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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; tumor ; carcinoma ; Germany ; human ; IN-VIVO ; VITRO ; VIVO ; SITE ; SITES ; GENE ; HYBRIDIZATION ; PROTEIN ; DIFFERENTIATION ; TISSUE ; TUMORS ; PATIENT ; CARCINOGENESIS ; KERATINOCYTES ; SKIN ; IN-SITU ; PROGRESSION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; immunohistochemistry ; CHROMOSOMAL-ABERRATIONS ; skin carcinogenesis ; LOCALIZATION ; PHENOTYPE ; SQUAMOUS-CELL CARCINOMA ; CARCINOMAS ; squamous cell carcinoma ; p21 ; NONMELANOMA SKIN CANCERS ; FLUORESCENCE ; OVEREXPRESSION ; ORGANIZATION ; TERMINAL DIFFERENTIATION ; P53 MUTATIONS ; SKIN-CANCER ; CYCLIN D1 ; in situ hybridization ; CELL CARCINOMA ; REGRESSION ; RE ; TUMORIGENICITY ; CANCER DEVELOPMENT ; LOCUS ; function ; CANCERS ; in vivo ; genomic ; aberrant differentiation ; cdk4 ; KERATINOCYTES HACAT ; keratoacanthoma ; nonmelanoma skin cancer ; ORGANOTYPIC COCULTURE ; tumor regression
    Abstract: Non-melanoma skin cancers, in particular keratoacanthomas (KAs) and squamous cell carcinomas (SCCs), have become highly frequent tumor types especially in immune-suppressed transplant patients. Nevertheless, little is known about essential genetic changes. As a paradigm of 'early' changes, that is, changes still compatible with tumor regression, we studied KAs by comparative genomic hybridization and show that gain of chromosome 11q is not only one of the most frequent aberration (8/18), but in four tumors also the only aberration. Furthermore, 11q gain correlated with amplification of the cyclin D1 locus (10/14), as determined by fluorescence in situ hybridization, and overexpression of cyclin D1 protein (25/31), as detected by immunohistochemistry. For unraveling the functional consequence, we overexpressed cyclin D1 in HaCaT skin keratinocytes. These cells only gained little growth advantage in conventional and in organotypic cocultures. However, although the control vector-transfected cells formed a well-stratified and orderly differentiated epidermis-like epithelium, they showed deregulation of tissue architecture with an altered localization of proliferation and impaired differentiation. The most severe phenotype was seen in a clone that additionally upregulated cdk4 and p21. These cells lacked terminal differentiation, exhibited a more autonomous growth in vitro and in vivo and even formed tumors in two injection sites with a growth pattern resembling that of human KAs. Thus, our results identify 11q13 gain/cyclin D1 overexpression as an important step in KA formation and point to a function that exceeds its known role in proliferation by disrupting tissue organization and thereby allowing abnormal growth
    Type of Publication: Journal article published
    PubMed ID: 16547504
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  • 2
    Keywords: GENE ; DELETION ; COMPARATIVE GENOMIC HYBRIDIZATION ; IN-SITU HYBRIDIZATION ; TRANSLOCATION ; HEART-DISEASE ; CLINICAL-APPLICATION ; CHROMOSOMAL REARRANGEMENTS ; IDIOPATHIC MENTAL-RETARDATION ; DE-LANGE-SYNDROME
    Abstract: Cryptic subtelomeric chromosome rearrangements are a major cause of mild to severe mental retardation pointing out the necessity of sensitive screening techniques to detect such aberrations among affected patients. In this prospective study a group of 30 patients with unexplained developmental retardation and dysmorphic features or congenital abnormalities were analysed using the recently published multiplex FISH telomere (M-TEL) integrity assay in combination with conventional G-banding analysis. The patients were selected by one or more of the following criteria defined by de Vries et al.: (a) family history with two or more affected individuals, (b) prenatal onset growth retardation, (c) postnatal growth abnormalities, (d) facial dysmorphic features, (e) non-facial dysmorphism and congenital abnormalities. In addition, we included two patients who met these criteria and revealed questionable chromosome regions requiring further clarification. In four patients (13.3%) cryptic chromosome aberrations were successfully determined by the M-TEL integrity assay and in two patients with abnormal chromosome regions intrachromosomal aberrations were characterized by targetted FISH experiments. Our results accentuate the requirement of strict selection criteria prior to patient testing with the M-TEL integrity assay. Another essential precondition is high-quality banding analysis to identify structural abnormal chromosomes. The detection of familial balanced translocation carriers in 50% of the cases emphasizes the significance of such an integrated approach for genetic counselling and prenatal diagnosis.
    Type of Publication: Journal article published
    PubMed ID: 12136233
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  • 3
    Keywords: CANCER ; ACTIVATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; TUMOR-SUPPRESSOR GENE ; MALIGNANT-MELANOMA ; C-MYC ; LONG-TERM CULTURE ; RAS MUTATIONS ; SHORT ARM ; EPIDERMAL STEM-CELLS
    Abstract: Two developmentally highly divergent nonmelanoma skin cancers, the epidermal squamous cell carcinomas (SCC) and the neuroendocrine Merkel cell carcinomas (MCC), occur late in life at sun-exposed body sites. To determine whether these similarities may indicate common genetic alterations, we studied the genetic profile of 10 MCCs and analyzed 6 derived cell lines and 5 skin SCC lines by comparative genomic hybridization (CGH) and molecular genetic analyses. Although the MCCs were highly divergent-only 3 of the 10 tumors exhibited common gains and losses-they shared gain of 8q21-q22 and loss of 4p15-pter with the genetically much more homogeneous SCC lines. In addition, 2 of 5 SCC and 2 of 6 MCC lines exhibited UV-B-type-specific mutations in the p53 tumor-suppressor gene and a high frequency (9/11) of CC--〉TT double base changes in codon 27 of the Harvey (Ha)-ras gene. Since 45% of the tumor lines were homozygous for this nucleotide substitution compared to 14% of the controls and in 1 MCC patient the wild-type allele was lost in the tumor, this novel polymorphism may contribute to tumor development. On the other hand, loss of 3p, characteristic for SCCs, was rare in MCCs. Although in 2 of 3 SCC lines 3p loss was correlated with reduced expression of the FHIT (fragile histidine triad) gene, the potential tumor suppressor mapped to 3p14.2 and 2 MCC lines with normal 3p showed aberrant or no FHIT transcripts. Taken together, in addition to the common UV-B-specific mutations in the p53 and Ha-ras gene, MCCs and SCCs also share chromosomal imbalances that may point to a common environmental-derived (e.g., UV-A) oxidative damage.
    Type of Publication: Journal article published
    PubMed ID: 11992403
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  • 4
    Keywords: CANCER ; tumor ; carcinoma ; CELL ; Germany ; human ; larynx ; NEW-YORK ; SITE ; DISTINCT ; HYBRIDIZATION ; TUMORS ; primary ; PAIRS ; chromosome ; DELETION ; STAGE ; COMPARATIVE GENOMIC HYBRIDIZATION ; metastases ; DELETIONS ; MARKERS ; TUMOR-SUPPRESSOR GENE ; REGION ; REGIONS ; LOCALIZATION ; HEAD ; NECK ; squamous cell carcinoma ; SQUAMOUS-CELL CARCINOMAS ; FREQUENT ; SELECTION ; head and neck ; GAINS ; ORAL CAVITY ; GENOMIC HYBRIDIZATION ; CGH ; HETEROGENEITY ; ORIGIN ; PROGNOSTIC MARKERS ; 3P ALLELE LOSS ; CHROMOSOMAL ALTERATIONS ; CLONAL EVOLUTION ; CYCLIN D1 ; EPIGENETIC INACTIVATION ; NECK-CANCER ; REGION 3P21.3
    Abstract: Little is known about the extent of intratumoral genetic heterogeneity in head and neck squamous cell carcinoma (HNSCC). We therefore examined 79 stage III and IV primary HNSCCs (P) and matched lymph node metastases (M) for over- and underrepresentation of specific chromosome regions by comparative genomic hybridization (CGH). The overall ratio of gains and losses was higher in metastases than in primary tumors (4/1 vs. 2.5/1). Gains of 3q (78.1% P vs. 87.5% M) and 11q (78.1% P vs. 62.5% M) and deletions of 3p (43.8% P vs. 34.4% M) and 9p (31.3% P vs. 15.6% M) were most frequently detected. The highest rate of intratumoral discordance was observed for primary tumors and corresponding metastases (32.8%) compared with matched pairs of two metastases (26.5%) and of two anatomically distinct sides of one primary tumor (24.3%). Furthermore, the discordance rate was dependent on the primary tumor site (oral cavity 49.2%, oropharynx 31%, hypopharynx 30.3%, and larynx 27.3%). In some tumors, the extent of genomic discordance argues against a monoclonal origin. In conclusion, we found a high individual variation of intratumoral genomic heterogeneity depending on the localization and selection of matched pairs. These findings are of specific importance in view of establishing prognostic markers. (C) 2003 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12850380
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  • 5
    Keywords: CELLS ; INVASION ; Germany ; MODEL ; PROTEIN ; PROTEINS ; DNA ; SKIN ; CYCLE ; chromosome ; DELETION ; AMPLIFICATION ; NUMBER ; FUSION ; ABERRATIONS ; DELETIONS ; REGION ; MAMMALIAN-CELLS ; PHENOTYPE ; DEGRADATION ; NORMAL HUMAN FIBROBLASTS ; TRANSLOCATION ; GENOMIC INSTABILITY ; CHROMOSOMES ; SINGLE ; TRANSLOCATIONS ; RE ; AMPLIFICATIONS ; HUMAN CANCER ; SKIN KERATINOCYTES ; END ; PART ; anaphase bridges ; BASE PAIR ; Bridge-Fusion Breakage cycle ; chromosomal abberations ; CHROMOSOMAL TRANSLOCATIONS ; ONCOPROTEINS ; p53 mutation ; senescence ; telomere ; telomeric aggregates ; telomeric length ; TO-END FUSIONS
    Abstract: Telomeres are specialized DNA-protein structures at the ends of the linear chromosomes. In mammalian cells, they are composed of multifold hexameric TTAGGG repeats and a number of associated proteins. The double-stranded telomeric DNA ends in a 3' single stranded overhang of 150 to 300 base pair (bp) which is believed to be required for a higher order structure (reviewed in (Blackburn, 2001)). One important model is that the telomeres form loop structures, the T-loops, and by invasion of the 3' overhang into the duplex region of the double stranded part protect the DNA against degradation and hinder the cellular machinery to recognize the ends as broken DNA, thus providing chromosomal integrity (Griffith et al, 1999). If telomeres become critically short they loose their capping function, become sticky, and are prone to illegitimate chromosome end-to-end fusions. The resulting dicentric chromosomes are highly unusable and because of bridge-fusion-breakage cycles they give rise to chromosomal translocations, deletions, and amplifications. Thus, critically short telomeres are thought to be responsible for the onset of genomic instability. In addition, we provide evidence that in a length-independent manner telomeres can confer to genomic instability by forming telomeric aggregates which through chromosomal dys-locations contribute to chromosomal aberrations
    Type of Publication: Journal article published
    PubMed ID: 16358816
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  • 6
    Keywords: CANCER ; CANCER CELLS ; CELLS ; tumor ; carcinoma ; Germany ; GENE ; GENES ; PROTEIN ; PROTEINS ; TUMORS ; MECHANISM ; colon ; mechanisms ; cell cycle ; FREQUENCY ; LESIONS ; PROGRESSION ; NUMBER ; inactivation ; p53 ; DAMAGE ; CANCER-CELLS ; COLON-CANCER ; INSTABILITY ; MUTATIONS ; DUPLICATION ; p21 ; CHROMOSOMES ; colon cancer ; SOLID TUMORS ; REQUIREMENT ; centrosome ; CHROMOSOMAL INSTABILITY ; LEVEL ; LOSSES ; HIGH-FREQUENCIES ; ANEUPLOIDY ; hyperdiploidy ; Q-FISH ; SPINDLE CHECKPOINT ; telomerase inhibition ; telomere dysfunction
    Abstract: Aneuploidy is a fundamental principle of many cancer cells and is mostly related to defects in mitotic segregation of chromosomes. Many solid tumors as well as some preneoplastic lesions have been shown to contain polyploid chromosome numbers. The exact mechanisms behind whole-genome duplications are not known but have been linked to compromised mitotic checkpoint genes. We now report that the telomere checkpoint plays a key role for polyploidy in colon cancer cells. Telomerase suppression by a dominant-negative mutant of hTERT and consecutive telomere dysfunction in wild-type HCT116 colon cancer cells resulted in only minor stable chromosomal alterations. However, higher ploidy levels with up to 350 chromosomes were found when the cell-cycle checkpoint proteins p53 or p21 were absent. These findings indicate that telomere dysfunction in the absence of cell-cycle control may explain the high frequency of alterations in chromosome numbers found in many solid tumors
    Type of Publication: Journal article published
    PubMed ID: 16547498
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  • 7
    Keywords: CANCER ; EXPRESSION ; proliferation ; tumor ; CELL ; human ; CLASSIFICATION ; SYSTEM ; GENE ; PROTEIN ; PROTEINS ; ACCUMULATION ; MICE ; ACTIVATION ; primary ; KERATINOCYTES ; SKIN ; BIOLOGY ; E7 ; MOLECULAR-BIOLOGY ; papillomavirus ; skin cancer ; ABERRATIONS ; p53 ; human papillomavirus ; FRANCE ; HPV ; BETA ; E6 ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; ONCOPROTEIN ; SQUAMOUS-CELL CARCINOMAS ; OVEREXPRESSION ; GENOMIC INSTABILITY ; SKIN-CANCER ; ORDER ; molecular biology ; molecular ; RE ; TUMOR-SUPPRESSOR ; GENOMIC ABERRATIONS ; mRNA ; CHROMOSOMAL INSTABILITY ; LEVEL ; SUPPRESSOR ; TELOMERASE ACTIVITY ; USA ; Delta Np73 ; nonmelanoma skin cancer ; PREVENTS ; retinoblastoma ; telomere dysfunction ; viral ; REVERSE-TRANSCRIPTASE HTERT ; CELL BIOLOGY ; ECTOPIC EXPRESSION ; tumor suppressor ; viral proteins ; HPV38 ; genomic aberration ; chromosomal abnormalities ; HPV38 E6 and E7 ; telomere dysfunctions
    Abstract: The skin human papillomavirus (HPV) types belonging to the genus beta of the HPV phylogenetic tree appear to be associated with nonmelanoma skin cancer. We previously showed that the beta HPV type 38 E6 and E7 oncoproteins are able to inactivate the tumor suppressors p53 and retinoblastoma. Here, both viral proteins were expressed in primary human skin keratinocytes in order to study their effects on the telomere/telomerase system. We show that immortalization of skin keratinocytes induced by HPV38 E6/E7 is associated with hTERT gene overexpression. This event is, in part, explained by the accumulation of the p53-related protein, Delta Np73. Despite elevated levels of hTERT mRNA, the telomerase activity detected in HPV38 E6/E7 keratinocytes was lower than that observed in HPV16 E6/E7 keratinocytes. The low telomerase activation in highly proliferative HPV38 E6/E7 keratinocytes resulted in the presence of extremely short and unstable telomeres. In addition, we observed anaphase bridges, mitotic multipolarity, and dramatic genomic aberrations. Interestingly, the ectopic expression of hTERT prevents both telomere erosion and genomic instability. Thus, we showed that in HPV38 E6/E7 keratinocytes characterized by unscheduled proliferation, suboptimal activation of telomerase and subsequent extensive telomere shortening result in genomic instability facilitating cellular immortalization
    Type of Publication: Journal article published
    PubMed ID: 17898088
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  • 8
    Keywords: CANCER ; CELLS ; GROWTH ; IN-VITRO ; IRRADIATION ; tumor ; carcinoma ; CELL ; Germany ; human ; EXPOSURE ; TUMORS ; MICE ; radiation ; COMPLEX ; DNA ; MECHANISM ; CARCINOGENESIS ; INDUCTION ; KERATINOCYTES ; mechanisms ; SKIN ; BIOLOGY ; MOLECULAR-BIOLOGY ; PROGRESSION ; ASSAY ; skin carcinogenesis ; genetics ; NUDE-MICE ; ABERRATIONS ; COMET ASSAY ; DAMAGE ; CARCINOMA-CELLS ; ONCOGENE ; CARCINOMAS ; FRAGMENTS ; OXIDATIVE STRESS ; heredity ; HaCaT ; micronuclei ; molecular biology ; molecular ; ONCOLOGY ; RE ; TUMORIGENICITY ; HUMAN FIBROBLASTS ; telomere length ; STRAND BREAKS ; FRAGMENT ; ENGLAND ; BREAKS ; CELL BIOLOGY ; chromosomal aberrations ; tumor formation ; DNA double strand breaks ; H2AX PHOSPHORYLATION ; radiation regimes
    Abstract: The role of UVA-radiation-the major fraction in sunlight-in human skin carcinogenesis is still elusive. We here report that different UVA exposure regime (4 x 5 J/cm(2) per week or 1 x 20 J/cm(2) per week) caused tumorigenic conversion (tumors in nude mice) of the HaCaT skin keratinocytes. While tumorigenicity was not associated with general telomere shortening, we found new chromosomal changes characteristic for each recultivated tumor. Since this suggested a nontelomere-dependent relationship between UVA irradiation and chromosomal aberrations, we investigated for alternate mechanisms of UVA-dependent genomic instability. Using the alkaline and neutral comet assay as well as gamma-H2AX foci formation on irradiated HaCaT cells (20-60 J/cm(2)), we show a dosedependent and long lasting induction of DNA single and double (ds) strand breaks. Extending this to normal human skin keratinocytes, we demonstrate a comparable damage response and, additionally, a significant induction and maintenance of micronuclei (MN) with more acentric fragments (indicative of ds breaks) than entire chromosomes particularly 5 days post irradiation. Thus, physiologically relevant UVA doses cause long-lasting DNA strand breaks, a prerequisite for chromosomal aberration that most likely contribute to tumorigenic conversion of the HaCaT cells. Since normal keratinocytes responded similarly, UVA may likewise contribute to the complex karyotype characteristic for human skin carcinomas
    Type of Publication: Journal article published
    PubMed ID: 18372922
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  • 9
    Keywords: human ; HYBRIDIZATION ; SURGERY ; COMPLEX ; COMPLEXES ; IN-SITU ; AGE ; FISH ; ANOMALIES ; 5Q DELETION ; chromosome 5q- ; complex heart defect ; hCsx ; YAC clones
    Abstract: We describe a boy with multiple congenital anomalies including a complex heart defect, club feet, adducted thumbs, and facial dysmorphic features. He died at the age of 2 months following cardiac surgery. G-banding analysis identified an abnormal chromosome 5q suspected to be an interstitial deletion (5)(q33q35). Breakpoints of the deleted segment were confirmed as del(5)(q33.3q35) by multicolor fluorescence in situ hybridization (FISH) using two sets of combinatorially labeled band specific YAC clones. Findings are discussed in view of previously published cases
    Type of Publication: Journal article published
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  • 10
    Keywords: SPECTRA ; CANCER ; SURVIVAL ; tumor ; carcinoma ; Germany ; human ; NEW-YORK ; HYBRIDIZATION ; SAMPLE ; SAMPLES ; TUMORS ; PATIENT ; DNA ; LYMPH-NODES ; chromosome ; BREAST ; breast cancer ; BREAST-CANCER ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; COPY-NUMBER ; DIFFERENCE ; AGE ; LINKAGE ANALYSIS ; OVARIAN-CANCER ; WOMEN ; METASTASIS ; ABERRATIONS ; TUMOR-SUPPRESSOR GENE ; REGION ; PROGNOSTIC-FACTORS ; REGIONS ; BREAST-CARCINOMA ; CARCINOMAS ; DNA AMPLIFICATION ; GAINS ; SUSCEPTIBILITY GENE ; ALLELIC LOSS ; CGH ; COPY NUMBER CHANGES ; CARCINOMA IN-SITU ; YOUNG-WOMEN ; early onset breast cancer,comparative genomic hybridization,loss of 8p,gain of 8q ; HETEROZYGOSITY REGION ; HISTOLOGICAL GRADE
    Abstract: Sporadic breast cancer in young women is different from the one in older patients regarding pathological features and aggressiveness of the tumors, but the spectrum of genetic alterations are largely unknown. We used comparative genomic hybridization (CGH) to analyze DNA copy number changes in 88 tumor samples from women less than or equal to35 years of age. Findings were compared to histopathological data including tumor type, grading, lymph nodes and metastasis. Genomic gains clustered to chromosome arms 1q (64.8%), 8q (61.4%), 17q (50.0%), 20q (33.0%), 3q (20.5%), 1p (17.0%), 5p (17.0%) and 15q (17%). Losses were commonly located on 8p (19.3 %), 11q (11.4%), 16q (11.4%), 17p (1 1.4%) and 18q (10.2%). A comparison with published CGH data from breast carcinomas of similar type and grade showed the following differences: (1) gains were much more frequent than losses, and (2) losses on 8p22-p23 were more prevalent in patients with positive lymph node metastasis (p = 0.02), and Grade III tumors were associated with gains on the long arm of chromosome 8 (p = 0.01). Therefore, alterations in these genomic regions may be responsible for the reduced survival of patients with early onset breast cancer. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 14520696
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