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  • 1
    Keywords: EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; TYROSINE KINASE ; screening ; SITE ; SITES ; DISTINCT ; microarray ; PROTEIN ; TISSUE ; TUMORS ; primary ; GROWTH-FACTOR RECEPTOR ; FREQUENCY ; FREQUENCIES ; STAGE ; PROGRESSION ; immunohistochemistry ; ABERRATIONS ; HEAD ; ONCOPROTEIN ; CARCINOMAS ; NECK ; squamous cell carcinoma ; GREECE ; gene amplification ; head and neck ; laryngeal carcinoma ; OROPHARYNGEAL ; C-MYC ; CANCER PATIENTS ; CYCLIN D1 OVEREXPRESSION ; cytogenetic aberration ; head and neck squamous cell carcinoma (HNSCC) ; immunohistochemistry (IHC) ; MICROARRAY ANALYSIS ; oncoprotein overexpression ; OVEREXPRESSION ; POOR-PROGNOSIS ; tissue microarray (TMA) ; tumor classification
    Abstract: Background: Tissue microarray (TMA) analysis is a high-throughput approach that allows the screening of large tumor collectives for cytogenetic aberrations. In this study, a TMA of a large collection of clinically well-defined primary squamous cell carcinomas of the head and neck (HNSCC) was used to determine the expression of several oncoproteins. Materials and Methods: A TMA containing 547 primary HNSCC was used for the analysis of cyclinD1, c-myc, erbb1 and erbb2 expression by immunohistochemistry (IHC). Results: CyclinD1 and c-myc were overexpressed at higher frequencies in primary pharyngeal and laryngeal carcinomas compared with primary oral carcinomas (p 〈 0.001 and p 〈 0.001), while erbb1 and erbb2 overexpression was associated with oral site (p 〈 0.001 and p = 0.04, respectively). Furthermore, cyclinD1 overexpression correlated with stage IV primary carcinomas (p = 0.04). Conclusion: HNSCC is a heterogenous group of tumors, which, depending on anatomic sites and clinical stage, shows variable expressions of the oncoproteins described. This indicates a specific pathogenic role of these oncoproteins in different subtypes of HNSCC and may have therapeutic implications
    Type of Publication: Journal article published
    PubMed ID: 14666705
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  • 2
    Keywords: CANCER ; Germany ; screening ; NEW-YORK ; NEOPLASIA ; WOMEN ; cervical cancer ; CERVICAL-CANCER ; COUNTRIES ; HUMAN-PAPILLOMAVIRUS ; STRATEGIES ; UTERINE CERVIX ; NATURAL-HISTORY ; PRECURSORS ; ACETIC-ACID ; SETTINGS ; VISUAL INSPECTION
    Type of Publication: Journal article published
    PubMed ID: 14506730
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  • 3
    Keywords: SPECTRA ; EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; COHORT ; SITE ; SITES ; DISTINCT ; microarray ; PROTEIN ; TISSUE ; TUMORS ; PATIENT ; DNA ; prognosis ; DOMAIN ; SIGNAL ; STAGE ; PROGRESSION ; AMPLIFICATION ; immunohistochemistry ; MUTATION ; TUMOR PROGRESSION ; inactivation ; p53 ; MUTATIONS ; HUMAN-PAPILLOMAVIRUS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; PROGNOSTIC-SIGNIFICANCE ; NECK ; squamous cell carcinoma ; PROGNOSTIC VALUE ; PREVALENCE ; head and neck ; OVEREXPRESSION ; SEQUENCE-ANALYSIS ; CYCLE CONTROL ; protein expression ; CELL CARCINOMA ; ADVANCED BREAST-CANCER ; ADVANCED LARYNGEAL CARCINOMA ; GENE ALTERATIONS ; head and neck cancer ; mutation and expression ; PROTEIN OVEREXPRESSION ; SUPPRESSOR GENE ; SYSTEMIC THERAPY ; tumor sites
    Abstract: The tumor site is a strong clinical factor in head and neck squamous cell carcinoma (HNSCC). To clarify the biologic and clinical role of p53 alterations in HNSCC, we have examined the prevalence and the nature of p53 alterations in a large cohort of tumors from the different sites. For immunohistochemical analysis of p53 protein expression, we introduced tyramide signal amplification immunohistochemistry (TSA-IHC) on a tissue microarray. This allowed the discrimination between normal low-level expression and reduced or lost expression. Two hundred fifty-three tumors were subjected to mutational analysis by genomic DNA sequencing, employing also the p53 GeneChip from Affymetrix. The prevalence of all p53 alterations, i.e., mutations, overexpression and loss of expression, was significantly higher in hypopharyngeal tumors than in the other sites (p = 0.001). Laryngeal tumors showed the lowest rate of p53 alterations, but revealed a distinct mutation spectrum: most mutations affected exon 5 (p = 0.013) and the S2' domain (p = 0.002), and most hot-spot 248 mutations occurred in the larynx (p 〈 0.001). Sequencing by p53 GeneChip technology was shown to be only insignificantly more sensitive than dideoxy sequencing. In agreement with p53 mutations occurring prior to invasiveness, their prevalence did not increase with tumor stage, and all mutation classes lacked prognostic significance. The large patient cohort of this study showed that p53 is differentially affected in the different tumor sites of the head and neck, but its mode of inactivation does not play a major role in tumor progression. (C) 2004 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15239130
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  • 4
    Keywords: EXPRESSION ; carcinoma ; CELL ; Germany ; human ; THERAPY ; GENE ; HYBRIDIZATION ; microarray ; PROTEIN ; TISSUE ; SURGERY ; ACTIVATION ; CONTRAST ; TARGET ; IN-SITU ; PROGRESSION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; immunohistochemistry ; CATALYTIC SUBUNIT ; NUMBER ; metastases ; CANCER-CELLS ; HEAD ; CARCINOMAS ; NECK ; squamous cell carcinoma ; pathology ; FLUORESCENCE ; fluorescence in situ hybridization ; protein expression ; in situ hybridization ; CELL CARCINOMA ; development ; methods ; tissue microarray ; tissue microarray analysis ; CANDIDATE ; SQUAMOUS-CELL ; reverse transcriptase ; human telomerase ; IMMORTALITY ; oral squamous cell carcinoma ; TERT
    Abstract: BACKGROUND: Gene copy number gain of chromosomal arm 5p is frequently found in oral squamous cell carcinoma (OSCC) suggesting the activation of proto-oncogenes. TERT is a candidate gene encoding for human telomerase reverse transcriptase (hTERT). The aim of the present study was to elucidate the relevance of TERT copy number gain and high hTERT expression in OSCC. METHODS: Fluorescence in situ hybridization (FISH) for TERT and immunohistochemistry (IHC) for hTERT were performed to analyze TERT copy numbers and hTERT expression, respectively, on tissue microarray (TMA) sections including n = 247 OSCC and n = 105 pharyngeal and laryngeal squamous cell carcinomas (PSCC/LSCC). RESULTS: Increased hTERT protein expression was more frequently found in OSCC (71.1 %, 155/218) than in PSCC/LSCC (36.0%, 35/89) (13 〈 0.001). By contrast, specific TERT amplifications were less common in OSCC (2.1%, 4/191) compared with PSCC/LSCC (9.9%, 8/81) (P = 0.047). CONCLUSIONS: High hTERT expression is a frequent finding in OSCC. It might be a promising target for the development of specific anti-neoplastic therapy approaches
    Type of Publication: Journal article published
    PubMed ID: 17448136
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  • 5
    Keywords: CANCER ; carcinoma ; CARCINOGENESIS ; CANCER-PATIENTS ; CANCER PATIENTS ; BIOPSY ; cancer research ; CARCIN
    Abstract: We have investigated interferon-kappa (IFN-kappa) regulation in the context of human papillomavirus (HPV)-induced carcinogenesis using primary human foreskin keratinocytes (HFK), immortalized HFKs encoding individual oncoproteins of HPV16 (E6, E7, and E6/E7), and cervical carcinoma cells. Here, IFN-kappa was suppressed in the presence of E6, whereas its expression was not affected in HFKs or E7-immortalized HFKs. Transcription could be reactivated after DNA demethylation but was decreased again upon drug removal. Partial reactivation could also be accomplished when E6 was knocked down, suggesting a contribution of E6 in IFN-kappa de novo methylation. We identified a single CpG island near the transcriptional start site as being involved in selective IFN-kappa expression. To prove the functional relevance of IFN-kappa in building up an antiviral response, IFN-kappa was ectopically expressed in cervical carcinoma cells where protection against vesicular stomatitis virus-mediated cytolysis could be achieved. Reconstitution of IFN-kappa was accompanied by an increase of p53, MxA, and IFN-regulatory factors, which was reversed by knocking down either IFN-kappa or p53 by small interfering RNA. This suggests the existence of a positive feedback loop between IFN-kappa, p53, and components of IFN signaling pathway to maintain an antiviral state. Our in vitro findings were further corroborated in biopsy samples of cervical cancer patients, in which IFN-kappa was also downregulated when compared with normal donor tissue. This is the first report showing an epigenetic silencing of type I IFN after HPV16 oncogene expression and revealing a novel strategy on how high-risk HPVs can abolish the innate immune response in their genuine host cells.
    Type of Publication: Journal article published
    PubMed ID: 19887612
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  • 6
  • 7
    Keywords: DNA methylation ; RETINOIC ACID ; EPIGENETIC INACTIVATION ; NECK-CANCER ; TUMOR-SUPPRESSOR ; PROMOTER METHYLATION ; ONCOGENIC HUMAN-PAPILLOMAVIRUS ; ACTIVE HUMAN-PAPILLOMAVIRUS ; HIGH VIRAL LOAD ; TONSILLAR CANCER
    Abstract: High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.
    Type of Publication: Journal article published
    PubMed ID: 23635773
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  • 8
    Keywords: CANCER ; CELLS ; tumor ; BLOOD ; CELL ; human ; MODEL ; MODELS ; COMMON ; RISK ; PROTEIN ; PROTEINS ; TUMORS ; PATIENT ; DNA ; MECHANISM ; E7 ; papillomavirus ; ASSOCIATION ; antibodies ; antibody ; ASSAY ; PLASMA ; etiology ; cervical cancer ; CERVICAL-CANCER ; COUNTRIES ; PCR ; cancer risk ; RISK FACTOR ; human papillomavirus ; HPV ; E6 ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; POLYMERASE-CHAIN-REACTION ; case-control studies ; TOBACCO ; L1 ; POLYMERASE CHAIN-REACTION ; SMOKERS ; EARLY PROTEINS ; HPV TYPE-16 ; INTERVIEW ; INVASIVE CERVICAL-CANCER ; MULTICENTER ; NECK CANCERS ; ORAL CAVITY ; RAPID DETECTION ; TONSILLAR CARCINOMAS
    Abstract: Background: Human papillomavirus (HPV), the causal agent of cervical cancer, appears to be involved in the etiology of cancer of the oral cavity and oropharynx. To investigate these associations, we conducted a multicenter case-control study of cancer of the oral cavity and oropharynx in nine countries. Methods: We recruited 1670 case patients (1415 with cancer of the oral cavity and 255 with cancer of the oropharynx) and 1732 control subjects and obtained an interview, oral exfoliated cells, and blood from all participants and fresh biopsy specimens from case patients. HPV DNA was detected by polymerase chain reaction (PCR). Antibodies against HPV16 L1, E6, and E7 proteins in plasma were detected with enzyme-linked immunosorbent assays. Multivariable models were used for case-control and case-case comparisons. Results: HPV DNA was detected in biopsy specimens of 3.9% (95% confidence interval [CI] = 2.5% to 5.3%) of 766 cancers of the oral cavity with valid PCR results and 18.3% (95% CI = 12.0% to 24.7%) of 142 cancers of the oropharynx (oropharynx and tonsil combined) with valid PCR results. HPV DNA in cancer biopsy specimens was detected less frequently among tobacco smokers and paan chewers and more frequently among subjects who reported more than one sexual partner or who practiced oral sex. HPV16 DNA was found in 94.7% of HPV DNA-positive case patients. HPV DNA in exfoliated cells was not associated with cancer risk or with HPV DNA detection in biopsy specimens. Antibodies against HPV16 L1 were associated with risk for cancers of the oral cavity (odds ratio [OR] = 1.5, 95% CI = 1.1 to 2.1) and the oropharynx (OR = 3.5, 95% CI = 2.1 to 5.9). Antibodies against HPV16 E6 or E7 were also associated with risk for cancers of the oral cavity (OR = 2.9, 95% CI = 1.7 to 4.8) and the oropharynx (OR = 9.2. 95% CI = 4.8 to 17.7). Conclusions: HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of the oral cavity. The most common HPV type in genital cancers (HPV16) was also the most common in these tumors. The mechanism of transmission of HPV to the oral cavity warrants further investigation
    Type of Publication: Journal article published
    PubMed ID: 14652239
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  • 9
    Keywords: CANCER ; EXPRESSION ; tumor ; carcinoma ; COMBINATION ; Germany ; DISEASE ; DISEASES ; CDNA ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; PROTEINS ; DIFFERENTIATION ; TISSUE ; FAMILY ; CONTRAST ; KERATINOCYTES ; SKIN ; DYNAMICS ; IDENTIFICATION ; PROGRESSION ; immunohistochemistry ; PATTERNS ; gene expression ; microarrays ; MEMBRANE ; mass spectrometry ; MASS-SPECTROMETRY ; cytoskeleton ; HEAD ; NECK ; squamous cell carcinoma ; CDNA MICROARRAYS ; CDNA MICROARRAY ; MASSES ; keratinocyte ; HNSCC ; ULTRAVIOLET ; S100 PROTEINS ; transcript ; CELL-CARCINOMA ; EXPRESSION PATTERNS ; ENVELOPE ; protein biomarkers ; S100 and annexin protein family ; SELDI-TOF MS
    Abstract: The calcium-binding proteins of the S100 and the annexin protein families have been implicated in a variety of important physiological functions including membrane remodeling, calcium-related Intracellular signaling, cytoskeleton dynamics. tissue homeostasis, and formation of the cornified envelope in differentiating keratinocytes. Deregulated expression of members of these families has been reported in different types of neoplasia and other diseases, but the results were not consistent. Here we have applied a combination of cDNA microarrays, quantitative reverse transcriptase-PCR (qRT-PCR) and surface enhanced laser desorption ionisation-time of flight mass spectrometry (SELDI-TOF MS) to Study differential expression of these genes in head and neck squamous cell carcinoma (HNSCC). The calgranulins A and B and annexins 1 and 2 were found to be down-regulated in HNSCC, compared with normal mucosa, at both the mRNA and protein level. Upon validation of the differential gene expression by tissue microarray immunohistochemistry, we detected novel expression patterns of calgranulins A and B both in normal mucosa as well as in HNSCC. In contrast to squamous cancer of skin and other cancers in which the calgranulins were found to be up-regulated, most HNSCC showed reduced and widely deranged staining patterns including heterogeneous nuclear, cytoplasmic and membranous staining, and even enhanced staining in the tumor stroma. These observations suggest that the normal function of the calgranulins A and B in mucosa might be different from that in skin. (c) 2005 Elsevier GmbH. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15819419
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  • 10
    Keywords: CANCER ; EXPRESSION ; INHIBITOR ; tumor ; carcinoma ; CELL ; Germany ; CLASSIFICATION ; DIAGNOSIS ; RISK ; PROTEIN ; SAMPLES ; PATIENT ; BIOLOGY ; ASSOCIATION ; FIELD ; ALPHA ; STAGE ; IDENTIFICATION ; IN-SITU ; immunohistochemistry ; genetics ; ABERRATIONS ; MASS-SPECTROMETRY ; ONCOGENE ; HUMAN-PAPILLOMAVIRUS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; NECK ; RISK ASSESSMENT ; heredity ; BIOPSY ; protein expression ; PROTEOMICS ; PROTEOMIC ANALYSIS ; NECK-CANCER ; CELL CARCINOMA ; ONCOLOGY ; TUMORIGENESIS ; ARRAY ; HNSCC ; LYMPH-NODE METASTASIS ; development ; analysis ; PROFILES ; EVENTS ; protein biomarkers ; HISTOLOGY ; FRAGMENT ; SELDI-TOF-MS ; BIOPSIES ; CLINICAL-IMPLICATIONS ; aberration ; comparison ; acyl-CoA-binding protein ; CANCERIZATION ; field cancerization ; GENETICALLY ALTERED FIELDS ; HUMAN NEUTROPHIL PEPTIDE-1 ; TUMOR-DISTANT EPITHELIA
    Abstract: Development of head and necksquamous cell carcinoma (HNSCC) is a multistep process and in many cases involves a phenomenon coined 'field cancerization'. In order to identify changes in protein expression occurring at different stages of tumorigenesis and field cancerization, we analysed 113 HNSCCs and 73 healthy, 99 tumor-distant and 18 tumor-adjacent squamous mucosae by SELDI-TOF-MS on IMAC30 ProteinChip Arrays. Forty-eight protein peaks were differentially expressed between healthy mucosa and HNSCC. Calgizarrin (S100A11), the Cystein proteinase inhibitor Cystatin A, Acyl-CoA-binding protein, Stratifin (14-3-3 sigma), Histone H4, alpha- and beta-Hemoglobin, a C-terminal fragment of beta-hemoglobin and the alpha-defensins 1-3 were identified by mass spectrometry. The alpha-defensins showed various alterations in expression as validated by immunohistochemistry (IHC). Supervised prediction analysis revealed excellent classification of healthy mucosa (94.5% correctly classified) and tumor samples (92.9% correctly classified). Application of this classifier to the tumor-adjacent and tumor-distant mucosa samples disclosed dramatic changes: only 59.6% of the tumor-distant biopsies were classified as normal, 27.3% were predicted as aberrant or HNSCC. Strikingly, 72% of the tumor-adjacent mucosae were predicted as aberrant. These data provide evidence for the existence of genetically altered fields with inconspicuous histology. Comparison of the protein profiles in the tumor-distant-samples with clinical outcome of 32 patients revealed a significant association between aberrant profiles with tumor relapse events (P = 0.018; Fisher's exact test, two-tailed). We conclude that proteomic pro. ling in conjunction with protein identification greatly outperforms histopathological diagnosis and may have significant predictive power for clinical outcome and personalized risk assessment
    Type of Publication: Journal article published
    PubMed ID: 16819514
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