Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Well-designed and conducted Phase II clinical trials are very important to cancer chemoprevention drug development. Three critical aspects govern the design and conduct of these trials--well-characterized agents, suitable cohorts, and reliable biomarkers for measuring efficacy that can serve as surrogate endpoints for cancer incidence. Requirements for the agent are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the chemopreventive activity observed. Agents that meet these criteria for chemoprevention of cervical cancer include antiproliferative drugs (e.g., 2-difluoromethylornithine), retinoids, folic acid, antioxidant vitamins and other agents that prevent cellular oxidative damage. Because of the significant cervical cancer risk associated with human papilloma virus (HPV) infection, agents that interfere with the activity of HPV products may also prove to be effective chemopreventives. In endometrium, unopposed estrogen exposure has been associated with cancer incidence. Thus, pure antiestrogens and progestins may be chemopreventive in this tissue. Ovarian cancer risk is correlated to ovulation frequency; therefore, oral contraceptives are potentially chemopreventive in the ovary. Recent clinical observations also suggest that retinoids, particularly all-trans-N-4-hydroxyphenylretinamide, may be chemopreventive in this tissue. The cohort should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen. In the cervix, patients with cervical intraepithelial neoplasia (CIN) and in endometrium, patients with atypical hyperplasia, fit these criteria. Defining a cohort for a Phase II trial in the ovary is more difficult. This tissue is less accessible for biopsy; consequently, the presence of precancerous lesions is more difficult to confirm. The criteria for biomarkers are that they fit expected biological mechanisms (i.e., differential expression in normal and high-risk tissue, on or closely linked to the causal pathway for the cancer, modulated by chemopreventive agents, and short latency compared with cancer), may be assayed reliably and quantitatively, measured easily, and correlate to decrease cancer incidence. They must occur in sufficient incidence to allow their biological and statistical evaluation relevant to cancer. Since carcinogenesis is a multipath process, single biomarkers are difficult to validate as surrogate endpoints, perhaps appearing on only one or a few of the many possible causal pathways. Panels of biomarkers, particularly those representing the range of carcinogenesis pathways, may prove more useful as surrogate endpoints. It is important to avoid solely on biomarkers that do not describe cancer but represent isolated events that may or may not be on the causal pathway or otherwise associated with carcinogenesis. These include markers of normal cellular processes that may be increased or expressed during carcinogenesis. Chemoprevention trials should be designed to evaluate fully the two or three biomarkers that appear to be the best models of the cancer. Additional biomarkers should be considered only if they can be analyzed efficiently and the sample size allows more important biomarkers to be evaluated completely. Two types of biomarkers that stand out regarding their high correlation to cancer and their ability to be quantified are measures of intraepithelial neoplasia and indicators of cellular proliferation. Measurements made by computer-assisted image analysis that are potentially useful as surrogate endpoint biomarkers include nuclear polymorphism comprising nuclear size, shape (roundness), and texture (DNA distribution patterns); nucleolar size and number of nucleoli/nuclei; DNA ploidy, and proliferation biomarkers such as S-phase fraction and PCNA...
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PMID:Strategies for phase II cancer chemoprevention trials: cervix, endometrium, and ovary. 874 72

The inability to identify relevant markers for presymptomatic screening in early stage or "preinvasive" ovarian cancer has plagued investigators and clinicians facing the problems of early detection. The characteristic late stage of disease at initial presentation has hindered our understanding of the biologic progression and stepwise molecular alterations that result in ovarian carcinoma. To date, most screening studies have focused on identifying early anatomic changes using ultrasound or fluctuations in serum biomarkers such as CA-125. These screening methodologies have proven inadequate in both sensitivity and specificity for early stage ovarian cancer detection. Molecular analysis of ovarian carcinomas has revealed alterations in oncogenes and tumor suppressor genes associated with these tumors. The HER-2/neu oncogene, a member of the epidermal growth factor family, is amplified or overexpressed in approximately 25-30% of ovarian carcinomas. Significant data substantiate an important role for HER-2/neu in the pathophysiology of ovarian cancer. While potentially an attractive surrogate endpoint biomarker (SEB), serum HER-2/neu levels have not proven to be a useful screening modality. In response to the urgent need for improved early detection for ovarian cancer, our current research efforts include differential hybridization studies between normal and malignant ovarian epithelium to define potentially unique ovarian cancer antigens which may ultimately have utility; defining physical alterations that occur in malignant ovarian tissues using implanted telemetry systems; studies using positron emission tomography to detect changes in glucose metabolism between normal and malignant ovarian tissues; and screening studies using a 3-dimensional ultrasound unit to improve the accuracy of this technique in recognizing early neoplastic changes. By taking diverse approaches to tackle this problem, an improved understanding of ovarian carcinogenesis should translate into the identification of appropriate SEBs for early detection.
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PMID:Screening for ovarian cancer: what are the optimal surrogate endpoints for clinical trials? 874 1

Recently, much attention in both the medical and lay communities has been focused on a possible association between fertility drug use and invasive ovarian cancer, and ovarian tumors of low malignant potential. A causal relationship, if shown to exist, has important implications. In the past year, several large case-control and cohort studies have attempted to address this issue. However, interpretation of the available data has been hampered by a number of factors. Retrospective study designs, small numbers of ovarian cancer cases, and inconsistent reporting of fertility drug use and type of infertility have all been common methodological shortcomings. The known ovarian cancer risk factors of low parity and infertility have been particularly difficult to separate from any effect of ovulation induction. The current epidemiologic data are insufficient to implicate conclusively specific fertility medications in ovarian carcinogenesis. The data do suggest that women with refractory infertility may constitute a high-risk population for developing ovarian cancer, independent of fertility drug use. Until the relationship between ovulation induction and ovarian cancer risk is defined more accurately, a high index of clinical suspicion for ovarian neoplasms is indicated before, during, and after treating women for infertility.
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PMID:The risk of ovarian cancer after treatment for infertility. 877 56

DNA instability, reflected in altered patterns of short tandem repeat sequences (microsatellites) in dividing cells, has been described in hereditary non-polyposis colon cancer (HNPCC) and in other tumor types. Ovarian cancer (OC), although most often a sporadic cancer, can recur, with HNPCC, as part of the Lynch cancer family syndrome. In an investigation of microsatellite instability (MIN) in 90 OC cases, we found MIN in 3/28 (11%) OC cases with, and 8/62 (13%) without, a family history of cancer. For 2/3 MIN+ OC cases with family cancer history consistent with the Lynch cancer family syndrome, we found additional bands in the microsatellite patterns in tumor versus normal tissue (HNPCC-type of MIN), but no germline mutations in two DNA mismatch repair genes, hMSH2 and hMLH1. In 7/8 MIN+ sporadic OC cases distinct MIN patterns not commonly reported in HNPCC were found. These are characterized by partial or total band shifting, leading to fewer bands and/or changes in the intensity of individual bands restricted to the tumor. In only one case was a germline change in hMSH2 or hMLH1 identified: this was subsequently found to be a polymorphism. An apparent hMLH1 somatic change confined to the tumor was found in another case. The fact that we found no germline pathologic mutations in hMSH2 and hMLH1 (predominant sites of mutation in HNPCC) in MIN+ OC cases, suggests that the genetic basis of MIN in OC can be different from that in HNPCC; our finding that distinct microsatellite banding patterns largely distinguish sporadic from familial OC, may reflect the involvement of different DNA repair genes in MIN in individual OC cases.
Carcinogenesis 1996 Sep
PMID:Microsatellite instability differences between familial and sporadic ovarian cancers. 882 98

To understand the role of specific fats on carcinogenesis, we have studied the effects of lipids derived from the ascites fluids of ovarian cancer patients on oncogenic components, associated with the regulation of proliferation. The treatment of tumor cells with patient-derived fats produced increased cell proliferation, as indicated by an increase in the number of S-phase cells. A similar enhancement in cell proliferation was not observed in normal fibroblasts, following lipid treatment. The effects of patient-derived lipids on the expression of c-jun, c-fos, and c-erbB2 gene products were examined. The cellular expression of the proto-oncogene product, c-fos, was increased in all three ovarian tumor cell lines, following lipid treatment. Expression of c-jun gene product was not detected in SKOV-3 or OVCAR-3 and was not induced by fat treatment. UL-1 cells did not express detectable levels of c-jun prior to fat treatment and treatment with patient-derived fat induced significant levels of c-jun product. All three ovarian tumor cell lines expressed the c-erbB2 gene product and it was generally enhanced by treatment with patient-derived lipids. When specific fatty acids were tested, 14:0, 16:1, and 18:1 were principally responsible for the observed enhancement of c-erbB2 levels, while the fatty acids, 18:0 and 20:4, produced the greatest increase in c-fos expression. Many alterations caused by fats are consistent with the loss of normal growth regulation and may account for the epidemiologic link between certain fats and the risk for ovarian cancer.
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PMID:Effect of patient-derived lipids on in vitro expression of oncogenes by ovarian tumor cells. 884 Jan 78

It has been proposed that epithelial ovarian cancers are of unifocal origin and arise from a single cell. Many alterations occur during the multistep carcinogenesis including interaction of peptide growth factors, activation of protooncogenes, and loss of tumor-suppressor genes. Increased activity of TGF-alpha and decreased activity of TGF-beta may contribute to the development of many ovarian cancers. Loss of TGF-beta responsiveness has been associated with the downregulation of c-myc expression in the development of ovarian cancer. Alternative expression of many oncogenes including ras, erbB2 and c-myc, were detected in many studies. p53 mutation was detected in 50% of advanced ovarian cancer, suggesting that loss of tumor-suppressor gene function facilitates transformation. Serum parameters like AFP, CEA, CA-125, IAP, LDH, SA, TGF-alpha, and M-CSF have been used as ovarian tumor markers. None of these biochemical markers is presently consistent and specific enough to be an early detection for ovarian cancers.
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PMID:Molecular biology of human ovarian cancer. 891 82

The EVI-1 gene was originally detected as an ectopic viral insertion site and encodes a nuclear zinc finger DNA-binding protein. Previous studies showed restricted EVI-1 RNA or protein expression during ontogeny; in a kidney and an endometrial carcinoma cell line; and in normal murine oocytes and kidney cells. EVI-1 expression was also detected in a subset of acute myeloid leukaemias (AMLs) and myelodysplasia. Because EVI-1 is expressed in the urogenital tract during development, we examined ovarian cancers and normal ovaries for EVI-1 RNA expression using reverse transcription polymerase chain reaction (RT-PCR) and RNAase protection. Chromosome abnormalities were examined using karyotypes and whole chromosome 3 and 3q26 fluorescence in situ hybridisation (FISH). RNA from six primary ovarian tumours, five normal ovaries and 47 tumour cell lines (25 ovarian, seven melanoma, three prostate, seven breast and one each of bladder, endometrial, lung, epidermoid and histiocytic lymphoma) was studied. Five of six primary ovarian tumours, three of five normal ovaries and 22 of 25 ovarian cell lines expressed EVI-1 RNA. A variety of other non-haematological cancers also expressed EVI-1 RNA. Immunostaining of ovarian cancer cell lines revealed nuclear EVI-1 protein. In contrast, normal ovary stained primarily within oocytes and faintly in stroma. Primary ovarian tumours showed nuclear and intense, diffuse cytoplasmic staining. Quantitation of EVI-1 RNA, performed using RNAase protection, showed ovarian carcinoma cells expressed 0 to 40 times the EVI-1 RNA in normal ovary, and 0-6 times the levels in leukaemia cell lines. Southern analyses of ovarian carcinoma cell lines showed no amplification or rearrangements involving EVI-1. In some acute leukaemias, activation of EVI-1 transcription is associated with translocations involving 3q26, the site of the EVI-1 gene. Ovarian carcinoma karyotypes showed one line with quadruplication 3(q24q27), but no other clonal structural rearrangements involving 3q26. However, whole chromsome 3 and 3q26 FISH performed on lines with high EVI-1 expression showed translocations involving chromosome 3q26. EVI-1 is overexpressed in ovarian cancer compared with normal ovaries, suggesting a role for EVI-1 in solid tumour carcinogenesis or progression. Mechanisms underlying EVI-1 overexpression remain unclear, but may include rearrangements involving chromosome 3q26.
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PMID:Expression of the zinc finger gene EVI-1 in ovarian and other cancers. 893 29

Cyclin-dependent kinase-4 inhibitor genes (INK4) regulate the cell cycle and are candidate tumor-suppressor genes. To determine if alterations in the coding regions of the p18 and p19 genes, which are novel members of the INK4 family and if they correlate with the development of human cancer, 100 human cancer cell lines were analyzed. Two other INK4 gene family members, p15INK4b/MTS2 and p16INK4/MTS1 genes were also analyzed. Homozygous deletions of the p15INK4b/MTS2 gene were detected in 29 cancer cell lines. Thirty-five homozygous deletions and 7 intragenic mutations of the pl6INK4/MTS1 gene were also detected in these cell lines. Neither homozygous deletions nor intragenic mutations of the p18 and p19 genes were found except in an ovarian cancer cell line, SKOV3, harboring a single base pair deletion in exon 1 of p19. In p16INK4/MTS1 expression analysis, 5 cell lines with both authentic and alternative spliced p16INK4/MTS1 mRNA had no detectable p16INK4/MTS1 protein. These results suggest the hypotheses that either post-translational modification or enhanced degradation may be responsible for the lack of detection of the p16INK4/MTS1 protein. Using Western blot analysis, subsets of 26 human cancer cell lines were examined for p18 expression and 39 cell lines for p19 expression. All of these cell lines expressed the p18 or p19 protein, with the exception of SKOV3, which did not express p19. Therefore, the INK4 gene family may be divided into 2 groups. One group includes p15INK4b/MTS2 and p16INK4/MTS1, in which genetic and epigenetic alterations might contribute to the development of human cancers. The other group includes p18 and p19, in which somatic mutations are uncommon in many types of human cancer, and their role in human carcinogenesis and cancer progression is uncertain.
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PMID:Molecular analysis of the cyclin-dependent kinase inhibitor genes p15INK4b/MTS2, p16INK4/MTS1, p18 and p19 in human cancer cell lines. 893 42

Traditional polymerase chain reaction (PCR) amplification of multiple microsatellite markers to detect microsatellite instability (MI) is labor intensive and may be marker dependent. An arbitrarily primed polymerase chain reaction (AP-PCR) is a modification of PCR that generates a genomic DNA fingerprint using a single, arbitrarily chosen primer which is useful in the detection of somatic genetic alterations. We hypothesize that AP-PCR of an AluI DNA restriction digest, which we term Alu/AP-PCR, identifies genomic instability as well. In order to test this hypothesis, we correlated Alu/AP-PCR fingerprints with analyses of traditional PCR amplified microsatellite markers using paired germline and tumor DNA samples obtained from 68 patients with ovarian cancer. The microsatellite markers tested included dinucleotide, trinucleotide, and tetranucleotide repeats. We found that MI is more common in ovarian cancer than previously thought. We estimate a minimum incidence of MI at 37% based on the 10 traditional markers we tested, to an incidence of 53% based upon our Alu/AP-PCR analysis. All cases of MI were associated with an abnormal Alu/AP-PCR banding pattern. Both MI, detected by polymorphic markers (P=0.03), and an abnormal Alu/AP-PCR pattern (P=0.01) were significantly associated with the occurrence of a second primary malignancy in the same patient. In addition, abnormal Alu/AP-PCR patterns were associated with higher grade lesions (P=0.02), and family history of cancer (P=0.009). These findings suggest: (1) MI may play an important role in ovarian carcinogenesis, and (2) Alu/AP-PCR is a novel technique for identification of genomic instability.
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PMID:Genomic instability in ovarian cancer: a reassessment using an arbitrarily primed polymerase chain reaction. 895 95

The many genetic changes associated with human carcinogenesis include the activation and/or inactivation of various genes. Polymerase-chain reaction and single-strand conformation polymorphism analysis [PCR-SSCP] was used to detect alterations at exon 1 of the K-ras gene in 20 lesions of human endometrium. Six cases of endometrial hyperplasia, 13 of endometrial carcinoma and one of endometrial metastasis of ovarian cancer were analyzed. Mutations at exon 1 of the K-ras gene were detected in two of 13 human endometrial carcinoma [15%]; both were histologically defined adenocarcinomas, stage Ib and stage IIa according to the FIGO. Alterations were also observed in the single case of endometrial metastasis of ovarian cancer. It is worthy of note that among the six women with hyperplasic endometrial lesions K-ras gene mutation were not reported. These data suggest that K-ras activation is rare in Polish women and when it does occur it is in cancerous, but not in precancerous, lesions of human endometrium.
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PMID:Detection of K-ras mutations in cancerous lesions of human endometrium. 906 33


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