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  • TUMORS  (8)
  • 1
    Keywords: tumor ; Germany ; COHORT ; GENE ; HYBRIDIZATION ; TUMORS ; PATIENT ; MARKER ; SEQUENCE ; DELETION ; STAGE ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; PATTERNS ; microarrays ; NUMBER ; MARKERS ; REGION ; REGIONS ; PHENOTYPE ; REVEALS ; CHILDREN ; SEGMENTS ; 1p ; neuroblastoma ; CHROMOSOMES ; SUBSET ; CYTOGENETIC ANALYSIS ; BREAKPOINTS ; MYCN-AMPLIFICATION ; function ; LOSSES ; HIGH-RESOLUTION ANALYSIS ; genomic ; GENOMIC ALTERATIONS ; 11Q ; CGH ANALYSIS ; DNA-COPY-NUMBER
    Abstract: The study of genomic alterations in neuroblastoma is of particular importance since several cytogenetic markers proved to be closely associated with the clinical phenotype. To disclose patterns of gains and losses, we performed high-resolution oligonucleotide array-based comparative genomic hybridization (aCGH). A total cohort of 90 patients was classified into 6 subsets according to tumor stage and outcome: Stages 1-3+ (with event), Stage 1-3- (no event), Stage 4+/-, and Stage 4S+/-. The aberration patterns in Stages 1-3- and 4S- tumors differed from all other groups as they were predominantly characterized by losses (3, 4, 14, X) and gains (7, 17) of whole chromosomes. However, 59/65 (91%) tumors of Stages 1-3+ or Stage 4 revealed numerous structural copy number alterations (sCNA). While deletions in chromosomes 1, 3, and I I discriminated outcome in Stage 4, there were no specific sCNA that distinguished tumor stage within the subgroup of unfavorable tumors. sCNA in 1p, 3p, 11q, 17q, or MYCN amplification (MNA) was seen among 22/24 patients who died, 10/12 with metastatic relapses, and 5/9 with local recurrences. Detailed breakpoint analyses on chromosomes 1, 3, 11, and 17 disclosed preferred breaking areas, although breakpoints were not identical. Amplifications were found in 18 patients and involved 2p24 (MYCN) and other segments of chromosome 2, as well as regions on chromosome arms 6q, 12q, and 17q. One single feature in 21q21.1 (BU678720, without known function yet) attracted particular attention since five patients showed a homozygous loss of this sequence. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16958102
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  • 2
    Keywords: EXPRESSION ; TUMORS ; ABERRATIONS ; METHYLATION ; EMBRYONIC STEM-CELLS ; MULTIFORME ; HIGH-GRADE GLIOMAS ; TELOMERES ; INTEGRATED GENOMIC ANALYSIS ; ATRX
    Abstract: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases(1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked)(5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres(6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 22286061
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  • 3
    Keywords: CANCER ; GROWTH ; TUMORS ; NERVOUS-SYSTEM ; ADULT ; MOUSE MODELS ; PEDIATRIC MEDULLOBLASTOMA ; HEDGEHOG PATHWAY INHIBITOR ; TERT PROMOTER MUTATIONS ; ITRACONAZOLE
    Abstract: Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children 〉3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
    Type of Publication: Journal article published
    PubMed ID: 24651015
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; human ; KINASE ; PATHWAY ; PATHWAYS ; TYROSINE KINASE ; COHORT ; DEATH ; LONG-TERM ; GENE ; DIFFERENTIATION ; TUMORS ; NEUROBLASTOMA-CELLS ; PATIENT ; ACTIVATION ; MECHANISM ; DOMAIN ; BINDING ; CELL-DEATH ; REGION ; LONG-TERM SURVIVAL ; specificity ; DOMAINS ; neuroblastoma ; signaling ; NEURONS ; medulloblastoma ; interaction ; LEVEL ; cell death ; TECHNOLOGY ; USA ; pediatric ; MEDIATOR ; TYROSINE ; 2-HIT MECHANISM ; CEREBRAL CAVERNOUS MALFORMATIONS ; P75 NEUROTROPHIN RECEPTOR
    Abstract: The TrkA receptor tyrosine kinase is crucial for differentiation and survival of nerve-growth-factor-dependent neurons. Paradoxically, TrkA also induces cell death in pediatric tumor cells of neural origin, via an unknown mechanism. Here, we show that CCM2, a gene product associated with cerebral cavernous malformations, interacts with the juxtamembrane region of TrkA via its phosphotyrosine binding (PTB) domain and mediates TrkA-induced death in diverse cell types. Both the PTB and Karet domains of CCM2 are required for TrkA-dependent cell death, such that the PTB domain determines the specificity of the interaction, and the Karet domain links to death pathways. Downregulation of CCM2 in medulloblastoma or neuroblastoma cells attenuates TrkA-dependent death. Combined high expression levels of CCM2 and TrkA are correlated with long-term survival in a large cohort of human neuroblastoma patients. Thus, CCM2 is a key mediator of TrkA-dependent cell death in pediatric neuroblastic tumors
    Type of Publication: Journal article published
    PubMed ID: 19755102
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  • 5
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; CELL ; Germany ; IN-VIVO ; VITRO ; VIVO ; GENE ; transcription ; cell line ; TISSUE ; TUMORS ; LINES ; PATIENT ; ACTIVATION ; TRANSCRIPTION FACTOR ; MARKER ; REDUCTION ; TISSUES ; CELL-LINES ; NO ; AMPLIFICATION ; COPY NUMBER ; ASSAY ; NUMBER ; RATES ; CELL-LINE ; chemotherapy ; LINE ; MELANOMA ; METASTATIC MELANOMA ; PCR ; ONCOGENE ; MALIGNANT-MELANOMA ; MELANOMA PATIENTS ; real-time PCR ; cell lines ; ONCOLOGY ; RE ; PATIENT SURVIVAL ; chemosensitivity ; LINEAGE ; REAL-TIME ; TUMOR TISSUE ; biomarker ; analysis ; methods ; USA ; correlation ; cancer research ; in vivo ; LINEAGE SURVIVAL ; MITF ; quantitative ; MELANOMAS ; LUMINESCENCE ; chemotherapeutics ; MASTER REGULATOR
    Abstract: Purpose: The microphthalmia-associated transcription factor (MITF) is regarded as a key oncogene of the melanocytic lineage since it was detected by a genome-wide analysis to be strongly amplified in 15% to 20% of metastatic melanomas. MITF gene amplification was shown to be associated with a reduced survival in metastatic melanoma patients, and reduction of MITF activity was shown to sensitize melanoma cell lines to chemotherapeutics, suggesting the intratumoral MITF gene copy number as a predictive biomarker of response and survival after chemotherapy. Patients and Methods: To validate this hypothesis, we investigated MITF gene amplification in tumor tissues obtained from 116 metastatic melanoma patients before an individualized sensitivity-directed chemotherapy using quantitative real-time PCR. MITF amplification rates were correlated with tumor chemosensitivity quantified by an ATP-based luminescence assay and with chemotherapy outcome in terms of response and survival. Results: Of 116 tumor tissues, 104 were evaluable for MITF gene amplification. Strong amplification (〉= 4 copies per cell) was detected in 24 of 104 tissues (23%), whereas 62 of 104 tissues (60%) harbored 〉3 copies per cell. Strong MITF gene amplification was associated with a reduced disease-specific survival (P = 0.031). However, no correlation was found between MITF copy number and in vitro chemosensitivity or in vivo chemotherapy response. Conclusion: Our findings suggest that strong amplifications of the melanoma oncogene MITF affects patient survival but does not influence tumor chemosensitivity and chemotherapy response. Thus, the MITF gene copy number seems a useful prognostic marker in metastatic melanoma but could not be confirmed as a predictive marker of chemosensitivity and chemotherapy response
    Type of Publication: Journal article published
    PubMed ID: 17975146
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  • 6
    Keywords: EXPRESSION ; SURVIVAL ; carcinoma ; CELL ; Germany ; CLASSIFICATION ; DIAGNOSIS ; FOLLOW-UP ; RISK ; SITE ; SITES ; GENES ; PROTEIN ; TISSUE ; TUMORS ; PATIENT ; IMPACT ; IDENTIFICATION ; REGION ; RECURRENCE ; REGIONS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; NECK ; pathology ; relapse ; PROTEOMICS ; PROTEOMIC ANALYSIS ; NECK-CANCER ; CELL CARCINOMA ; ONCOLOGY ; HNSCC ; PROFILES ; prospective ; SELDI-TOF-MS ; SQUAMOUS-CELL ; PROFILE ; field cancerization ; tumours ; HEAD-AND-NECK ; Follow up ; proteomic ; biomarker protein profiles ; CHROMOSOME-17 ; ORAL EPITHELIAL DYSPLASIA ; pharynx and oesophagus carcinoma
    Abstract: 'Field cancerization' in head and neck squamous cell carcinoma (HNSCC) is poorly understood and it may extend from the pharynx into the oesophagus. Both local recurrences and second primary carcinomas/second field tumours may originate from field cancerization. Our prospective pilot study aimed at the identification of patients suffering from field cancerization on the basis of mucosal protein profiles. Five mucosal biopsies from the oropharynx, hypopharynx and from three regions of the oesophagus were taken from 24 patients. Protein profiles were generated from the mucosal biopsies. After classifier learning, using the profiles of the patients without tumour diagnosis (n = 9), we were able to discriminate between the different mucosal sites and between healthy mucosa and HNSCC using tumour and healthy tissue samples. Mucosal biopsies of tumour patients (n = 15) revealed changes in the protein profiles similar to those in the tumours. During 42 months median follow-up, six tumour patients experienced local recurrences and second field tumours, of which three occurred in the oesophagus. In all six cases, tumour relapse was correctly predicted by altered mucosal protein profiles (p = 0.007, Fisher's exact test, two-tailed). Consequently, molecular field cancerization had a strong impact on progression-free survival (p = 0.007, log-rank test). Protein profiles of small diagnostic biopsies hold great promise to improve personalized risk assessment in HNSCC. Larger studies are needed to further substantiate these findings. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
    Type of Publication: Journal article published
    PubMed ID: 20593486
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  • 7
    Keywords: CELLS ; EXPRESSION ; GROWTH ; INVASION ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; COMMON ; GENE ; GENE-EXPRESSION ; GENES ; TUMORS ; TRANSDUCTION ; MECHANISM ; CARCINOGENESIS ; colon ; mechanisms ; BIOLOGY ; MEMBER ; MEMBERS ; MOLECULAR-BIOLOGY ; MOLECULE ; cytokines ; TARGET ; STAGE ; PROGRESSION ; MALIGNANCIES ; ENCODES ; MEMBRANE ; METASTASIS ; genetics ; COLORECTAL-CANCER ; COMPONENT ; inactivation ; EXTRACELLULAR-MATRIX ; ONCOGENE ; SUPERFAMILY ; CARCINOMAS ; beta-catenin ; GROWTH-FACTOR-BETA ; TARGETS ; TUMOR CELLS ; heredity ; REGULATOR ; FACTOR-BETA ; GAMMA-2 CHAIN ; CYTOKINE ; molecular biology ; molecular ; MATRIX ; CHAIN ; MALIGNANCY ; ONCOLOGY ; pancreas ; TUMOR-SUPPRESSOR ; basement membrane ; BASEMENT-MEMBRANE ; extracellular matrix ; secretion ; LEADS ; TRANSITION ; TGF-BETA ; pancreatic ; TUMOR-CELL ; SUPPRESSOR ; function ; COLON-CARCINOMA CELLS ; ENGLAND ; RECONSTITUTION ; LAMININ-5 ; CASCADE ; OCCURS ; Smad4 ; STABLE RNA INTERFERENCE ; DPC4 ; tumor suppressor Smad4
    Abstract: The tumor suppressor Smad4 is involved in carcinogenesis mainly of the pancreas and colon. Functional inactivation of Smad4 is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth. Smad4 encodes an intracellular messenger common to all signalling cascades induced by members of the transforming growth factor-beta (TGF-beta) superfamily of cytokines. Despite extensive knowledge about the mechanisms of TGF-beta/Smadsignal transduction, little is known about Smad4 targets involved in the transition to malignancy. The hallmark of invasive growth is a breakdown of the basement membrane ( BM), a specialized sheet of extracellular matrix produced through of epithelial and stromal cells. Laminin-5, a heterotrimeric epithelial-derived BM component, is commonly lost in carcinomas but not in premalignant tumors. Herein, we report that in human colon and pancreatic tumor cells, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-5. Coordinate re-expression of the three laminin-5 chains induced by reconstitution of Smad4 leads to secretion and deposition of the heterotrimeric molecule in BM-like structures. These data de. ne the expression control of an essential BM component as a novel function for the tumor suppressor Smad4
    Type of Publication: Journal article published
    PubMed ID: 16953227
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  • 8
    Keywords: EXPRESSION ; SURVIVAL ; TUMORS ; DNA ; INFECTION ; SKIN ; virus ; PREVALENCE ; FEATURES ; MCV ; ABUNDANCE
    Abstract: The majority of Merkel cell carcinomas (MCCs) are associated with the recently identified Merkel cell polyomavirus (MCV). However, as it is still unclear to which extent the presence of MCV impacts tumor characteristics or clinical outcome, we correlated the MCV status of tumor lesions obtained from 174 MCC patients including 38 MCC patients from Australia and 138 MCC patients from Germany with clinical characteristics, histomorphology, immunohistochemistry, and course of the disease. MCV DNA was present in 86% of MCCs and, in contrast to previous reports, no significant difference in MCV prevalence was present between Australian and German MCC cases. When patients were stratified according to their MCV status, only tumor localization (P = 0.001), gender (P = 0.024), and co-morbidity, i.e., frequency of patients with previous skin tumors (P = 0.024), were significantly different factors. In contrast, year of birth and diagnosis, age at diagnosis, or histological type and features representing the oncogenic phenotype such as mitotic rate or expression of p16, p53, RB1, and Ki67 were not significantly different between MCV-positive and MCV-negative MCCs. MCV status also did not influence recurrence-free, overall, and MCC-specific survival significantly. In summary, although MCV-positive and MCV-negative MCCs may have different etiologies, these tumors have comparable clinical behaviors and prognosis
    Type of Publication: Journal article published
    PubMed ID: 21562568
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