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    Keywords: CANCER ; SURVIVAL ; carcinoma ; COHORT ; HISTORY ; GENE ; TUMORS ; ACTIVATION ; breast cancer ; BREAST-CANCER ; MUTATION ; PCR ; real-time PCR ; oncogene amplifications ; PROGNOSTIC RELEVANCE ; bilateral breast cancer
    Abstract: Amplification of HER2, C-MYC and CCND1 oncogenes is a hallmark of breast cancer (BC); however, its involvement in the bilateral form of this disease has not been investigated yet. In this study, 50 bilateral BC (biBC) pairs (100 tumors) and 72 control unilateral BC were examined using real-time PCR analysis of microdissected archival tissues. In biBC, the frequency of 〉 3-fold oncogene amplification was 6/100 (6%) for HER2, 6/100 (6%) for C-MYC and 7/100 (7%) for CCND1. Altogether, 18/100 (18%) biBC tumors had increased gene dosage of at least one oncogene. Tumors forming synchronous biBC pairs had amplification in 11/46 cases (24%). In 3 of 8 patients with amplification-positive carcinomas, the amplification was detected in both neoplasms: 2 biBC had concordant activation of the same oncogene (HER2 and CCND1, respectively), and in the remaining case distinct oncogenes were affected (HER2 and C-MYC). In contrast, amplifications in metachronous biBC were strongly discordant: none of 27 first carcinomas carried this abnormality, while the frequency of amplification in second tumors (7/27; 26%) was similar to the one observed in unilateral BC (20/72; 28%). The trend toward concordance of oncogene amplification status in synchronous but not in metachronous biBC pairs can be explained by the nearly identical natural history of the disease in simultaneously arising tumors. The skewed pattern of amplifications in metachronous biBC might be attributed to their association with adverse BC prognosis; it appears that only patients with amplification-negative first BC have sufficient chances to survive until the development of the contralateral carcinoma. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17066426
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  • 3
    Keywords: APOPTOSIS ; PATHWAY ; GENES ; POOR-PROGNOSIS ; INCREASED EXPRESSION ; MICE LACKING ; high-throughput analysis ; ISLAND METHYLATOR PHENOTYPE ; D-DEPENDENT KINASES ; INK4 FAMILY
    Abstract: Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is a crucial determinant of neuroblastoma cell malignancy. Here we identify neuroblastoma-suppressive functions of the p19-INK4d CDK inhibitor and uncover mechanisms of its repression in high-risk neuroblastomas. Reduced p19-INK4d expression was associated with poor event-free and overall survival and neuroblastoma risk factors including amplified MYCN in a set of 478 primary neuroblastomas. High MYCN expression repressed p19-INK4d mRNA and protein levels in different neuroblastoma cell models with conditional MYCN expression. MassARRAY and 450K methylation analyses of 105 primary neuroblastomas uncovered a differentially methylated region within p19-INK4d. Hypermethylation of this region was associated with reduced p19-INK4d expression. In accordance, p19-INK4d expression was activated upon treatment with the demethylating agent, 2'-deoxy-5-azacytidine, in neuroblastoma cell lines. Ectopic p19-INK4d expression decreased viability, clonogenicity and the capacity for anchorage-independent growth of neuroblastoma cells, and shifted the cell cycle towards the G1/0 phase. p19-INK4d also induced neurite-like processes and markers of neuronal differentiation. Moreover, neuroblastoma cell differentiation, induced by all-trans retinoic acid or NGF-NTRK1-signaling, activated p19-/NK4dexpression. Our findings pinpoint p19-INK4d as a neuroblastoma suppressor and provide evidence for MYCN-mediated repression and for epigenetic silencing of p19-INK4d by DNA hypermethylation in high-risk neuroblastomas.
    Type of Publication: Journal article published
    PubMed ID: 25104850
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; TUMOR-CELLS ; CELL ; Germany ; INHIBITION ; MODEL ; SITE ; GENE ; PROTEIN ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; INDUCTION ; CONTRAST ; mechanisms ; BINDING ; cell cycle ; CELL-CYCLE ; CYCLE ; PROGRESSION ; CHROMATIN ; PROMOTER ; REGION ; DEGRADATION ; UBIQUITIN LIGASE ; REPRESSION ; S-PHASE ; TRANSCRIPTIONAL REPRESSION ; REGULATOR ; MYCN ; neuroblastoma ; INHIBITORS ; ONCOLOGY ; CORE ; SUBTYPES ; CANCERS ; PROTEIN-LEVELS
    Abstract: The cell cycle regulator, SKP2, is overexpressed in various cancers and plays a key role in p27 degradation, which is involved in tumor cell dedifferentiation. Little is known about the mechanisms leading to impaired SKP2 transcriptional control in tumor cells. We used neuroblastoma as a model to study SKP2 regulation because SKP2 transcript levels gradually increase with aggressiveness of neuroblastoma subtypes. The highest SKP2 levels are found in neuroblastomas with amplified MYCN. Accordingly, we found 5.5-fold (range, 2-9.5) higher SKP2 core promoter activity in MYCN-amplified cells. Higher SKP2 core promoter activity in MYCN-amplified cells is mediated through a defined region at the transcriptional start site. This region includes a specific E2F-binding site that makes SKP2 activation largely independent of mitogenic signals integrated through the SP1/ELK-1 site. We show by chromatin immunoprecipitation that SKP2 activation through the transcriptional start site in MYCN-amplified cells is associated with the low abundance of pRB-E2F1 complexes bound to the SKP2 promoter. Transcriptional control of SKP2 through this regulatory mechanism can be re-established in MYCN-amplified cells by restoring pRB activity using selective small compound inhibitors of CDK4. In contrast, doxorubicin or nutlin-3 treatment-both leading to p53-p21 activation-or CDK2 inhibition had no effect on SKP2 regulation in MYCN-amplified cells. Together, this implies that deregulated MYCN protein levels in MYCN-amplified neuroblastoma cells activate SKP2 through CDK4 induction, abrogating repressive pRB-E2F1 complexes bound to the SKP2 promoter. Cancer Res; 70(9); 3791-802. (C) 2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20424123
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  • 5
    Keywords: CANCER ; EXPRESSION ; GROWTH ; SURVIVAL ; MODEL ; CLASSIFICATION ; GENE ; transcription ; DIFFERENTIATION ; BINDING ; cell cycle ; DELETED REGION ; HELMINTHOSPORIUM-CARBONUM (HC)-TOXIN ; GLIOBLASTOMAS ; BINDING TRANSCRIPTION ACTIVATORS ; DEFINITION
    Abstract: A distal portion of human chromosome 1p is often deleted in neuroblastomas and other cancers and it is generally assumed that this region harbors one or more tumor suppressor genes. In neuroblastoma, a 261 kb region at 1p36.3 that encompasses the smallest region of consistent deletion pinpoints the locus for calmodulin binding transcription activator 1 (CAMTA1). Low CAMTA1 expression is an independent predictor of poor outcome in multivariate survival analysis, but its potential functionality in neuroblastoma has not been explored. In this study, we used inducible cell models to analyze the impact of CAMTA1 on neuroblastoma biology. In neuroblastoma cells that expressed little endogenous CAMTA1, its ectopic expression slowed cell proliferation, increasing the relative proportion of cells in G(1)/G(0) phases of the cell cycle, inhibited anchorage-independent colony formation, and suppressed the growth of tumor xenografts. CAMTA1 also induced neurite-like processes and markers of neuronal differentiation in neuroblastoma cells. Further, retinoic acid and other differentiation-inducing stimuli upregulated CAMTA1 expression in neuroblastoma cells. Transciptome analysis revealed 683 genes regulated on CAMTA1 induction and gene ontology analysis identified genes consistent with CAMTA1-induced phenotypes, with a significant enrichment for genes involved in neuronal function and differentiation. Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 21385898
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  • 6
    Keywords: HYBRIDIZATION ; SAMPLES ; AMPLIFICATION ; microsatellites ; PRODUCT ; DNA-pooling ; Formicidae ; microsatellite enrichment ; Myrmica ; social insects
    Abstract: Five polymorphic microsatellite loci were developed for the ant Myrmica scabrinodis using a magnetic bead hybridization selection protocol. The number of alleles per locus varied between three and six. Cross-species amplification of four of the loci yielded positive amplification products in four Myrmica species, suggesting their general suitability for microsatellite analysis within this taxonomic group
    Type of Publication: Journal article published
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  • 7
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    Keywords: EXPRESSION ; SURVIVAL ; tumor ; Germany ; human ; COHORT ; DISEASE ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; TUMORS ; PATIENT ; ASSOCIATION ; IDENTIFICATION ; AMPLIFICATION ; DESIGN ; AGE ; HETEROZYGOSITY ; BEHAVIOR ; MICROARRAY ANALYSIS ; neuroblastoma ; N-MYC ; CANDIDATE GENES ; REVERSE TRANSCRIPTION-PCR ; MUTATIONAL ANALYSIS ; INTERVAL ; EXPRESSION PATTERNS ; SHORT ARM ; 1P36.2 ; CHROMOSOME 1P ; GENOMIC STRUCTURE ; HOMOZYGOUSLY DELETED REGION ; TUMOR-SUPPRESSOR GENES
    Abstract: Purpose: A distal portion of 1p is frequently deleted in human neuroblastomas, and it is generally assumed that this region harbors at least one gene relevant for neuroblastoma development. A 1p36.3 commonly deleted region, bordered by D1S2731 and D1S214 has been defined. The present study surveys whether expression of genes mapping to this region is associated with tumor behavior. Experimental Design: Candidate genes localized within the deleted region were identified by sequence data analysis. Their expression was assessed in a cohort of 49 primary neuroblastomas using cDNA microarray analysis. Gene expression patterns associated with known prognostic markers and patient outcome were further evaluated by quantitative real-time reverse transcription-PCR in a cohort of 102 neuroblastomas. Results: The commonly deleted region spans 261 kb and encompasses two genes, FLJ10737 and CAMTA1. We found no evidence for an association of FLJ10737 expression with established prognostic variables or outcome. In contrast, low CAMTA1 expression characterized tumors with 1p deletion, MYCN amplification, and advanced tumor stages 3 and 4. Moreover, low CAMTA1 expression was significantly associated with poor outcome (P 〈 0.001). In multivariate analysis of event-free survival, the prognostic information of low CAMTA1 expression was independent of 1p status, MYCN status, tumor stage, and age of the patient at diagnosis (hazard ratio, 3.52; 95% confidence interval, 1.21-10.28; P = 0.02). Conclusions: Our data suggest that assessment of CAMTA1 expression may improve the prognostic models for neuroblastoma and that it will be important to define the biological function of CAMTA1 in this disease
    Type of Publication: Journal article published
    PubMed ID: 16397034
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  • 9
    Keywords: CANCER ; EXPRESSION ; tumor ; BLOOD ; Germany ; human ; GENE ; GENES ; PROTEIN ; SAMPLES ; PATIENT ; DNA ; MESSENGER-RNA ; IMPACT ; DOMAIN ; polymorphism ; VARIANTS ; ACID ; DELETION ; IDENTIFICATION ; MALIGNANCIES ; MUTATION ; HETEROZYGOSITY ; REGION ; MUTATIONS ; SUSCEPTIBILITY GENE ; LOH ; 1p ; neuroblastoma ; N-MYC ; SINGLE ; MALIGNANCY ; ONCOLOGY ; RE ; VARIANT ; SSCP ; SHORT ARM ; CHROMOSOME 1P ; ANKYRIN REPEAT ; CAMTA1 ; FLJ10737
    Abstract: Deletion of a distal portion of ip is seen in a wide range of human malignancies, including neuroblastoma. Here, a 1p36.3 commonly deleted region of 216 kb has been defined encompassing two genes, CAMTA1 and FLJ10737. Low expression of CAMTA1. has been recently shown to be an independent predictor of poor outcome in neuroblastoma patients. The present study surveys CAMTA1 and FLJ10737 for genetic alterations by fluorescence-based single strand conformation polymorphism (SSCP) using a panel of DNAs from 88 neuroblastomas, their matching blood samples and 97 unaffected individuals. Nucleotide variants encoding amino acid substitutions were found in both genes. One CAMTA1 variant (T13361) was not detected in 97 unaffected individuals, another (NI177K) resides in a conserved domain of the CAMTA1 protein and was found hemizygous in six neuroblastomas. We found no evidence for somatic mutations in FLJ10737 or CAMTA1. Further investigations are needed to address the functional impact of the identified variants and their possible significance for neuroblastoma. (c) 2006 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17222547
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  • 10
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; Germany ; PATHWAY ; VITRO ; COHORT ; DISEASE ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; TUMORS ; PATIENT ; MECHANISM ; MARKER ; primary ; prognosis ; mechanisms ; TARGET ; STAGE ; PROGRESSION ; immunohistochemistry ; gene expression ; microarrays ; DESIGN ; NUMBER ; PCR ; HIGH-RISK ; ONCOGENE ; PHENOTYPE ; MULTIVARIATE ; DEGRADATION ; TARGETS ; p27 ; S-PHASE ; protein expression ; MYCN ; CELL-CYCLE PROGRESSION ; CDNA MICROARRAY ; neuroblastoma ; N-MYC ; molecular ; ONCOLOGY ; PROGRAM ; SUBSET ; MOLECULAR-MECHANISM ; RE ; MOLECULAR-MECHANISMS ; LEVEL ; INTERVAL ; analysis ; SIGNATURE ; USA ; multivariate analysis ; CANDIDATE ; cancer research ; CDK INHIBITOR P27 ; quantitative ; CDNA-MICROARRAY ; ADVANCED-STAGE NEUROBLASTOMA ; BOX PROTEIN SKP2
    Abstract: Purpose: Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. However, a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels. Experimental Design: To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN-amplified and single-copy high-risk neuroblastomas, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk neuroblastoma tumors (n = 49) using cDNA microarrays. Candidate gene expression was validated in a separate cohort of 117 patients using quantitative PCR, and protein expression was analyzed in neuroblastoma tumors by immunoblotting and immunohistochemistry. Results: We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCFSkp2 E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n = 117) using quantitative PCR. High Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54; 95% confidence interval, 1.56-8.00; P = 0.002). Skp2 protein expression was inversely correlated with expression of p27, the primary target of the SCF Skp2 E3-ligase, in neuroblastoma tumors. Conclusion: Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches
    Type of Publication: Journal article published
    PubMed ID: 17652624
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