National Cancer Institute®
Last Modified: September 1, 2002
UI - 12161607
AU - Kauff ND; Perez-Segura P; Robson ME; Scheuer L; Siegel B; Schluger A;
TI - Rapaport B; Frank TS; Nafa K; Ellis NA; Parmigiani G; Offit K Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families.
SO - J Med Genet 2002 Aug;39(8):611-4
UI - 11881908
AU - Isaacs C; Peshkin BN; Schwartz M; Demarco TA; Main D; Lerman C
TI - Breast and ovarian cancer screening practices in healthy women with a strong family history of breast or ovarian cancer.
SO - Breast Cancer Res Treat 2002 Jan;71(2):103-12
AD - Department of Medical Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20007-2197, USA. firstname.lastname@example.org
Studies in women with a family history of cancer demonstrate a wide variability in the uptake of cancer screening measures. Little data exist regarding the breast and ovarian cancer screening practices of women who are members of hereditary breast cancer families. In order to address this issue, we examined the screening behaviors and the determinants of screening in a clinic based group of 216 women with a strong family history of breast or ovarian cancer who were participating in a free genetic counseling and testing research program. At baseline, prior to obtaining genetic counseling or testing, 50% of women ages 30-39, 83% of those age 40-49, 69% of those 50-64, and 53% of those >65 reported having a mammogram in the prior year. Adherence to mammography recommendations was correlated with age, number of relatives with breast cancer, and income. Twenty percent of participants had at least one CA- 125 performed and 31 % had ever obtained a screening ultrasound. Having at least one relative with ovarian cancer was very strongly associated with ovarian cancer screening [OR = 12.3, 95% CI = 4.6-33 for CA-125; OR=4.9, 95% CI=2.4, 10.1 for ultrasound]. No association between cancer worries/distress and either breast or ovarian cancer screening was found. In conclusion, the breast and ovarian screening uptake in healthy women from hereditary breast cancer families is suboptimal, even for women over age 50, for whom annual mammography is clearly indicated. These findings indicate a need for better education about screening guidelines for high-risk women.
UI - 12114473
AU - Tulinius H; Olafsdottir GH; Sigvaldason H; Arason A; Barkardottir RB;
TI - Egilsson V; Ogmundsdottir HM; Tryggvadottir L; Gudlaugsdottir S; Eyfjord JE The effect of a single BRCA2 mutation on cancer in Iceland.
SO - J Med Genet 2002 Jul;39(7):457-62
AD - Icelandic Cancer Society, Reykjavik, Iceland University of Iceland, Reykjavik, Iceland. email@example.com
OBJECTIVE: To estimate the risk of malignant diseases in families of probands with the same mutation in the BRCA2 gene. DESIGN: A cohort study using record linkage of a breast cancer family resource and the Icelandic Cancer Registry. SETTING: Iceland. SUBJECTS: Families of 995 breast cancer patients, from which 887 were tested for a single founder 999del5 mutation; 90 had the mutation and 797 did not. RESULTS: Relatives of probands with the mutation had significantly increased relative risk (RR) of breast cancer. For first degree relatives, the RR was 7.55 (95% CI 6.04 to 9.03) but was 1.72 (95% CI 1.49 to 1.96) in first degree relatives of probands without the mutation. For prostate and ovarian cancer, the first and second degree relatives of probands with the mutation had a significantly increased RR, but in families of probands without the mutation no significant familial risk was found. CONCLUSIONS: The 999del5 mutation in the BRCA2 gene explains a substantial proportion of familial risk of breast cancer in Iceland, but significant familial risk remains in relatives of probands without the mutation. For prostate and ovarian cancer, the mutation accounts for most of the familiality observed in families of breast cancer patients.
UI - 12114489
AU - MacDonald DJ; Choi J; Ferrell B; Sand S; McCaffrey S; Blazer KR; Grant
TI - M; Weitzel JN Concerns of women presenting to a comprehensive cancer centre for genetic cancer risk assessment.
SO - J Med Genet 2002 Jul;39(7):526-30
UI - 12114493
AU - Hofmann W; Wappenschmidt B; Berhane S; Schmutzler R; Scherneck S
TI - Detection of large rearrangements of exons 13 and 22 in the BRCA1 gene in German families.
SO - J Med Genet 2002 Jul;39(7):E36
UI - 11783065
AU - Huang G; Song Y; He G
TI - [mRNA expression and mutation of MTA1 and nm23H1 genes in ovarian carcinoma in relation to lymph node metastasis]
SO - Zhonghua Zhong Liu Za Zhi 2001 Jan;23(1):31-4
AD - Institute of Cancer Research, First Affiliated Hospital, West China University of Medical Sciences, Chengdu 610041, China.
OBJECTIVE: To investigate mRNA expression and mutation of MTA1 and nm23H1 genes in ovarian carcinoma (OC) in relation to lymph node (LN) metastasis. METHODS: A panel of eight normal ovarian tissues, twenty primary OC specimens and twenty corresponding LNs was examined for mRNA expression and mutation of MTA1 and nm23H1 genes by using RT-PCR and RT-PCR-SSCP. The level of expression was determined by the relative optic density (ROD) of the PCR products. RESULTS: The frequency of MTA1 overexpression was 100% (7/7) in primary OC with metastasis but only 38.5% (5/13) in those without metastasis (P = 0.0103). Overexpression of MTA1 was observed in 87.5% (6/7) of LNs with metastasis but in only 23% (3/13) of LNs without metastasis (P = 0.0118). In contrast with MTA1, low expression of nm23H1 mRNA was seen in 7 of 7 OC with metastasis but only in 4 of 13 (30%) of those without metastasis (P = 0.0043). Low nm23H1 expression was also seen in 7 of 7 LNs with metastasis but only in 5 of 13 (38.5%) nonmetastatic LNs (P = 0.0102). The ROD ratio of MTA1 to nm23H1 increased with the development of metastasis. No mutation of MTA1 and nm23H1 was found by SSCP analysis. CONCLUSION: The mRNA expression of MTA1 and nm23H1 is positively and negatively correlated with LN metastasis, respectively. Expression abnormalities but not mutation of the two genes are frequent events related to LN metastasis of ovarian cancer.
UI - 12133405
AU - Lu Y; Zhang A; Wang S; Li J; Wang C; Ma D
TI - [Role of vascular endothelial growth factor overexpression in ovarian tumor invasion and mechanism]
SO - Zhonghua Fu Chan Ke Za Zhi 2002 May;37(5):294-7
AD - Department of Ostetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China.
OBJECTIVE: To study the role of vascular endothelial growth factor (VEGF) overexpression in ovarian tumor metastasis and associated mechanism. METHODS: The VEGF cDNA was transfected into ovarian tumor cell lines CAOV3 and COC1. Transfected and nontransfected cells were screened for VEGF, gelatinase A (MMP-2) mRNA and protein by reverse transcription polymerase chain reaction (RT-PCR), Western blot and substrate zymography, respectively. The invasive ability of two ovarian tumor cell lines was analysed with Boyden chamber invasion assay before and after VEGF cDNA transfection. RESULTS: The expression of VEGF, MMP-2 mRNA and protein were increased (P < 0.05) after VEGF cDNA transfection, detected by RT-PCR, Western blot and substrate zymography. After VEGF cDNA transfection, the mean invasion percentage of two ovarian tumor cells [CAOV3: (42.5 +/- 4.1)%; COC1: (26.8 +/- 2.4)%] were higher than that before transfection [CAOV3: (24.7 +/- 1.9)%; COC1: (8.6 +/- 1.1)%, P < 0.05]. CONCLUSION: The expression of VEGF correlates to the in vitro invasion of ovarian tumor cell and induction of MMP-2 by VEGF is a key component of VEGF-induced ovarian tumor cell invasion.
UI - 12133406
AU - Zhang H; Li Z; Chen M; Zhang G; Xu K
TI - [Loss of heterozygosity at chromosome 3p14, 25 in serum DNA from ovarian cancer patients]
SO - Zhonghua Fu Chan Ke Za Zhi 2002 May;37(5):298-300
AD - Department of Molecular Diagnosis, Shanghai Cancer Institute, Shanghai 200032, China.
OBJECTIVE: Investigate the frequency of loss of heterozygosity (LOH) at chromosome arm the short arm chromosome 3p14, 25 in the serum DNA from ovarian cancer and its clinical application. METHODS: Thirty-eight ovarian cancer serum samples with 18 corresponding tumor tissues and 8 benign ovarian tumors were obtained, and DNA samples extracted from serum and tissue were examined for 3p14, 25 LOH by using of polymerase chain reaction with four polymorphic microsatellite markers (D3S1029, D3S1228, D3S1300, D3S1481). RESULTS: Matched serum and tissue DNAs from 18 ovarian cancer patients showed significant concordance of 3p14, 25 LOH (P < 0.05). 3p14, 25 LOH in at least one of four loci occurred in 29 out of 38 (76%) serum samples, while 17 serum samples (45%) exhibited LOH at more than one locus. According to International Federation of Gynecology and Obstetrics (FIGO) staging, there was a trend that the rate of LOH was higher in advanced stages, and the frequency of loss in stage II, III, IV was 2/4, 78%, 8/9 respectively. It was also found that the number of microsatellite markers with 3p14, 25 LOH was increased with tumor progressed. No significant association of pathological types with LOH in serum DNA could be demonstrated except at locus D3S1029. CONCLUSIONS: Since the strong correlation of 3p14, 25 LOH between serum DNA and tumor tissue DNA, as well as the frequency of 3p14, 25 LOH associated with malignancy of ovarian cancer, it is suggested that detection of serum DNA 3p14, 25 LOH may be used as a molecular marker for staging and monitoring human ovarian cancer.
UI - 11936817
AU - Cozen W; Peters R; Reichardt JK; Ng W; Felix JC; Wan P; Pike MC
TI - Galactose-1-phosphate uridyl transferase (GALT) genotype and phenotype, galactose consumption, and the risk of borderline and invasive ovarian cancer (United States).
SO - Cancer Causes Control 2002 Mar;13(2):113-20
AD - Department of Preventive Medicine, USC Keck School of Medicine, USC/Norris Cancer Center, Los Angeles, CA 90033, USA.
OBJECTIVE: Previous studies have suggested that high levels of galactose consumption and/or low levels of galactose-I-phosphate uridyl transferase (GALT) activity may result in an increased risk of epithelial ovarian cancer. Similarly, some have reported that carriers of the N314D (asparagine at codon 314 replaced by aspartate) GALT polymorphism, which can be associated with low GALT activity, may have a higher risk of ovarian cancer. We examined these issues as part of a large case-control study of ovarian cancer conducted in Los Angeles between 1992 and 1998. METHODS: A total of 1,439 histologically confirmed borderline and invasive ovarian cancer cases among English-speaking non-Asian women were ascertained through the population-based cancer registry for Los Angeles County and completed in-person interviews were obtained from 689 of these (78% of cases approached). Controls consisted of 645 English-speaking non-Asian women with at least one intact ovary matched to cases on race/ethnicity (African-American, Latina, non-Latina White), date of birth (+/-3 years), and neighborhood of residence. Interviewer-administered questionnaires included information on reproductive factors, exogenous hormone use, medical history, and diet. Dietary information for the year before each case's diagnosis (and the same period for her matched control) was obtained using a self-administered food-frequency questionnaire. Blood samples were obtained from 452 controls, 136 cases with borderline ovarian cancer, and 312 cases with invasive ovarian cancer. The N314D polymorphism was characterized using PCR-RFLP and GALT enzyme activity, and was determined for a sample of the subjects with GALT genotype using an erythrocyte-based radioactive enzyme assay. RESULTS: We found no effect of N314D GALT genotype on the risk of borderline ovarian cancer (odds ratio (OR)=0.91; 95% confidence interval (CI)=0.54-1.6) or invasive ovarian cancer (OR=0.78; 95% CI= 0.53-1.2). Neither did we observe a relationship between GALT activity or lactose/galactose intake and risk of borderline or invasive ovarian cancer. Among N314D carriers, galactose consumption was associated with an increased risk of borderline (OR = 2.7, p = 0.01), but not invasive (OR = 1.2, p = 0.34), ovarian cancer; however, this result was based on only 24 N314D-positive borderline cases. CONCLUSIONS: Differences in galactose intake and GALT metabolism do not contribute significantly to the risk of ovarian cancer. There is some evidence that galactose intake may play a role in the development of borderline ovarian cancer among women who carry the uncommon GALT N314D polymorphism. More data are needed if this latter suggestion is to be definitively addressed.
UI - 12080712
AU - Zhang Y; Chao Y; Yang Z
TI - [Mutation and expression of p16 in human ovarian neoplasms]
SO - Hunan Yi Ke Da Xue Xue Bao 1999;24(6):529-32
AD - Xiangya Hospital, Hunan Medical University, Changsha 410008.
OBJECTIVES: To detect mutation and expression of p16 in human ovarian neoplasms and to understand the relations between p16 and development of ovarian neoplasms. METHODS: Polymerase chain reaction-single strand polymorphism analysis and immunohistochemistry were respectively used to detect mutations in exon 1 and 2 and protein expression in 14 patients with ovarian neoplasms. Metastasis tissue of 5 mentioned patients were screened at the same time. RESULTS: No expression of p16 was found in 7 ovarian neoplasm tissues. No mutation in exon 1 of p16 was found in any patient tissues, but mutations in exon 2 were found in 4 patients tissues and expression of p16 was not found in 2 of them. There was correspondence between primary focus and metastasis in either gene mutation or protein expression. CONCLUSIONS: Inactivation of p16 may be involved in the development of ovarian neoplasms. Gene mutation is a kind of inactivation. Alterations of p16 probably occur before metastasis.
UI - 12184039
AU - Cherry C; Vacchiano SA
TI - Ovarian cancer screening and prevention.
SO - Semin Oncol Nurs 2002 Aug;18(3):167-73
AD - Family Risk Assessment Program, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111, USA.
OBJECTIVES: To review current ovarian cancer prevention and detection recommendations using a risk assessment framework, and discuss the genes related to hereditary ovarian cancer syndromes. DATA SOURCES: Published articles, consensus opinions, and reports. CONCLUSIONS: Women at highest risk are those with a family history and/or genetic predisposition. Management guidelines include pelvic exam, CA125, and transvaginal ultrasound, although their efficacy is limited. Individualized risk assessment can be useful in assisting women who face decisions regarding prevention options. IMPLICATIONS FOR NURSING PRACTICE: Nurses are challenged to identify women at increased risk for ovarian cancer, and to recognize the complex issues faced when these women pursue screening and prevention strategies.
UI - 9415688
AU - Benkendorf JL; Reutenauer JE; Hughes CA; Eads N; Willison J; Powers M;
TI - Lerman C Patients' attitudes about autonomy and confidentiality in genetic testing for breast-ovarian cancer susceptibility.
SO - Am J Med Genet 1997 Dec 19;73(3):296-303
AD - Department of Obstetrics and Gynecology, Georgetown University Medical Center, Washington, DC 20007, USA.
The identification of BRCA1 and BRCA2, two breast-ovarian cancer susceptibility genes, has brought many ethical and social issues to the forefront. This paper presents the results of a survey assessing the attitudes of 238 unaffected first-degree relatives of women with breast or ovarian cancer regarding the ethical issues of autonomy and confidentiality as they relate to BRCA1/2 testing. Baseline knowledge about BRCA1/2 and ethnic and psychosocial characteristics of our study population were examined to determine their association with women's attitudes. The majority of women (86-87%) felt that health care providers should not disclose the results of genetic tests for breast-ovarian cancer susceptibility to insurance companies or employers without written consent; however, only 56-57% felt that written consent should be required for a spouse or immediate family to receive this information. Ninety-eight percent of the women surveyed agreed that genetic testing for breast-ovarian cancer risk should be voluntary. Likewise, most women (95%) agreed that a person should be able to have genetic testing against a doctor's recommendation and 88% of the women surveyed agreed that parents should be able to consent to genetic susceptibility testing on behalf of their minor children. African American women were less concerned than Caucasian women about the protection of confidentiality in families, they were more likely to agree that an individual should still have access to testing when their physicians recommended against it, and they were more supportive of parents' rights to consent to genetic predisposition testing on behalf of their minor children. Women with coping styles characterized by higher optimism were more likely to favor access to genetic testing when a physician recommended against it, and to support parents' rights to consent to testing of their minor children. Therefore, the setting and manner in which genetic counseling and testing are delivered must be appropriately tailored to reflect these attitudinal differences and preferences.
UI - 12168882
AU - Hogdall EV; Hogdall CK; Christensen L; Glud E; Blaakaer J; Bock JE;
TI - Vuust J; Norgaard-Pedersen B; Kjaer SK Distribution of p53 codon 72 polymorphisms in ovarian tumour patients and their prognostic significance in ovarian cancer patients.
SO - Anticancer Res 2002 May-Jun;22(3):1859-64
AD - Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen. firstname.lastname@example.org
BACKGROUND: The p53 gene is frequently mutated in various human tumours. In addition, single nucleotide polymorphisms are often observed in exons and introns of the p53 gene in normal tissues and tumours. MATERIALS AND METHODS: The prevalence of a polymorphism involving codon 72 of exon 4 in the p53 gene was studied in peripheral white blood cells and tumour tissues from Danish ovarian tumour patients and in peripheral white blood cells from controls. The analyses were performed by Polymerase Chain Reaction (PCR), Restriction Fragment Length Polymorphism (RFLP) and DNA sequencing. The amino acid residue at this position is either arginine (p53-Arg) or proline (p53-Pro). RESULTS: There was no correlation between the frequency of the three genotypes (Pro/Pro, Arg/Arg and Arg/Pro) and age, stage or histological type of the tumour. A significant difference in survival was observed between ovarian cancer stage III patients with a shift from one genotype in the blood to another genotype in the tissue and patients with no shift (p=0.0216). CONCLUSION: Kaplan-Meier survival analyses and multivariate Cox regression analysis stratified to stage III ovarian cancer patients showed that a shift from one genotype in the blood to another genotype in the tissue is a prognostic factor in Danish ovarian cancer patients.
UI - 12174480
AU - Malik IA
TI - A prospective study of clinico-pathological features of epithelial ovarian cancer in Pakistan.
SO - J Pak Med Assoc 2002 Apr;52(4):155-8
AD - National Cancer Institute, Karachi.
BACKGROUND: Although geographic and racial differences in the incidence of cancer are well recognized, information regarding any dissimilarity in clinico-pathological behavior of cancers is scarce. In particular, information from the developing countries regarding clinico-pathologic features of even some of the common cancers such as ovarian cancer is lacking. METHODS: Information was prospectively collected on all patients with epithelial ovarian cancer referred to the National Cancer Institute, Karachi, Pakistan between January 1, 1993 and June 30, 1998. Information was obtained directly from the patients and a close relative. Medical records were reviewed and radiologic and pathologic re-evaluation was done when necessary. RESULTS: Two hundred and eighty six patients were accrued. Mean age was 49.5 (+/- 13) years. Most of the well defined risk factors such as early menarche, late menopause, nulliparity, lack of lactation were uncommonly observed. Twenty percent of the patients had a positive family history of cancer. Most of these relatives were young (46.1 years), first degree (68%) and had breast or ovarian cancer. Clinical presentation, histologic features and stage of disease were similar to the North American or European women with epithelial ovarian cancer. CONCLUSION: Younger age at presentation and higher frequency of positive family history are two unusual features of Pakistani patients with epithelial ovarian cancer. This suggests a more significant role played by the genetic factors in these patients. Further work is needed.
UI - 12174914
AU - Galani E; Sgouros J; Petropoulou C; Janinis J; Aravantinos G;
TI - Dionysiou-Asteriou D; Skarlos D; Gonos E Correlation of MDR-1, nm23-H1 and H Sema E gene expression with histopathological findings and clinical outcome in ovarian and breast cancer patients.
SO - Anticancer Res 2002 Jul-Aug;22(4):2275-80
AD - National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens, Greece.
The development of a molecular screening method for cancer patients is of great importance, since it would contribute to the selection of the most effective chemotherapy regimen for each patient. In the present study we applied such a method, semi-quantative RT-PCR analysis, and we examined the expression of the multidrug resistance gene MDR-1, the metastasis suppressor gene nm23-H1 and the non-MDR drug resistant gene H Sema E in 53 ovarian and breast cancer specimens. Moreover, we have correlated the expression profile of these genes with the histopathological findings and clinical outcome of the examined patients. The majority of specimens were found to be positive for MDR-1 and H Sema E gene expression, while nm23-H1 was detected in less than 50% of the patients. Correlation and statistical analysis of the molecular data with clinicopathological features showed that nm23-H1 could serve as a good prognostic factor for ovarian cancer patients. In breast cancer patients, nm23-H1 expression was associated with a 6.1 higher death risk. Ovarian cancer patients who express nm23-H1, but not MDR-1 and H Sema E, tend to have longer survival than patients with any other gene combination. Finally, breast cancer patients with advanced disease showed a better response when they were negative for all the three genes studied. In conclusion this work proposes that the combined study of the expression of different genes may be a useful approach for evaluating patients' response to therapy.
UI - 11956590
AU - Curci A; Capasso I; Romano A; Bruni P; Motti ML; Pignata S; D'Aiuto G;
TI - Casamassimi A; D'Urso M; Fusco A; Viglietto G Characterization of 2 novel and 2 recurring BRCA1 germline mutations in breast and/or ovarian carcinoma patients from the area of Naples.
SO - Int J Oncol 2002 May;20(5):963-70
AD - Istituto Nazionale Tumori, Fondazione Pascale, Naples, Italy.
We have analyzed 18 families with high incidence of breast cancer or breast and ovarian cancer for the presence of BRCA1 mutations. We identified 4 mutations in the BRCA1 gene in 4 unrelated probands who belong to families with at least 1 case of breast and 1 case of ovarian cancer. Two of the mutations reported in this study are novel (GAA(1172)-->TAA in family Naples 14, GAA(1765)-->TAA in family Naples 20) whereas the others are already present in the Breast Cancer Information Core Electronic Database (http://nchgr.nih.gov/ Intramural research/Lab transfer/Bic/) (5382insC in family Naples 18 and 2080delA in family Naples 19). Conversely, no mutation in the BRCA1 gene was detected in 14 families characterized by 2 or more cases of breast cancer only, even if bilateral and with early-onset. These results indicate that germline mutations in the BRCA1 gene highly predispose for a cancer syndrome that involves the presence of both breast and ovarian cancer.
UI - 11975969
AU - Rao GG; Ashfaq R; Schorge JO
TI - Transitional cell ovarian carcinoma in a BRCA1 mutation carrier.
SO - Obstet Gynecol 2002 May;99(5 Pt 2):944-6
AD - Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
BACKGROUND: BRCA1 mutation carriers are at high risk of developing epithelial ovarian cancer, but the transitional cell variant has not been previously reported in these patients. CASE:A nulligravid, perimenopausal woman underwent exploratory laparotomy for a pelvic mass, ascites, and omental caking. Intraoperatively, frozen section of a tumor implant revealed high-grade epithelial ovarian carcinoma. Optimal surgical cytoreduction was performed. The final surgical pathology confirmed International Federation of Gynecology and Obstetrics stage IIIC transitional cell ovarian carcinoma. Her family history was significant for a sister with premenopausal breast cancer and a paternal aunt with ovarian cancer. The patient was counseled and elected to undergo genetic testing. Comprehensive gene sequence analysis detected the germline BRCA1 5382insC mutation. CONCLUSION: Transitional cell ovarian carcinoma is a rare histologic variant of epithelial ovarian cancer that may occur in BRCA1 mutation carriers.
UI - 12192099
AU - Miturski R; Bogusiewicz M; Ciotta C; Bignami M; Gogacz M; Burnouf D
TI - Mismatch repair genes and microsatellite instability as molecular markers for gynecological cancer detection.
SO - Exp Biol Med (Maywood) 2002 Sep;227(8):579-86
AD - Second Department of Gynecological Surgery, University School of Medicine, Lublin, Poland. email@example.com
Due to major developments in genetics over the past decade, molecular biology tests are serving promising tools in early diagnosis and follow-up of cancer patients. Recent epidemiological studies revealed that the risk for each individual to develop cancer is closely linked to his/her own genetic potentialities. Some populations that are defective in DNA repair processes, for example in Xeroderma pigmentosum or in the Lynch syndrome, are particularly prone to cancer due to the accumulation of mutations within the genome. Such populations would benefit from the development of tests aimed at identifying people who are particularly at risk. Here, we review some data suggesting that the inactivation of mismatch repair is often found in endometrial cancer and we discuss molecular-based strategies that would help to identify the affected individuals in families with cases of glandular malignancies.
UI - 9721864
AU - Vaisman A; Varchenko M; Umar A; Kunkel TA; Risinger JI; Barrett JC;
TI - Hamilton TC; Chaney SG The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts.
SO - Cancer Res 1998 Aug 15;58(16):3579-85
AD - Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill 27599-7260, USA.
Defects in mismatch repair are associated with cisplatin resistance, and several mechanisms have been proposed to explain this correlation. It is hypothesized that futile cycles of translesion synthesis past cisplatin-DNA adducts followed by removal of the newly synthesized DNA by an active mismatch repair system may lead to cell death. Thus, resistance to platinum-DNA adducts could arise through loss of the mismatch repair pathway. However, no direct link between mismatch repair status and replicative bypass ability has been reported. In this study, cytotoxicity and steady-state chain elongation assays indicate that hMLH1 or hMSH6 defects result in 1.5-4.8-fold increased cisplatin resistance and 2.5-6-fold increased replicative bypass of cisplatin adducts. Oxaliplatin adducts are not recognized by the mismatch repair complex, and no significant differences in bypass of oxaliplatin adducts in mismatch repair-proficient and -defective cells were found. Defects in hMSH3 did not alter sensitivity to, or replicative bypass of, either cisplatin or oxaliplatin adducts. These observations support the hypothesis that mismatch repair defects in hMutL alpha and hMutS alpha, but not in hMutS beta, contribute to increased net replicative bypass of cisplatin adducts and therefore to drug resistance by preventing futile cycles of translesion synthesis and mismatch correction.
UI - 10337997
AU - Bussey KJ; Lawce HJ; Olson SB; Arthur DC; Kalousek DK; Krailo M; Giller
TI - R; Heifetz S; Womer R; Magenis RE Chromosome abnormalities of eighty-one pediatric germ cell tumors: sex-, age-, site-, and histopathology-related differences--a Children's Cancer Group study.
SO - Genes Chromosomes Cancer 1999 Jun;25(2):134-46
AD - Children's Cancer Group, Arcadia, California, USA.
The chromosomes of 81 pediatric germ cell tumors (GCTs) were analyzed as part of two clinical treatment trials, INT-0098 and INT-0097, conducted by the Children's Cancer Group. The analysis of chromosome results showed differences with respect to sex, age, tumor location, and histology. Sixteen of 17 benign teratomas of infants and children less than 4 years old and from gonadal and extragonadal locations were chromosomally normal. Twenty-three malignant GCTs from gonadal and extragonadal locations of the same age group were endodermal sinus tumors and varied in their karyotypic findings. The most common abnormalities were gains of 1q and chromosome 3. Of eight benign ovarian teratomas from older girls, five with normal G-banded karyotypes were determined to be homozygous for Q-band heteromorphisms, suggesting a meiosis II error. Among the 12 malignant ovarian GCTs from older girls, the common abnormalities were loss of 1p/gain of 1q, +3, +8, +14, and +21. Four of eight extragonadal tumors from older boys demonstrated +21; one had +X. Five of the eight had associated constitutional chromosome abnormalities, including one trisomy 21 and three with Klinefelter syndrome. The testicular GCTs of adolescents had abnormalities resembling those found in adult testicular GCT, including near-triploidy, loss of chromosomes 11, 13, and 18, and gain of chromosomes 7, 8, the X chromosome, and an isochromosome 12p. The gain of an isochromosome 12p was only frequent in the tumors from adolescent boys. Deletion of 1p/gain of 1q and +3 were the most common abnormalities among the malignant tumors from both sexes.
UI - 11753956
AU - Gras E; Catasus L; Arguelles R; Moreno-Bueno G; Palacios J; Gamallo C;
TI - Matias-Guiu X; Prat J Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors.
SO - Cancer 2001 Dec 1;92(11):2829-36
AD - Department of Pathology, Hospital Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
BACKGROUND: Microsatellite instability (MI) is frequent in endometrial carcinomas (ECs), but its occurrence in ovarian tumors is uncertain. Microsatellite instability positive ECs frequently are associated with frameshift mutations in coding mononucleotide tracts in IGFIIR, BAX, hMSH6, and hMSH3. METHODS: DNA from 52 consecutive patients with ovarian tumors (10 benign, 7 borderline, and 35 malignant) was obtained from neoplastic and normal tissue. After preliminary results, the series was expanded by including 41 additional, previously selected, endometrioid and clear cell carcinomas. Microsatellite instability analysis was assessed by evaluating three (CA)n dinucleotide repeats (D2S123, D5S346, D17S250) and two mononucleotide tracts (BAT 25 and BAT 26). Frameshift mutations at coding mononucleotide repeats (IGFIIR, TGF beta II, BAX, hMSH6, and hMSH3) were investigated by single-strand conformation polymorphism analysis and DNA sequencing. MLH-1 methylation was assessed by methylation specific PCR. RESULTS: Microsatellite instability was identified in only 2 of the 52 (3.8%) tumors of the initial series (1 endometrioid and 1 clear cell carcinoma). After expanding the initial series of 15 endometrioid and clear cell carcinomas with 41 additional endometrioid and clear cell carcinomas, MI was found in 7 of the total series of 56 endometrioid and clear cell carcinomas (12.5%). Frameshift mutations in coding mononucleotide tracts were detected in BAX (6 of 7), IGFIIR (1 of 7), and MSH3 (2 of 7). MLH-1 promoter hypermethylation was identified in three of six MI positive tumors. CONCLUSIONS: Microsatellite instability was infrequent in this series of ovarian tumors, and it was limited to endometrioid and clear cell carcinomas. Like EC, many ovarian carcinomas with MI follow the same process of MLH-1 promoter methylation and accumulation of mutations in coding mononucleotide tracts. Copyright 2001 American Cancer Society.
UI - 12014680
AU - Arzimanoglou II; Hansen LL; Chong D; Li Z; Psaroudi MC; Dimitrakakis C;
TI - Jacovina AT; Shevchuk M; Reid L; Hajjar KA; Vassilaros S; Michalas S; Gilbert F; Chervenak FA; Barber HR Frequent LOH at hMLH1, a highly variable SNP in hMSH3, and negligible coding instability in ovarian cancer.
SO - Anticancer Res 2002 Mar-Apr;22(2A):969-75
AD - Department of Obstetrics-Gynecology, Weill Medical College of Cornell University, New York, NY 10021, USA. Arziman@lycosmail.com
BACKGROUND: Molecular alterations such as DNA microsatellite instability (MSI/RER), single nucleotide polymorphism (SNP) and loss of heterozygosity (LOH) can occur throughout the genome and be associated with different types of cancer. In the present study, we aimed at detecting molecular alterations within the mismatch DNA repair genes in ovarian cancer (OC), using a sensitive, accurate and reliable protocol we have developed. MATERIALS AND METHODS: A combination of high-resolution GeneScan software analysis and automated DNA cycle sequencing was used. RESULTS: Negligible coding MSI was observed in selected sequences of mismatch DNA repair genes in our series of sixty-two ovarian tumors and matched blood DNAs. Unlike MSI, loss of one hMLH1 allele was scored in almost half (47%) of the informative cases. In addition, an SNP in hMSH3/intron 5 was found to be highly variable in OC patients. CONCLUSION: 1) Coding DNA instability is likely to be a very rare event in OC and, therefore, may not significantly contribute to the development of OC, and 2) the high frequency of LOH at hMLH1 observed in our ovarian tumors suggests that further investigation is needed to determine if such a trend exists in other mismatch DNA repair and/or critical genes.
UI - 12160602
AU - Harlap S; Olson SH; Barakat RR; Caputo TA; Forment S; Jacobs AJ;
TI - Nakraseive C; Xue X Diagnostic x-rays and risk of epithelial ovarian carcinoma in Jews.
SO - Ann Epidemiol 2002 Aug;12(6):426-34
AD - Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016, USA. firstname.lastname@example.org
PURPOSE: To test the hypothesis that there would be ethnic differences in susceptibility to ionizing radiation from diagnostic x-rays. METHODS: In a hospital-based study we compared reports of diagnostic x-rays to the lower abdomen and pelvis in incident cases of epithelial ovarian carcinoma (N = 161), community controls (N = 156) and convenience controls (N = 87). RESULTS: Thirty-nine per cent of cases and 31% of controls recalled x-rays more than 10 years before; 27% of cases and 14% of controls reported four Jewish grandparents. Comparing the cases with community controls, the odds ratio (95% confidence interval) for Jews versus non-Jews among women reporting no x-rays was 1.02 (0.37-2.79); among women reporting x-rays the estimate for Jews was 8.91 (2.00-39.6). Consistent results were seen with inclusion of convenience controls. Jewish cases reported an excess of pelvic diagnostic x-rays from age 20 onward and an excess of barium enemas and pyelograms. CONCLUSIONS: These preliminary findings require confirmation in other studies. They suggest that the known excess risk of this carcinoma in Jews might be associated with exposure to x-rays and add to a previous observation of an altered susceptibility to ionizing radiation in Jews. If confirmed, they would suggest a need for continued vigilance to evaluate the risks and benefits of diagnostic x-rays in individuals, regardless of ethnic origin, who might carry mutations in DNA repair genes.
UI - 12214269
AU - Matei D; Graeber TG; Baldwin RL; Karlan BY; Rao J; Chang DD
TI - Gene expression in epithelial ovarian carcinoma.
SO - Oncogene 2002 Sep 12;21(41):6289-98
AD - Department of Medicine, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, California, CA 90095, USA.
We analysed the mRNA levels corresponding to 12,600 transcripts in primary cultures of ovarian epithelial cells derived from nine normal ovaries and 21 epithelial ovarian carcinoma. The class distinction and hierarchical clustering of expression data revealed a clear distinction in gene expression between normal and carcinoma-derived ovarian epithelial cells. Comparison of expression levels revealed 111 genes with mean expression values of >2.5-fold higher in carcinoma cells. Similarly, 62 genes were expressed at >2.5-fold higher levels in normal ovarian epithelial cells. For a few selected genes, we demonstrate that the pattern of differential expression observed in cultured epithelial cells is present in the normal ovaries and epithelial ovarian carcinoma. Use of cultured epithelial cells represents a novel strategy to study gene expression in a cell-type specific manner.
UI - 12183409
AU - Alfonso-De Matte MY; Yang H; Evans MS; Cheng JQ; Kruk PA
TI - Telomerase is regulated by c-Jun NH2-terminal kinase in ovarian surface epithelial cells.
SO - Cancer Res 2002 Aug 15;62(16):4575-8
AD - University of South Florida and the H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
Telomerase activity is present in >90% of all tumors and appears to be regulated by the phosphatidylinositol 3-kinase signaling pathway. Here we demonstrate that Akt is not involved in the signaling cascade for telomerase regulation in ovarian surface epithelial cells. However, we showed that c-Jun NH2-kinase induces telomerase activity, that inhibition of JNK by JIP abrogates telomerase activity, and that JNK expression activates transcription of a reporter gene fused to the hTERT promoter sequence. Consequently, our data show that JNK is a key regulator of telomerase activity and, hence, may provide new perspectives on tumorigenesis that could be exploited for novel therapeutic strategies.
UI - 12183431
AU - Schwartz DR; Kardia SL; Shedden KA; Kuick R; Michailidis G; Taylor JM;
TI - Misek DE; Wu R; Zhai Y; Darrah DM; Reed H; Ellenson LH; Giordano TJ; Fearon ER; Hanash SM; Cho KR Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas.
SO - Cancer Res 2002 Aug 15;62(16):4722-9
AD - Departments of Pathology, The University of Michigan, Ann Arbor, Michigan. 48109, USA.
Biologically and clinically meaningful tumor classification schemes have long been sought. Some malignant epithelial neoplasms, such as those in the thyroid and endometrium, exhibit more than one pattern of differentiation, each associated with distinctive clinical features and treatments. In other tissues, all carcinomas, regardless of morphological type, are treated as though they represent a single disease. To better understand the biological and clinical features seen in the four major histological types of ovarian carcinoma (OvCa), we analyzed gene expression in 113 ovarian epithelial tumors using oligonucleotide microarrays. Global views of the variation in gene expression were obtained using PCA. These analyses show that mucinous and clear cell OvCas can be readily distinguished from serous OvCas based on their gene expression profiles, regardless of tumor stage and grade. In contrast, endometrioid adenocarcinomas show significant overlap with other histological types. Although high-stage/grade tumors are generally separable from low-stage/grade tumors, clear cell OvCa has a molecular signature that distinguishes it from other poor-prognosis OvCas. Indeed, 73 genes, expressed 2- to 29-fold higher in clear cell OvCas compared with each of the other OvCa types, were identified. Collectively, the data indicate that gene expression patterns in ovarian adenocarcinomas reflect both morphological features and biological behavior. Moreover, these studies provide a foundation for the development of new type-specific diagnostic strategies and treatments for ovarian cancer.
UI - 12144681
AU - Papageorgiou T; Stratakis CA
TI - Ovarian tumors associated with multiple endocrine neoplasias and related syndromes (Carney complex, Peutz-Jeghers syndrome, von Hippel-Lindau disease, Cowden's disease).
SO - Int J Gynecol Cancer 2002 Jul-Aug;12(4):337-47
AD - Unit on Genetics & Endocrinology (UGEN), Developmental Endocrinology Branch (DEB), National Institute of Child Health and Human Development (NICHD)/NIH, Building 10, Room 10 N262, 10 Center Drive MSC 1862, Bethesda, MD 20892, USA.
Despite the relatively high prevalence of ovarian cancer (1% of American women will develop this disease in their lifetime) and recent developments in its molecular genetic understanding (several proto-oncogenes, such as AKT2 and cKRAS, and tumor suppressor genes, such as BRCA1 and BRCA2, have been implicated), little is known about the presence of ovarian tumors and cancer in women already diagnosed with other familial multiple tumor syndromes. In this review, we focus on the possible association of ovarian tumors with multiple endocrine neoplasias (MENs) and their related syndromes, such as Carney complex (CNC), Peutz-Jeghers syndrome (PJS), von Hippel-Lindau disease (VHLD), and Cowden's disease (CD). These conditions recently have been molecularly elucidated, and some of the genes responsible for them (including STK11/LKB1 and PTEN, the genes responsible for PJS and CD, respectively) have already been investigated in series of sporadic ovarian lesions, mostly carcinomas. A brief description of each disease is followed by a literature search for affected patients with ovarian tumors; we review our own experience with CNC patients and ovarian tumors. An association between PJS and CNC and ovarian neoplasms seems likely; carcinoids of the ovary may occur in patients with MEN 1. Only few patients with CD and VHLD have any ovarian pathology, but PTEN, the CD gene has been investigated in sporadic ovarian tumors. The aim of the present report is to alert clinicians who care for patients with MENs, CNC, PJS, VHLD, CD, and other syndromes for possible associations between various types of ovarian tumors and these conditions.
UI - 11218898
AU - Tong Y; Pan L; Zhou S
TI - [Study of mdr1 antisense oligodeoxynucleotides on reversal of multidrug resistance in ovarian carcinoma cell line SKOV3]
SO - Zhonghua Fu Chan Ke Za Zhi 2000 Nov;35(11):677-9
AD - Department of Obstetrics and Gynecology, General Hospital of Air Force, People's Liberation Army, Beijing 100036, China.
OBJECTIVE: To investigate the effect of mdr1 antisense oligodeoxynucleotides (ASON) on reversal of multidrug resistance in ovarian carcinoma cells. METHODS: Drug resistance ovarian carcinoma cells SKOV3/mdr1 transducted with human multidrug resistance gene (mdr1) were served as models. The positive rate and function of the mdr1 gene product P-glycoprotein (P-gp) in SKOV3/mdr1 cells after mdr1-ASON (250 micrograms/ml) treatment were determined by flow cytometry and rhodamine 123 efflux trial. Drug resistance of SKOV3/mdr1 cells was also observed by cell colony culture. RESULTS: P-gp positive rate of SKOV3/mdr1 cells after mdr1-ASON treatment was decreased from 38.9% to 21.3% (P < 0.01). Intracellular rhodamine retension in SKOV3/mdr1 cells after mdr1-ASON treatment was increased from 32.1% to 50.7% (P < 0.01). Under effect of Taxol 5 ng/ml, the relative percents of drug-resistant colony in mdr1-ASON treated SKOV3/mdr1 cells and in SKOV3/mdr1 cells was 8% and 63%, respectively, (P < 0.01). Under effect of Doxorubicin 100 ng/ml, the relative percents of drug-resistant colony in mdr1-ASON treated SKOV3/mdr1 cells and in SKOV3/mdr1 cells was 34% and 79%, respectively, (P < 0.01). CONCLUSION: mdr1-ASON can reverse multidrug resistance of ovarian carcinoma cell in a certain extent so as to increase chemotherapeutic sensitivity of ovarian carcinoma cells.
UI - 11838966
AU - Bennett NA; Pattillo RA; Lin RS; Hsieh CY; Murphy T; Lyn D
TI - TSG101 expression in gynecological tumors: relationship to cyclin D1, cyclin E, p53 and p16 proteins.
SO - Cell Mol Biol (Noisy-le-grand) 2001 Nov;47(7):1187-93
AD - Department of Biochemistry, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Recent studies have shown that in vitro steady-state expression of the tumor susceptibility gene TSG101 is important for maintenance of genomic stability and cell cycle regulation. To determine the contribution of TSG101 expression in neoplastic formation, expression of TSG101 protein levels were evaluated in primary ovarian and endometrial adenocarinoma tumors. Expression of TSG101 was also examined in various tumor cell lines (PA-1, AN3CA, HeLa, HS578T, HCT116). Full-length TSG101 protein was detected in these tumors and cell lines indicating that intragenic deletions were not characteristic of TSG101. In addition, TSG101 protein levels were compared with aberrations of prominent cell cycle regulatory molecules such as cyclin D1, cyclin E, p16 and p53. Reduced TSG101 protein was observed in 36% (8/22) of ovarian and 17% (1/6) of endometrial adenocarcinoma. Aberrant levels of p53, p16, cyclin D or E were comparable to published studies indicating that the clinicopathological distribution of these cases did not favor advanced stage tumors. Altogether, these findings suggest that a down-regulation of TSG101 is associated with tumorigenesis in a subgroup of gynecological tumors.
UI - 12014998
AU - Vega A; Torres M; Martinez JI; Ruiz-Ponte C; Barros F; Carracedo A
TI - Analysis of BRCA1 and BRCA2 in breast and breast/ovarian cancer families shows population substructure in the Iberia