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  • DKFZ Publication Database  (3)
  • 1
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; tumor ; AGENTS ; carcinoma ; SITES ; GENE ; GENE-EXPRESSION ; GENES ; HYBRIDIZATION ; TUMORS ; RESOLUTION ; LINES ; CANDIDATE GENE ; TARGET ; NEOPLASIA ; PROGRESSION ; AMPLIFICATION ; chromosome 2 ; COMPARATIVE GENOMIC HYBRIDIZATION ; OVARIAN-CANCER ; CHROMOSOMAL-ABERRATIONS ; MUTATION ; cervical intraepithelial neoplasia ; MUTATIONS ; SQUAMOUS-CELL CARCINOMA ; intraepithelial neoplasia ; UTERINE CERVIX ; cervical carcinoma ; gene amplification ; E7 ONCOPROTEINS ; LOH ; CGH ; CHILDHOOD NEUROBLASTOMAS ; PRECANCEROUS LESIONS ; RECURRENT PATTERN
    Abstract: We performed comparative genomic hybridization (CGH) and high- resolution deletion mapping of the long arm of chromosome 2 (2q) in invasive cervical carcinoma (CC). The CGH analyses on 52 CCs identified genetic losses at 2q33-q36, gain of 3q26-q29, and frequent chromosomal amplifications. Characterization of 2q deletions by loss of heterozygosity (LOH) in 60 primary tumors identified two sites of minimal deleted regions at 2q35-q36.1 and 2q36.3-q37.1. To delineate the stage at which these genetic alterations occur in CC progression, we analysed 33 cervical intraepithelial neoplasia (CIN) for LOH. We found that 89% of high-grade (CINII and CINIII) and 40% of low-grade (CINI) CINs exhibited LOH at 2q. To identify the target tumor suppressor gene (TSG), we performed an extensive genetic and epigenetic analyses of a number of candidate genes mapped to the deleted regions. We did not find inactivating mutations in CASP10, BARD1, XRCC5, or PPP1R7 genes mapped to the deleted regions. However, we did find evidence of downregulated gene expression in CFLAR, CASP10 and PPPIR7 in CC cell lines. We also found reactivated gene expression in CC cell lines in vitro after exposure to demethylating and histone deacetylase (HDAC) inhibiting agents. Thus, these data identify frequent chromosomal amplifications in CC, and sites of TSGs at 2q35- q36.1 and 2q36.3-q37.1 that are critical in CC development
    Type of Publication: Journal article published
    PubMed ID: 12776201
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  • 2
    Keywords: CANCER ; EXPRESSION ; carcinoma ; CELL ; INHIBITION ; PATHWAY ; EXPOSURE ; NEW-YORK ; GENE ; GENE-EXPRESSION ; GENES ; cell line ; LINES ; PATIENT ; COMPLEX ; COMPLEXES ; DNA ; CELL-LINES ; treatment ; STAGE ; gene expression ; PROMOTER ; BRCA1 ; CELL-LINE ; LINE ; inactivation ; PHENOTYPE ; CANCER-RESEARCH ; HISTONE DEACETYLASE ; MANAGEMENT ; SUBSET
    Abstract: Patients with advanced stage invasive cervical cancer (CC) exhibit highly complex genomic alterations and respond poorly to conventional treatment protocols. In our efforts to understand the molecular genetic basis of CC, we examined the role of Fanconi Anemia (FA)-BRCA pathway. Here, we show that FANCF gene is disrupted by either promoter hypermethylation and/or deregulated gene expression in a majority of CC. Inhibition of DNA methylation and histone deacetylases induces FANCF gene re-expression in CC cell lines. FANCF-deregulated CC cell lines also exhibit a chromosomal hypersensitivity phenotype after exposure to an alkylating agent, a characteristic of FA patients. We also show the involvement of BRCA1 gene by promoter hypertmethylation or down-regulated expression in a small subset of CC patients. Thus, we have found inactivation of genes in the FA-BRCA pathway by epigenetic alterations in a high proportion of CC patients, suggesting a major role for this pathway in the development of cervical cancer. Thus, these results have important implications in understanding the molecular basis of CC tumorigenesis and clinical management in designing targeted experimental therapeutic protocols
    Type of Publication: Journal article published
    PubMed ID: 15126331
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; INHIBITION ; COMMON ; DIAGNOSIS ; NEW-YORK ; GENE ; GENES ; GENOME ; HYBRIDIZATION ; microarray ; transcription ; DRUG ; METABOLISM ; cell line ; TUMORS ; validation ; LINES ; COMPLEX ; COMPLEXES ; CELL-LINES ; chromosome ; FORM ; DELETION ; IDENTIFICATION ; IN-SITU ; PROGRESSION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; ARRAYS ; NUMBER ; genetics ; cervical cancer ; CERVICAL-CANCER ; CELL-LINE ; LINE ; DELETIONS ; PATHOGENESIS ; PCR ; REGION ; REGIONS ; ONCOGENE ; RT-PCR ; immune response ; IMMUNE-RESPONSE ; UTERINE CERVIX ; RECURRENT ; FLUORESCENCE ; MICROARRAY ANALYSIS ; fluorescence in situ hybridization ; cell lines ; heredity ; HIGH-LEVEL ; CDNA MICROARRAY ; in situ hybridization ; molecular ; ONCOLOGY ; ARRAY ; LEVEL ; analysis ; PROFILES ; DYSPLASIA ; EXPRESSION PROFILES ; USA ; CANDIDATE ; genomic ; DRUG-METABOLISM ; CDNA-MICROARRAY ; EPHB2 ; 19Q13.3 ; COMPARATIVE-GENOMIC-HYBRIDIZATION ; INVASIVE-CARCINOMA ; MUC4 EXPRESSION
    Abstract: Cervical cancer (CC) cells exhibit complex karyotypic alterations, which is consistent with deregulation of numerous critical genes in its formation and progression. To characterize this karyotypic complexity at the molecular level, we used cDNA array comparative genomic hybridization (aCGH) to analyze 29 CC cases and identified a number of over represented and deleted genes. The aCGH analysis revealed at least 17 recurrent amplicons and six common regions of deletions. These regions contain several known tumor-associated genes, such as those involved in transcription, apoptosis, cytoskeletal remodeling, ion-transport, drug metabolism, and immune response. Using the fluorescence in situ hybridization (FISH) approach we demonstrated the presence of high-level amplifications at the 8q24.3, 11q22.2, and 20q13 regions in CC cell lines. To identify amplification-associated genes that correspond to focal amplicons, we examined one or more genes in each of the 17 amplicons by Affymetrix UI33A expression arrays and serniquantitative reverse-transcription PCR (RT-PCR) in 31 CC tumors. This analysis exhibited frequent and robust upregulated expression in CC relative to normal cervix for genes EPHB2 (1p36), CDCA8 (1p34.3), AIM2 (1q22-23), RFC4, MUC4, and HRASLS (3q27-29), SKP2 (5p12-13), CENTD3 (Sq31.3), PTK2, RECQL4 (8q24), MMP1 and MMP13 (11q22.2), AKT1 (14q32.3), ABCC3 (17q21-22), SMARCA4 (19p13.3) LIG1 (19q13.3), UBE2C (20q13.1), SMCIL1 (Xp11), KIRA (Xq12), TMSN8 (Xq22), and CSAG2 (Xq28). Thus, the gene dosage and expression profiles generated here have enabled the identification of focal amplicons characteristic for the CC genome and facilitated the validation of relevant genes in these amplicons. These data, thus, form an important step toward the identification of biologically relevant genes in CC pathogenesis. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/ 10452257/suppmat. (c) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17243165
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