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  • CANCER  (20)
  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; carcinoma ; GENE ; GENE-EXPRESSION ; COMPLEXES ; BREAST-CANCER ; COMPARATIVE GENOMIC HYBRIDIZATION ; gene expression ; MUTATION ; METASTASIS ; SIGNALING PATHWAYS ; SOLID TUMORS ; PRIMARY TUMORS ; SUBTYPES ; GENETIC ALTERATIONS ; LYMPH-NODE METASTASES
    Abstract: Introduction: With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer. Methods: Patterns of chromosomal aberrations in primary breast tumors and brain metastases were compared with array-comparative genetic hybridization (CGH). The most significant region was further characterized in more detail by microsatellite and gene-expression analysis, and finally, the possible target gene was screened for mutations. Results: The array CGH results showed that brain metastases, in general, display similar chromosomal aberrations as do primary tumors, but with a notably higher frequency. Statistically significant differences were found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (P 〈 0.01; false discovery rate (fdr) 〈 0.04). Allelic imbalance (AI) patterns at 10q were further verified in 77 unmatched primary tumors and 21 brain metastases. AI at PTEN loci was found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared with primary tumors from patients without relapse (18%; P = 0.003) or relapse other than brain tumors (12%; P = 0.006). Loss of PTEN was especially frequent in HER2-negative brain metastases (64%). Furthermore, PTEN mRNA expression was significantly downregulated in brain metastases compared with primary tumors, and PTEN mutations were frequently found in brain metastases. Conclusions: These results demonstrate that brain metastases often show very complex genomic-aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation
    Type of Publication: Journal article published
    PubMed ID: 22429330
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  • 2
    Keywords: CANCER ; PATHWAY ; GENES ; ACTIVATION ; MUTATIONS ; SUBGROUPS ; LANDSCAPE ; TETRAPLOID TUMOR-CELLS ; TBR1
    Abstract: Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
    Type of Publication: Journal article published
    PubMed ID: 22832583
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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: CANCER ; GENE ; GENOME ; MUTATIONS ; STEM-CELLS ; ZINC-FINGER PROTEIN ; T-CELL LYMPHOMAGENESIS ; MYC ; SUPER-ENHANCERS ; SUBGROUP
    Abstract: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Type of Publication: Journal article published
    PubMed ID: 25043047
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; carcinoma ; Germany ; INHIBITION ; GENE ; PROTEIN ; PROTEINS ; LINES ; INFECTION ; MECHANISM ; prognosis ; CARCINOGENESIS ; mechanisms ; CELL-LINES ; E7 ; DELETION ; LESIONS ; PROGRESSION ; CARCINOMA CELLS ; WOMEN ; COLORECTAL-CANCER ; CERVICAL-CANCER ; LINE ; TUMOR-SUPPRESSOR GENE ; human papillomavirus ; CARCINOMA-CELLS ; BETA ; CERVICAL-CARCINOMA ; CARCINOMAS ; squamous cell carcinoma ; intraepithelial neoplasia ; UTERINE CERVIX ; GROWTH-FACTOR-BETA ; POOR-PROGNOSIS ; cell lines ; GENOMIC INSTABILITY ; FACTOR-BETA ; molecular ; DEFICIENCY ; TUMOR-SUPPRESSOR ; TUMOR-GROWTH ; TGF-BETA ; MOLECULAR-MECHANISMS ; RESPONSIVENESS ; carcinoma cell ; CIN lesion ; cytogenetic ; DPC4 INACTIVATION ; multistep carcinogenesis ; PAPILLOMAVIRUS INFECTIONS ; SUPPRESSOR ; TGF beta ; tumor suppressor gene
    Abstract: Squamous cell carcinoma of the uterine cervix is one of the most frequent cancers affecting women worldwide. Carcinomas arise from cervical intraepithelial lesions, in which infection with high-risk human papillomavirus types has led to deregulated growth control through the actions of the viral E6 and E7 oncoproteins. The molecular mechanisms underlying progression to invasive tumor growth are poorly understood. One important feature, however, is the escape from growth inhibition by transforming growth factor beta (TGF-beta). Loss of chromosomal arm 18q is among the most frequent cytogenetic alterations in cervical cancers and has been associated with poor prognosis. Since the TGF-beta response is mediated by Smad proteins and the tumor suppressor gene Smad4 resides at 18q21, we have analysed the Smad4 gene for cervical cancer-associated alterations in cell lines and primary carcinomas. Here, we report Smad4 deficiency in four out of 13 cervical cancer cell lines which is due to an intronic rearrangement or deletions of 30 exons. All cell lines, however, showed either absent or moderate responsiveness to TGF-beta irrespective of their Smad4 status. In 41 primary squamous cervical carcinomas analysed, 10 samples showed loss of Smad4 protein expression and 26 samples a reduced expression. Altogether, our results strongly suggest that Smad4 gene alterations are involved in cervical carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 15531914
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  • 6
    Keywords: CANCER ; MUTATION ; TARGETS ; METHYLATION ; EMBRYONIC STEM-CELLS ; HYPERMETHYLATION ; GLIOBLASTOMA ; POLYCOMB ; INTRINSIC PONTINE GLIOMAS ; HISTONE H3.3
    Abstract: Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in approximately 50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.
    Type of Publication: Journal article published
    PubMed ID: 24183680
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  • 7
    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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  • 8
    Keywords: RECEPTOR ; CANCER ; CELLS ; SURVIVAL ; tumor ; carcinoma ; Germany ; CLASSIFICATION ; DIAGNOSIS ; FOLLOW-UP ; COHORT ; DISEASE ; HISTORY ; LONG-TERM ; NEW-YORK ; POPULATION ; GENE ; PROTEIN ; SAMPLE ; SAMPLES ; PATIENT ; RANTES ; DNA ; IMPACT ; primary ; polymorphism ; NO ; PROGRESSION ; MELANOMA ; METASTATIC MELANOMA ; PCR ; MULTIVARIATE ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; vaccination ; chemokine ; SERUM ; ONCOLOGY ; TUMOR-GROWTH ; PATIENT SURVIVAL ; CCR5 ; analysis ; methods ; USA ; immunology
    Abstract: Purpose Chemokines influence both tumor progression and anti-tumor immune response. A 32-bp-deletion polymorphism in the chemokine receptor 5 gene (CCR5 Delta 32) has been shown to result in a non-functional protein. This study was aimed at evaluating the potential impact of this gene polymorphism on disease progression and treatment outcome in patients with melanoma. patients and methods CCR5 genotyping was performed by PCR on DNA extracted from serum samples of 782 cutaneous melanoma patients with known disease history and long-term clinical follow-up. Genotypes were correlated with patient survival and types of treatment. Results Of 782 melanoma patients, 90 (11.5%) were heterozygous and 12 (1.5%) were homozygous for CCR5 Delta 32. Analyzing the complete cohort, the disease-specific survival from date of primary diagnosis was not influenced by CCR5 status. Similarly, no significant impact could be detected on the treatment outcome of stage III patients. In 139 stage IV patients receiving immunotherapy, CCR5 Delta 32 was associated with a decreased survival compared to patients not carrying the deletion (median 12.5 vs. 20.3 months, P = 0.029). Multivariate analysis revealed the CCR5 genotype as an independent factor impacting disease-specific survival in this patient population (P = 0.002), followed by gender (P = 0.019) and pathological classification of the primary (pT; P = 0.022). Conclusion The presence of the CCR5 Delta 32 polymorphism in patients with stage IV melanoma results in a decreased survival following immunotherapy and may help to select patients less likely to benefit from this type of treatment
    Type of Publication: Journal article published
    PubMed ID: 17909797
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  • 9
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; SITE ; SITES ; GENE ; GENES ; transcription ; COMPONENTS ; MOLECULES ; TISSUE ; MECHANISM ; FAMILY ; TRANSCRIPTION FACTOR ; IMPACT ; CARCINOGENESIS ; INDUCTION ; mechanisms ; BINDING ; SIGNAL ; MOLECULE ; ALPHA ; cytokines ; TARGET ; DELETION ; CHROMATIN ; PROMOTER ; MEMBRANE ; PROMOTERS ; MUTATION ; inactivation ; DERIVATIVES ; REGION ; CANCER-CELLS ; REGIONS ; MUTATIONS ; BETA ; SUPERFAMILY ; GROWTH-FACTOR-BETA ; TRANSCRIPTIONAL REGULATION ; GAMMA-2 CHAIN ; CYTOKINE ; molecular ; ONCOLOGY ; FAMILIES ; TUMOR SUPPRESSION ; TUMOR-SUPPRESSOR ; basement membrane ; TRANSFECTION ; TGF-BETA ; interaction ; MOLECULAR-MECHANISMS ; methods ; SUPPRESSOR ; TGF beta ; SIGNALS ; COLON-CARCINOMA CELLS ; BARRIER ; ENGLAND ; UPSTREAM ; response ; synthesis ; Smad4 ; SUPPRESSOR E-CADHERIN ; chromatin immunoprecipitation ; tumor suppressor ; FUNCTIONAL INACTIVATION ; BINDING SITE ; ACTIVATOR PROTEIN-1 ; AP-1 COMPLEX
    Abstract: Background: Functional inactivation of the tumor suppressor Smad4 in colorectal and pancreatic carcinogenesis occurs coincident with the transition to invasive growth. Breaking the basement membrane ( BM) barrier, a prerequisite for invasive growth, can be due to tumor induced proteolytic tissue remodeling or to reduced synthesis of BM molecules by incipient tumor cells. Laminin-332 (laminin-5), a heterotrimeric BM component composed of alpha 3-, beta 3- and gamma 2-chains, has recently been identified as a target structure of Smad4 and represents the first example for expression control of an essential BM component by a tumor and invasion suppressor. Biochemically Smad4 is a transmitter of signals of the TGF beta superfamily of cytokines. We have reported previously, that Smad4 functions as a positive transcriptional regulator of constitutive and of TGF beta-induced transcription of all three genes encoding Laminin-332, LAMA3, LAMB3 and LAMC2. Methods: Promoter-reporter constructs harboring 4 kb upstream regions, each of the three genes encoding Laminin-322 as well as deletion and mutations constructs were established. Promoter activities and TGF beta induction were assayed through transient transfections in Smad4-negative human cancer cells and their stable Smad4-positive derivatives. Functionally relevant binding sites were subsequently confirmed through chromatin immunoprecipitation. Results: Herein, we report that Smad4 mediates transcriptional regulation through three different mechanisms, namely through Smad4 binding to a functional SBE site exclusively in the LAMA3 promoter, Smad4 binding to AP1 (and Sp1) sites presumably via interaction with AP1 family components and lastly a Smad4 impact on transcription of AP1 factors. Whereas Smad4 is essential for positive regulation of all three genes, the molecular mechanisms are significantly divergent between the LAMA3 promoter as compared to the LAMB3 and LAMC2 promoters. Conclusion: We hypothesize that this divergence in modular regulation of the three promoters may lay the ground for uncoupled regulation of Laminin-332 in Smad4-deficient tumor cells in response to stromally expressed cytokines acting on budding tumor cells
    Type of Publication: Journal article published
    PubMed ID: 18664273
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  • 10
    Keywords: CANCER ; SURVIVAL ; CLASSIFICATION ; DIAGNOSIS ; FOLLOW-UP ; DEATH ; DISEASE ; POPULATION ; PROTEIN ; PROTEINS ; PATIENT ; MARKER ; prognosis ; BIOMARKERS ; CYCLE ; STAGE ; IDENTIFICATION ; colorectal cancer ; COLORECTAL-CANCER ; mass spectrometry ; SPECTROMETRY ; chemotherapy ; MARKERS ; MASS-SPECTROMETRY ; SURFACE ; NETHERLANDS ; PROTEOMIC ANALYSIS ; ONCOLOGY ; monitoring ; overall survival ; MS ; biomarker ; PROFILES ; colorectal ; PROFILE ; STAGE OVARIAN-CANCER ; TREATMENT RESPONSE ; transthyretin ; Follow up ; APOLIPOPROTEIN A1 ; prognostic ; proteomic
    Abstract: Colorectal cancer (CRC) is the second most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early detection mandatory. This study aimed to identify novel disease specific biomarkers of CRC, validate our previously identified biomarkers of CRC and identify serum biomarkers predicting treatment response and for monitoring. Serum of patients with metastatic CRC was collected, according to a predefined schedule, prior to start of standard first-line chemotherapy with oxaliplatin and capecitabine and serially before each 3 weekly treatment cycle and analyzed for proteomic profile by standardized SELDI-TOF MS. Serum proteomic mass spectrometry data of all subjects were processed using the tbimass R-package and proteomic profiles of CRC patients were compared with those of matched normal control subjects. Furthermore, changes in proteomic profiles during the course of chemotherapy were recorded according to treatment response. In total, 42 patients with advanced CRC were treated and mean follow-up was 13.5 months. The response rate was 50% and the median overall survival 19.5 months (95% CI: 16-23). By comparing CRC patients and healthy controls we identified 13 potential biomarkers of CRC (m/z 2.0-31.9 kDa) whereas two proteins, m/z 14060 and 28100 Da (apolipoprotein A-I), were highly significant (p〈0.0001). Comparison of responding and non-responding patients identified 6 proteins potentially predicting response, where of m/z 3330 Da was significant (p=0.007). Serial analysis identified 2 proteins, m/z 2022 and 28100 Da, that changed during chemotherapy in accordance with response. We identified 13 m/z values discriminating between CRC patients and healthy controls, including the previously identified apolipoprotein A-I as a candidate biomarker for CRC and treatment monitoring
    Type of Publication: Journal article published
    PubMed ID: 20514444
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