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Untitled Document
CANCER GENOMICS & PROTEOMICS
Volume 1, Number
3, May-June 2004
| CONTENTS |
PAGE |
| Germline Telomere Length Dynamics and Mutagen Sensitivity Studies in a Family with Acute Reactions to Sun Exposure: Involvement of Three Generations. S. PATHAK, A. S. MULTANI, S. NARAYAN, C. L. FURLONG T. C. HSU (Houston, TX; Gainesville, FL, U.S.A.) |
199 |
| Methylation Profiling Identifies Epigenetic Markers for High-grade Gliomas. A. WAHA, F. J. RODRIGUES, A. WAHA, B. MEYER-PUTTLITZ, W. K. CAVENEE, T. HUI-MING HUANG, O. D. WIESTLER, P. S. YAN (Bonn, Germany; Columbus, Ohio; La Jolla, California, U.S.A.) |
209 |
66Gene Expression Profiling of 2-(4-Aminophenyl)benzothiazole-resistant
MCF-7 Cells Using cDNA Microarrays. Q. YU, L. R. HIORNS, T. D. BRADSHAW, M. F. G. STEVENS, B. LEYLAND-JONES (Montreal, QC, Canada; Sutton, Surrey; Nottingham, U.K.) |
215 |
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Quantitative Analysis of Ku70 and Ku80 mRNA Gene Expression in Melanoma Brain Metastases. Correlation with Immunohistochemistry and In Situ Hybridization. M. KORABIOWSKA, F. KONIG, T. SCHLOTT, P. SLOTTY, B. ROMEIKE, C. CORDON-CARDO, U. BRINCK (Gottingen; Homburg Saar, Germany; New York, U.S.A.; Wilhelmshaven, Germany) |
225 |
| Increased Expression of the Genes for Mitotic Spindle Assembly and Chromosome Segregation in Both Lung and Pancreatic Carcinomas. K. HAMADA, M. UEDA, M. SATOH, N. INAGAKI, H. SHIMADA, H. YAMADA-OKABE (Kamakura, Kanagawa; Aobaku, Sendai, Miyagi; Yokohama, Kanagawa, Japan) |
231 |
| The Carcinoma-associated Antigen EpCAM Induces Glyoxalase 1 Resulting in Enhanced Methylglyoxal Turnover. M. MUNZ, T. HOFMANN, B. SCHEIBE, M. GANGE, K. T. JUNGHANNS, R. ZEIDLER, O. GIRES (Munich; Freiburg, Germany) |
241 |
| Lung Cancer Protein Expression Profiles of Smokers and Non-Smokers. T. EFFERTH, R. KOOMAGI, J. MATTERN, M. VOLM (Heidelberg, Germany) |
249 |
| Prognostic Significance of Ets-1 and the Matrix Metalloproteinase-2 to Tissue Inhibitor of Matrix Metalloproteinase-2 Ratio in Egyptian Epithelial Ovarian Cancer Patients. S. K. KASSIM, S. T. FAYED, R. ALI-LABIB, L. SEADA (Cairo; Benha, Egypt) |
255 |
CANCER GENOMICS & PROTEOMICS 1: 199-208 (2004)
Germline Telomere Length Dynamics and Mutagen Sensitivity Studies in a Family with Acute Reactions to Sun Exposure: Involvement of Three Generations
SEN PATHAK1,2, ASHA S. MULTANI1, SATYA NARAYAN3, CYNTHIA L. FURLONG1, T. C. HSU1
Departments of 1 Cancer Biology and 2Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030;
3UF Shands Cancer Center and Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610, U.S.A.
Abstract: Most cancers are the result of an interaction between germline genetic susceptibility and exposure to environmental carcinogens. We studied chromosomal aberrations, telomeric associations, telomere signal intensity by fluorescence in situ hybridization, p53 germline mutation, bleomycin (Bleo) and 4-nitroquinoline-1-oxide (4NQO) sensitivity, and chromosome-specific telomere signals in T and B lymphocytes in a Caucasian family involving three generations and 13 family members. This family was chosen because eight of its members are extremely sensitive to sunlight and burn easily even upon short exposure. The family members have shown: (a) hypersensitivity either to Bleo or 4NQO mutagens, with values much higher than 1.00 breaks/cell (b/c) for Bleo and 0.40 b/c for 4NQO; (b) an increased rate of telomeric associations; (c) variable amounts of telomeric DNA not common for the person's age; (d) the presence of intron 7 polymorphism in the proband and no significant effect on N-methyl-N'-nitosoguanidine (MNNG)-induced p53 expression in two key family members; and (e) an incidence of epithelial malignancies in two family members. Seven additional members showed polymorphism of telomeric signals in the short arm of two homologous chromosome 17s, where the p53 gene is localized. A 78-year-old grandmother, who had developed colon cancer, was predicted to have metastatic cancer based on the telomeric DNA amount in her lymphocytes (2.90%); she subsequently developed metastatic lesions within a year and died. Based on these observations, we conclude that telomere erosion is the initial cause of genomic instability/susceptibility which, in turn, may be causal for the reproductive complications, premature aging phenotypes and, in some cases, predisposition to cancer development.
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CANCER GENOMICS & PROTEOMICS 1: 215-224 (2004)
Gene Expression Profiling of 2-(4 Aminophenyl) benzothiazoleresistant MCF-7 Cells Using cDNA Microarrays
QINGNAN YU1, LYNNE R. HIORNS2, TRACEY D. BRADSHAW3, MALCOLM F. G. STEVENS3, BRIAN LEYLAND-JONES1
1Department of Oncology, McGill University, Montreal, QC, Canada;
2Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, Surrey;
3Cancer Research Laboratories, University of Nottingham, Nottingham, U.K.
Abstract: Background: CJM126, 2-(4-aminophenyl) benzothiazole, is a potent inhibitor of human-derived breast carcinoma cell lines. Previous studies have shown that CJM126 elicits concentration-dependent, biphasic growth inhibitory effects against a panel of estrogen receptor-positive and receptor-negative human mammary carcinoma cell lines by a mechanism which has not been fully elucidated. Materials and Methods: In an effort to understand the mechanism(s) of resistance to CJM126, the present study used cDNA microarrays (Clontech Laboratories, Inc.) representing 1,176 human cancer-related genes to analyze expression profile changes of two CJM126-resistant cell lines, MCF-710nM126 and MCF-710ìM126, previously created by exposing MCF-7 cells to 10 nM and 10 ìM CJM126, respectively. Results: Expression changes in the CJM126-resistant MCF-7 cell lines were observed in genes involved in a variety of cell signaling pathways. Gene expression changes common to MCF-710nM126 and MCF-710ìM126 cells, as compared to sensitive MCF-7wt cells, were the shut-down of transcription factor Oct-2 and the up-regulation of the negative apoptosis regulator MCL-1, the G1-to-S-phase regulator ubiquitin carrier protein and the GTP-binding protein GST1-HS. These findings indicate the association of a CJM126-resistance phenotype with profound gene transcription dysregulation, decreased apoptotic activity and increased proliferation. Specific changes unique to each of the CJM126-resistant cell lines were also observed. Genes involved in the DNA mismatch-repair pathway, such as MSH2, DNA repair protein RAD51 and damage-specific DNA binding protein were down-regulated in MCF-710nM126, while genes involved in the nucleotide-excision repair pathway, such as ERCC1, RFC and PCNA were overexpressed in MCF-710ìM126. Conclusion: The differential changes in the DNA-repair pathways between MCF-710nM126 and MCF-710ìM126 cell lines indicate that different processes may have been employed to circumvent the growth inhibition produced by exposure to CJM126. This would also suggest that CJM126 may have concentration-dependent mechanisms of growth inhibition.
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CANCER GENOMICS & PROTEOMICS 1: 209-214 (2004)
Methylation Profiling Identifies Epigenetic Markers for High-grade Gliomas
ANDREAS WAHA1, FAUSTO J. RODRIGUES2, ANKE WAHA1, BIRGIT MEYER-PUTTLITZ1, WEBSTER K. CAVENEE3, TIM HUI-MING HUANG2, OTMAR D. WIESTLER1, PEARLLY S. YAN2
1Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany;
2Division of Human Cancer Genetics, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, U.S.A.;
3Ludwig Institute for Cancer Research, Department of Medicine, Center for Molecular Genetics, University of California at San Diego, La Jolla, California, U.S.A.
Abstract: Hypermethylation of CpG island is an epigenetic event prevalent in human gliomas. Here we employed a high-throughput microarray approach for a global search of DNA methylation to identify novel epigenetic loci in specific glioma subtypes. Hierarchical clustering analysis separated 20 glioma samples according to their WHO histopathological subtypes – pilocytic astrocytomas (PAs, grade I), oligoastrocytomas (OAs, grade II) and glioblastomas (GBMs, grade IV), based on their unique methylation patterns. The overall methylation frequency of the low-grade PAs was significantly less than that of the more aggressive OAs and GBMs (0.45% versus 2.0% and 1.4%; PAs versus OAs, p<0.01; PAs versus GBMs, p<0.01). The lower level of DNA methylation observed in PAs may be in part due to the increased methylation of multiple CpG islands which occur in more advanced tumors. However, the young age of onset of PAs may also contribute to this observed difference. Although there were many hypermethylated loci exclusive to the OA and GBM subtypes, the methylation frequencies between these groups were not significantly different. Analysis by methylation-specific PCR on an expanded set of samples and on more glioma subtypes further confirmed an epigenetic marker, SMARCA5, the hypermethylation of which was preferentially observed in grade IV, but not in grades I or II gliomas (p<0.0001). The intermediate grade III gliomas showed low levels of SMARCA5 hypermethylation. Epigenetic loci uncovered in the present study recapitulate the histopathological differences of these gliomas, indicating that these molecular changes may be responsible for the development of the different glioma subtypes. On-going work in our laboratory has shown that some of these loci are indeed hypermethylated in the early stages of astrocytic tumors.
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CANCER GENOMICS & PROTEOMICS 1: 225-230 (2004)
Quantitative Analysis of Ku70 and Ku80 mRNA Gene Expression in Melanoma Brain Metastases. Correlation with Immunohistochemistry and In Situ Hybridization
MONIKA KORABIOWSKA1, FATIMA KONIG2, THILO SCHLOTT1, PHILIP SLOTTY1, BERND ROMEIKE3,
CARLOS CORDON-CARDO4, ULRICH BRINCK5
1Department of Cytopathology,
2Department of Neuropathology, Georg-August University Gottingen, Robert Koch Str. 40, 37075 Gottingen;
3Department of Neuropathology, University of the Saarland, Homburg/Saar, 66421 Homburg Saar, Germany;
4Division of Molecular Pathology, Memorial Sloan Kettering Cancer Center, New York, 1075 York Avenue, New York 10021, U.S.A.;
2Department of Pathology, Reinhard Nieter Hospital, Wilhelmshaven, Germany, Teaching Hospital of the University Gottingen, Germany
Abstract: Background: Altered expression and prognostic significance of DNA double-strand repair genes Ku70 and Ku80 has been shown by our research group for malignant melanomas. High genomic instability known for melanoma brain metastases stimulated us to analyze Ku70 and Ku80 expression in melanoma brain metastases. Materials and Methods: Quantitative evaluation of mRNA Ku70 and Ku80 expression was performed in 13 melanoma brain metastases. Immunohistochemistry and in situ hybridization for Ku70 and Ku80 were applied to 34 metastatic tumours. Results: Quantitative analysis of Ku70 mRNA expression demonstrated values between 0.01 and 0.33. Ku80 mRNA expression ranged between 0.001 and 0.54. Immunohistochemistry demonstrated Ku70 and Ku80 expression in 34 and in 25 metastatic tumours, respectively. In situ hybridization detected Ku70 expression in 19/34 and Ku80 expression in 13/34 metastatic tumours. Correlation between Ku70 and Ku80 expression in melanoma brain metastases was lost. Conclusion: Ku70 and especially Ku80 expression is altered in melanoma brain metastases and corresponds with the high genomic instability of these lesions.
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CANCER GENOMICS & PROTEOMICS 1: 249-254 (2004)
Lung Cancer Protein Expression Profiles of Smokers and Non-Smokers
THOMAS EFFERTH1, REET KOOMÁGI2, JURGEN MATTERN2, MANFRED VOLM2
1Center of Molecular Biology of the University of Heidelberg;
2German Cancer Research Center, Heidelberg, Germany
Abstract: Epidemiological studies have established a causal relationship between cigarette smoking and respiratory tract cancer. The knowledge about the interaction of tobacco constituents with cellular systems is, however, still incomplete. Therefore, we analyzed 36 factors with known or assumed relevance and found that 8 proteins in lung cancer were associated with the smoking habits of 94 patients. These 8 factors belong to different functional classes including products of drug resistance-related proteins (P-glycoprotein, glutathione S-transferase-ð, lung resistance protein, catalase), proto-oncogenes and transcription factors (FOS, JUN, HIF-1â), and proliferative factors (cyclin D). By means of hierarchical cluster analysis, we were able to show that the 94 patients analyzed could be separated into three different clusters, of which one contained significantly more patients who smoked than the others (p=0.0026). This cluster also contained significantly more drug-resistant tumors than the others (p=0.0069), pointing to a close interrelationship between the smoking habits of patients and drug resistance of tumors.
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CANCER GENOMICS & PROTEOMICS 1: 241-248 (2004)
The Carcinoma-associated Antigen EpCAM Induces Glyoxalase 1 Resulting in Enhanced Methylglyoxal Turnover
MARKUS MUNZ1, TANJA HOFMANN2, BURGHARDT SCHEIBE3, MATTHIAS GANGE3,
KAY T. JUNGHANNS3, REINHARD ZEIDLER4, OLIVIER GIRES 1,2
1Clinical Cooperation Group Molecular Oncology, GSF-Research Center for Environment and Health, and Head and Neck Research Department Munich;
2Head and Neck Research Department, University Clinics Großhadern, Marchioninistr. 15, 81377 Munich;
3Amersham Biosciences Europe GmbH, Münzingerstr. 9, 79111 Freiburg;
4Vaecgene Biotech. Inc., Marchioninistr. 25, D-81377 Munich, Germany
Abstract: Background: The epithelial cell adhesion molecule (EpCAM) is a homophilic adhesion molecule expressed de novo on a variety of epithelial tumors. Overexpression of EpCAM results in enhanced proliferation and rapid induction of the proto-oncogene c-myc. Materials and Methods: The novel proteomics-based fluorescence difference gel electrophoresis (DIGE technology) was used to study EpCAM effects on the proteome of human epithelial cells. Results: DIGE analysis resulted in the identification of five proteins with a significantly changed regulation ranging from –1.3 to +5.8-fold. One of the identified proteins, namely glyoxalase 1, experienced a shift in the isoelectric point from pH 5.2 to 5.0 upon EpCAM expression. This shift correlated with a gain of enzymatic activity of glyoxalase 1 resulting in an enhanced methylglyoxal turnover. Conclusion: We show the potential of the DIGE technology to rapidly and quantitatively analyze proteomes for changed expression levels and, importantly, posttranslational modifications. Furthermore, we describe new targets of the carcinoma antigen EpCAM including glyoxalase1.
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CANCER GENOMICS & PROTEOMICS 1: 255-262 (2004)
Prognostic Significance of Ets-1 and the Matrix Metalloproteinase-2 to Tissue Inhibitor of Matrix Metalloproteinase-2 Ratio in Egyptian Epithelial Ovarian Cancer Patients
SAMAR K. KASSIM1, SALAH T. FAYED2, RANDA ALI-LABIB1, LAILA SEADA3
Departments of 1 Medical Biochemistry and 2Obstetrics and Gynecology, Faculty of Medicine, Ain Shams University, Cairo; and 3Pathology Department, Zagazig University, Benha, Egypt
Abstract: The invasive potential of epithelial ovarian cancer is the main factor determining its biological behavior. Ets-1 transcription factor is involved in the activation of several proteases participating in tumor invasion and metastasis. The balance of matrix metalloproteinase-2 and its inhibitor is important in the regulation of tumor invasion. This study included 31 tumors from patients with epithelial ovarian cancer in different stages, and 20 tissue samples from benign ovarian lesions as a control group. Ets-1 was assessed using immunohistochemistry. Matrix metalloproteinase-2 (MMP-2) and the MMP-2 inhibitor (TIMP-2) were measured in the cytosolic fractions using enzyme immunoassay. MMP-2 results were confirmed by gelatin zymography. ETS-1 was expressed only in the malignant group. MMP-2 and the MMP-2:TIMP-2 ratio were significantly higher in the malignant group (p=0.045 and 0.026, respectively) with significant correlation to stage and poor survival above the specified cut-off values (p=0.006 and 0.002, respectively). Log rank of Kaplan-Meier survival analysis was significant for FIGO stage, MMP-2 and the MMP-2:TIMP-2 ratio (p<0.05). Multivariate analysis demonstrated that the MMP-2:TIMP-2 ratio is an independent prognostic parameter. Ets-1 could be a future target for therapeutic strategies. Moreover, the MMP-2:TIMP-2 ratio might serve as a new independent prognostic indicator of poor prognosis in epithelial ovarian cancer patients.
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CANCER GENOMICS & PROTEOMICS 1: 231-240 (2004)
Increased Expression of the Genes for Mitotic Spindle Assembly and Chromosome Segregation in Both Lung and Pancreatic Carcinomas
KENJI HAMADA1, MICHIO UEDA3, MASAMI SATOH2, NAOHITO INAGAKI1, HIROSHI SHIMADA3, HISAFUMI YAMADA-OKABE1
1Pharmaceutical Research Department IV, Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530;
2Department of Surgery, Tohoku University, 4-1 Seiryoucho, Aobaku, Sendai, Miyagi 980-8575;
3Department of Surgery, School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama, Kanagawa 236-0004, Japan
Abstract: Genes whose expression was modulated in two different tumor types, lung or pancreatic carcinoma, were identified by DNA microarray and subsequent expression correlation analyses. For more accurate comparison of the gene expression between tumor and normal cells, tumor cells and normal epithelium cells were isolated by laser-captured microdissection. Genes whose expression was significantly altered in lung carcinomas or pancreatic carcinomas as compared to their normal counterparts were ranked by the T-values calculated from the Fisher's ratios and their corresponding background Fisher's ratios, followed by statistical confirmation using the Welch's t-test. Among the genes that were ranked in the top 150, either in lung carcinomas or pancreatic carcinomas, expressions of MAD2, BUB1, BUB1B, HEC, CENPE, ZWINT, KNSL1, SMC4, CCNB, TK and PMS2L6 were found to be significantly up-regulated in both tumor types. Interestingly, 8 of the above 11 genes code for the proteins involved in the mitotic spindle assembly and chromosome segregation. Furthermore, the search for genes whose expression correlated with one of the above 5 genes yielded additional genes that are also considered to be involved in mitotic spindle assembly and chromosome segregation. Thus, increased expression of the genes for mitotic spindle assembly and chromosome segregation are a common feature of at least lung carcinomas and pancreatic carcinomas and, therefore, such genes may be potential targets for widely effective anticancer agents.
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