. RESULTS: In 68.6% of ovarian cancers and 88% of borderline tumors, expression of HIF-1alpha was observed. There was a significant correlation of HIF-1alpha protein expression and MVD (P < 0.001). HIF-1alpha overexpression alone and MVD showed no impact on survival of cancer patients. Furthermore, the response to platinum-based chemotherapy was independent from HIF-1alpha expression. Expression of HIF-1alpha correlated with apoptotic rate in the majority of cases, especially in low malignant potential tumors. In contrast, in cancer patients with strong expression of HIF-1alpha and p53 protein overexpression, not only a significantly increased MVD (P = 0.032, Mann-Whitney test) but also a significantly shorter overall survival was observed (P < 0.0001, Cox regression). The apoptotic rate was very low in these tumors. CONCLUSIONS: HIF-1alpha protein overexpression alone has no impact on the prognosis of ovarian cancer. The combination of HIF-1alpha protein overexpression with nonfunctional p53, however, indicates a dismal prognosis.

31
UI - 21303199
AU - Konecny G; Untch M; Pihan A; Kimmig R; Gropp M; Stieber P; Hepp H; Slamon D; Pegram M
TI - Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer.
SO - Clin Cancer Res 2001 Jun;7(6):1743-9
AD - Division of Hematology-Oncology, Department of Medicine, University of California at Los Angeles, School of Medicine, Los Angeles, California 90095-1678, USA. gkonecny@ucla.edu
PURPOSE: Urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor (PAI)-1, have been shown to be related to poor prognosis in a variety of malignant solid tumors. Studies on the prognostic relevance of uPA and PAI-1 in ovarian cancer, however, have been inconclusive. The current study tests the hypothesis that elevated expression of uPA and PAI-1 is associated with prognosis and disease progression. EXPERIMENTAL DESIGN: uPA and PAI-1 were prospectively measured by quantitative ELISA in tumor samples from 103 ovarian cancer patients (82 primary invasive epithelial carcinomas, 9 low malignant potential tumors, and 12 recurrent ovarian carcinomas). RESULTS: uPA but not PAI-1 levels were consistently associated with malignant progression, with levels increased from low malignant potential tumors to primary tumors (uPA, P = 0.04; PAI-1, P = 0.019), from early to advanced disease stages (uPA, P = 0.014; PAI-1, P = 0.23), and from primary to intra-abdominal metastatic tumors (uPA, P = 0.001; PAI-1, P = 0.16). High uPA and PAI-1 levels were associated with residual tumor volumes of >1 cm (P = 0.001 and P = 0.016, respectively). Among invasive International Federation of Gynecologists and Obstetrician stages I-IV tumors, elevated levels of uPA (>5.5 ng/mg) and PAI-I (>18.8 ng/ml) were associated with a shortened progression-free survival (uPA, P = 0.003; PAI-1, P = 0.039) and overall survival (uPA, P = 0.0002; PAI-1, P = 0.007). In multivariate analysis, uPA retained prognostic independence for progression-free survival (P = 0.037) and overall survival (P = 0.006). CONCLUSIONS: These data suggest that the uPA/PAI-1 axis may play an important role in the intra-abdominal spread and reimplantation of ovarian cancer cells. The prognostic relevance of uPA and PAI-1 supports their possible role in the malignant progression of ovarian cancer.

32
UI - 21381633
AU - Moysich KB; Mettlin C; Piver MS; Natarajan N; Menezes RJ; Swede H
TI - Regular use of analgesic drugs and ovarian cancer risk.
SO - Cancer Epidemiol Biomarkers Prev 2001 Aug;10(8):903-6
AD - Department of Cancer Prevention, Epidemiology and Biostatistics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. kirsten.moysich@roswellpark.org
Analgesics have been shown to reduce risk for colorectal cancer. Results from three recent reports (D. W. Cramer et al., Lancet, 351: 104-107, 1998; C. Rodriguez et. al., Lancet, 352: 1354-1355, 1998; L. Rose

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