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  • tumor  (3)
  • 1
    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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  • 2
    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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  • 3
    Keywords: CELLS ; EXPRESSION ; proliferation ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; KINASE ; PATHWAY ; LUNG-CANCER ; PROTEIN ; LINES ; ACTIVATION ; SKIN ; ACTIVATED PROTEIN-KINASE ; CELL-LINES ; PHOSPHORYLATION ; signal transduction ; SIGNAL ; MAP KINASE ; IN-SITU ; MUTATION ; PROSTATE-CANCER ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; MELANOMA ; MUTATIONS ; cell lines ; TUMOR CELLS ; BRAF ; Ras ; CELL CARCINOMA ; TUMOR-CELL ; ERK ; MAP ; IMMUNOHISTOCHEMICAL ANALYSIS ; RELEVANCE ; KINASE INHIBITOR ; BRAF GENE ; INHIBITOR PROTEIN ; RAF ; RAF KINASE
    Abstract: Merkel cell carcinoma (MCC) is a highly metastatic skin tumor. To assess the relevance of the Ras/Raf/MEK/MAP kinase pathway, we analyzed for activating B-Raf mutations and we elucidated the presence of the Raf Kinase Inhibitor Protein (RKIP) and extracellular signal-regulated kinase (ERK) as well as the phosphorylation status of ERK. All MCC samples were negative for the B-Raf V600E mutation. Remarkably, RKIP, which was shown to interfere with the activation of MEK by Raf, was highly expressed in primary as well as in metastatic MCC. Immunohistochemical analysis of the phosphorylation status of ERK revealed in 42 out of 44 samples a complete lack of activated ERK in the tumor cells although ERK is expressed; in the two positive cases phosphorylated ERK was restricted to a minor fraction of the tumor cells. Western blot analysis of three MCC-derived cell lines revealed in one case the pattern present in situ (i.e. high RKIP expression and complete absence of phosphorylated ERK). In summary, our data demonstrate the inactivity of the classical MAP kinase signal transduction pathway in MCC, which seems to be because of lack of activation as well as active deactivation. These findings should be accounted for in future therapeutic approaches for this tumor
    Type of Publication: Journal article published
    PubMed ID: 16498399
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