Biomedical subjects

Stefan Joos

Publications and source records attributed to Stefan Joos.

At least 19 recordsLinked to original sources

PubMed2007

High survivin expression is associated with favorable outcome in advanced primary oral squamous cell carcinoma after radiation therapy.

Oral squamous cell carcinoma (OSCC) is a solid neoplasm exhibiting aggressive tumor phenotypes with unpredictable biological behavior. Recent studies suggested that high expression of the antiapoptotic protein survivin might be associated with adverse outcome in oral cancer patients. To investigate, whether increased copy numbers of the survivin-encoding gene BIRC5 results in elevated survivin levels and whether BIRC5 and survivin could serve as progression markers in the clinical course of OSCC, tumor tissue microarray analysis was performed applying fluorescence in situ hybridization and immunohistochemistry to 296 OSCC specimens. Gene copy number gain of BIRC5 was detected in 33.9% (150/227) of cases, which correlated significantly with high UICC stage and the presence of lymph node metastases (p = 0.003 and p = 0.001, respectively), but not with unfavorable patients' outcome (p > 0.05) in multivariate analysis. High survivin expression was found in 67.3% (169/251) of cases to predict increased 5- and 10-year overall survival of patients in a multivariate model including UICC stage and age as covariables (p = 0.035 and p = 0.026, respectively). Within a subgroup of patients, who received radiation therapy (n = 121), high survivin expression was found to be the only predictor of favorable 3-, 5- and 10-year overall survival in a multivariate cox regression analysis including UICC stage and age as covariables (p = 0.001, p = 0.004 and p = 0.006, respectively). In conclusion, high survivin expression might be useful to identify OSCC patients, who would benefit from radiotherapy.

Adolescent↗

PubMed2006

COX-2 upregulation in thymomas and thymic carcinomas.

The treatment of advanced stage thymomas and thymic carcinomas is a multimodal therapy. New therapeutic targets are currently under investigation, including the epidermal growth factor receptor (EGFR) as well as KIT. A number of studies have shown protumorigenic potential of Cyclooxygenase-2 (COX-2) in a variety of human malignancies, but so far it is unknown whether COX-2 is expressed in primary malignancies of the thymus. Using tissue microarrays, the expression of COX-2, microsomal-PGES-1 and -PGES-2 (mPGES-1 and mPGES-2), as well as EGFR was evaluated in different subtypes of thymoma and thymic carcinomas. COX-2 was expressed in all subtypes as determined by immunohistochemistry. Some cases of type B2 and thymic carcinomas had COX-2 staining levels classified as mild to moderate. However, when measuring the optical color intensity, no significant differences could be detected. Concerning the expression levels, a weak correlation between the expression of COX-2, mPGES-1 and mPGES-2 as well as EGFR was found. Furthermore, additional cases of thymomas and thymic carcinomas were analyzed by COX-2 Western immunoblot analysis and were compared to normal thymi. The analysis showed that thymomas and thymic carcinomas had a significantly stronger COX-2 expression than that of the normal thymi (p < 0.04). In summary, COX-2 is expressed in all subtypes of thymomas and thymic carcinomas and thus represents, in addition to EGFR and KIT, a potential therapeutic target. Further studies are needed in order to determine whether a combined therapy using COX-2 inhibitors in addition to the evolving anti-EGFR antibody therapy may be considered as a treatment option.

Adult↗

PubMed2006

Recurrent FGFR1 amplification and high FGFR1 protein expression in oral squamous cell carcinoma (OSCC).

Chromosomal aberrations are known to have an impact on the initiation and progression of oral squamous cell carcinoma (OSCC), but individual genes involved in OSCC pathogenesis are poorly described. To elucidate the molecular events underlying oral carcinogenesis, a set of primary OSCC were screened for distinct genetic imbalances by means of array-based comparative genomic hybridisation. For this, a DNA array was used containing 812 genomic targets including oncogenes, tumour-suppressor genes and chromosomal regions frequently altered in human neoplasms. The most frequent aberrations were amplification of MYC, EGFR, CCND1 and PIK3CA, whereas deletions affected TRAILR1 and ATM. Furthermore, a distinct high-level amplification of the fibroblast growth factor receptor 1 (FGFR1) locus was detected in two cases. Detailed FISH analysis on OSCC tissue microarray sections revealed amplification prevalence for FGFR1 of 17.4% (16/92). Furthermore, FGFR1 protein analysis by immunohistochemistry on a TMA containing 178 OSCC found a high FGFR1 expression in tumours of early t-stadium and UICC stage (T1/2 vs. T3/4: p=0.002; SI-II vs. S III-IV: p=0.048). Our results indicate that an increase in FGFR1 expression contributes to oral carcinogenesis at an early stage of development.

Carcinoma, Squamous Cell↗

PubMed2006

Recurrent coamplification of cytoskeleton-associated genes EMS1 and SHANK2 with CCND1 in oral squamous cell carcinoma.

Chromosomal band 11q13 is frequently amplified in oral squamous cell carcinoma (OSCC) and assumed to be critically involved in tumor initiation and progression by proto-oncogene activation. Though cyclin D1 (CCND1) is supposed to be the most relevant oncogene, several additional putative candidate genes are inside this chromosomal region, for which their actual role in tumorigenesis still needs to be elucidated. To characterize the 11q13 amplicon in detail, 40 OSCCs were analyzed by comparative genomic hybridization to DNA microarrays (matrix-CGH) containing BAC clones derived from chromosomal band 11q13. This high-resolution approach revealed a consistent amplicon about 1.7 Mb in size including the CCND1 oncogene. Seven BAC clones covering FGF3, EMS1, and SHANK2 were shown to be frequently coamplified inside the CCND1 amplicon. Subsequent analysis of tissue microarrays by FISH revealed amplification frequencies of 36.8% (88/239) for CCND1, 34.3% (60/175) for FGF3, 37.4% (68/182) for EMS1, and 36.3% (61/168) for SHANK2. Finally, quantitative mRNA expression analysis demonstrated consistent overexpression of CCND1 in all tumors and of EMS1 and SHANK2 in a subset of specimens with 11q13 amplification, but no expression of FGF3 in any of the cases. Our study underlines the critical role of CCND1 in OSCC development and additionally points to the functionally related genes EMS1 and SHANK2, both encoding for cytoskeleton-associated proteins, which are frequently coamplified with CCND1 and therefore could cooperatively contribute to OSCC pathogenesis.

Carcinoma, Squamous Cell↗

PubMed2006

Isochromosome breakpoints on 17p in medulloblastoma are flanked by different classes of DNA sequence repeats.

Medulloblastoma is a highly malignant embryonal tumor of the cerebellum that accounts for 20%-25% of all intracranial pediatric tumors. The most frequent chromosomal rearrangement in medulloblastoma is isochromosome 17, or i(17q). Its frequency suggests that it serves an important role in tumor pathogenesis, possibly mediated by the disruption or permanent activation of a gene at the breakpoint. To address this question, we performed a detailed analysis of chromosome 17 DNA copy number from 18 medulloblastomas previously shown to carry an apparent i(17q). We identified two breakpoint regions, one well within band 17p11.2 (n = 16) and a second within the pericentromeric region (n = 2). To map the breakpoints more precisely, we constructed a tiling-path matrix-CGH array covering chromosomal band 17p11.2 to the centromere and utilized it to delineate two small breakpoint intervals mapping at Mb 19.0 and 21.7 in seven of the medulloblastomas and in nine hematological neoplasias with i(17q). The former interval contains two breakpoint clusters that each colocalize with a pair of head-to-head inverted DNA sequence repeats, and the latter maps close to a region of alpha-satellite repeats. No consensus coding sequence localizes in these regions. Together, these data strongly suggest that the effects of i(17q) in medulloblastoma are mediated by gene-dosage effects of genes on 17p or 17q rather than by the disruption or deregulation of a "breakpoint" gene. Furthermore, we identified artifacts introduced in DNA copy number data by cross-hybridization of low-copy repeat sequences and discuss the challenge these can pose in the interpretation of diagnostic microarrays.

Cerebellar Neoplasms↗

PubMed2006

Frequent amplifications and abundant expression of TRIO, NKD2, and IRX2 in soft tissue sarcomas.

Copy number gains and high-level amplifications of the short arm of chromosome 5 are frequently observed in soft tissue sarcomas. To identify genes from this region possibly involved in tumor progression, we analyzed 34 soft tissue sarcomas (10 pleomorphic and 8 dedifferentiated liposarcomas, 6 malignant fibrous histiocytomas, and 10 malignant peripheral nerve sheath tumors (MPNST)) using a DNA microarray including 418 BAC clones representing 99% of chromosome arm 5p. In seven tumors, distinct high-level amplifications were identified affecting four different subregions. From these regions, genes TERT, TRIO, SKP2, FBXO32, NKD2, SLC6A3, IRX2, POLS, FYB, PTGER4, and FGF10 were selected for detailed quantitative expression analysis (RQ-PCR) based on their potential tumorigenic function. Of these, TRIO, coding for a guanidine nucleotide exchange factor, was consistently overexpressed in all cases, while IRX2 and NKD2, both involved in the regulation of developmental processes via the WNT pathway, showed a characteristic expression only in MPNSTs. Detailed nonparametric multidimensional scaling analysis further showed that the expression of TRIO, IRX2, and NKD2 strongly correlated with the gene copy number. In conclusion, we found TRIO, IRX2, and NKD2 frequently affected by high-level amplifications as well as up-regulated in a gene-dosage dependent manner. Thus, these genes represent candidate targets of 5p amplifications in soft tissue sarcomas and might play a crucial role during the progression of this disease.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Recurrent NMYC copy number gain and high protein expression in basal cell carcinoma.

Formation of basal cell carcinoma (BCC) has been linked to deregulation in the sonic hedgehogh (Shh) signalling pathway. Though mutations of the genes, PTCH1 and SMO, are known to be involved in aberrant Shh signalling, the distinct downstream effectors of these genes are poorly described. Studies have indicated that the NMYC oncogene is a potential Shh downstream effector. To assess the expression of Nmyc protein and gene copy numbers of the NMYC gene locus in a representative BCC tumour collection, immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) were performed on 273 BCC specimens of different growth patterns and anatomic localisations on tissue microarray (TMA) sections. High Nmyc protein expression was detected in 72.7% (160/220) of all BCC specimens. Strong Nmyc immunopositivity was more frequently found in infiltrative BCCs compared to nodular/superficial BCCs (p=0.005), and in BCCs of the head compared to BCCs of other anatomic localisations (p=0.021). The prevalence of NMYC copy number gains was 17.5% (37/211), including three tumours with nodular differentiation that exhibited a distinct high-level amplification of the NMYC locus. These data indicate that high expression of the Shh downstream mediator, Nmyc, is a frequent event in BCC, predominantly in more aggressive subtypes. Although the NMYC copy number gain found in a subset of cases might contribute to this aberrant Nmyc protein expression by a gene dosage effect, our data suggests that Nmyc protein can also be induced by aberrant Shh signalling, acting as an effector molecule of the Shh pathway. Novel systemic anti-sense NMYC inhibition strategies could be a promising option for therapy-refractory BCC.

Basal Cell Carcinoma↗

PubMed2005

Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma.

PURPOSE: Medulloblastoma is the most common malignant brain tumor in children. Despite multimodal aggressive treatment, nearly half of the patients die as a result of this tumor. Identification of molecular markers for prognosis and development of novel pathogenesis-based therapies depends crucially on a better understanding of medulloblastoma pathomechanisms. PATIENTS AND METHODS: We performed genome-wide analysis of DNA copy number imbalances in 47 medulloblastomas using comparative genomic hybridization to large insert DNA microarrays (matrix-CGH). The expression of selected candidate genes identified by matrix-CGH was analyzed immunohistochemically on tissue microarrays representing medulloblastomas from 189 clinically well-documented patients. To identify novel prognostic markers, genomic findings and protein expression data were correlated to patient survival. RESULTS: Matrix-CGH analysis revealed frequent DNA copy number alterations of several novel candidate regions. Among these, gains at 17q23.2-qter (P < .01) and losses at 17p13.1 to 17p13.3 (P = .04) were significantly correlated to poor prognosis. Within 17q23.2-qter and 7q21.2, two of the most frequently gained chromosomal regions, confined amplicons were identified that contained the PPM1D and CDK6 genes, respectively. Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas. Overexpression of CDK6 correlated significantly with poor prognosis (P < .01) and represented an independent prognostic marker of overall survival on multivariate analysis (P = .02). CONCLUSION: We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.

Biomarkers, Tumor↗

PubMed2005

Molecular classification of human gliomas using matrix-based comparative genomic hybridization.

Gliomas are the most frequent primary brain tumors and comprise a group of morphologically, biologically and clinically heterogeneous neoplasms. The different glioma types are associated with distinct genetic aberrations, which may provide useful information for tumor classification as well as prediction of prognosis and response to therapy. To facilitate the molecular classification of gliomas, we established a genomic microarray that consists of bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC) clones representing tumor suppressor genes, proto-oncogenes and chromosomal regions frequently gained or lost in gliomas. In addition, reference clones distributed evenly throughout the genome in approximately 15 Mbp intervals were spotted on the microarray. These customized microarrays were used for matrix-based comparative genomic hybridization (matrix CGH) analysis of 70 gliomas. Matrix CGH findings were validated by molecular genetic analyses of candidate genes, loss of heterozygosity studies and chromosomal CGH. Our results indicate that matrix CGH allows for the sensitive and specific detection of gene amplifications as well as low-level copy number gains and losses in clinical glioma samples. Furthermore, molecular classification based on matrix CGH data closely paralleled histological classification and was able to distinguish with few exceptions between diffuse astrocytomas and oligodendrogliomas, anaplastic astrocytomas and anaplastic oligodendrogliomas, anaplastic oligodendrogliomas and glioblastomas, as well as primary and secondary glioblastomas. Thus, matrix CGH is a powerful technique that allows for an automated genomic profiling of gliomas and represents a promising new tool for their molecular classification.

Adult↗

PubMed2005

Elevated NF-kappaB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas.

Transcription factor nuclear factor kappa B (NF-kappaB) plays a central role in the pathogenesis of classical Hodgkin lymphoma (cHL). In anaplastic large-cell lymphomas (ALCLs), which share molecular lesions with cHL, the NF-kappaB system has not been equivalently investigated. Here we describe constitutive NF-kappaB p50 homodimer [(p50)2] activity in ALCL cells in the absence of constitutive activation of the IkappaB kinase (IKK) complex. Furthermore, (p50)2 contributes to the NF-kappaB activity in Hodgkin/Reed-Sternberg (HRS) cells. Bcl-3, which is an inducer of nuclear (p50)2 and is associated with (p50)2 in ALCL and HRS cell lines, is abundantly expressed in ALCL and HRS cells. Notably, a selective overexpression of Bcl-3 target genes is found in ALCL cells. By immunohistochemical screening of 288 lymphoma cases, a strong Bcl-3 expression in cHL and in peripheral T-cell non-Hodgkin lymphoma (T-NHL) including ALCL was found. In 3 of 6 HRS cell lines and 25% of primary ALCL, a copy number increase of the BCL3 gene locus was identified. Together, these data suggest that elevated Bcl-3 expression has an important function in cHL and peripheral T-NHL, in particular ALCL.

B-Cell Lymphoma 3 Protein↗

PubMed2005

CGH-Profiler: data mining based on genomic aberration profiles.

BACKGROUND: CGH-Profiler is a program that supports the analysis of genomic aberrations measured by Comparative Genomic Hybridisation (CGH). Comparative genomic hybridisation (CGH) is a well-established, molecular cytogenetic method that allows the detection of chromosomal imbalances in entire genomes. This technique is widely used in routine molecular diagnostics. Typically, chromosomal imbalances are described in a complex syntax based on the International Standard for Cytogenetic Nomenclature (ISCN). This semantic description of chromosomal imbalances hinders a large-scale statistical analysis across different experiments, e.g. for finding aberration patterns associated with a particular disease type or state. RESULTS: CGH-Profiler circumvents the semantic ISCN description by importing data from different CGH system vendors and by directly transferring the data into a table format that is readily accessible for subsequent statistical analysis. CGH-profiler comes with different consistency checks, calculates various statistics and automatically assigns a median copy number ratio to each chromosomal band. Import of CGH profiles from different CGH system vendors is already supported; its extension to other systems can be readily achieved through Perl scripts.CGH profiler can also be used to analyse comparative expressed sequence hybridisation (CESH) data. CESH reveals gene expression patterns according to chromosomal locations in a similar manner as CGH detects chromosomal imbalances. CONCLUSION: CGH-Profiler is a useful tool for processing of CGH and CESH data.

Chromosome Aberrations↗

PubMed2005

Comparative genetic analysis of metachronous anaplastic oligoastrocytomas with extended recurrence-free interval.

Two metachronous anaplastic oligoastrocytomas with different cerebral locations were analyzed in a 51-year-old patient with an extended recurrence-free interval of 6 years and an a long survival of 9 years. Remarkably, the patient had not undergone adjuvant chemotherapy. Different cytogenetic and molecular techniques were performed including comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), allelic loss analysis, sequencing of p53, p16(INK4a)/CDKN2A and p14(ARF), EGFRamplification studies, investigation of the DNA mismatch repair system as well as tumor clonality. Using CGH and FISH a profile of low accumulation of cytogenetic aberrations was found in the second tumor, with no significant increase in the percentage of hyperdiploid nuclei. Microsatellite analysis showed a common pattern of allelic losses at 1p36, 19q13 and 9p21. Both specimens were also similar in that they retained heterozygosity at 10q23-q24 and 13q14 and that they harbor neither EGFR amplification nor mutations of p53, p16(INK4a)/CDKN2A or p14(ARF). The only further alteration in the second tumor was an allelic loss at p53. The X-chromosome inactivation (HUMARA) analysis revealed a polyclonal pattern in both samples. Our data strongly suggest that the second anaplastic oligoastrocytoma developed as a distant relapse of the first tumor. Whether the paucity of accumulation of the observed genetic alterations might be associated with the unusually extended relapse-free time of the patient remains to be elucidated.

Brain Neoplasms↗

PubMed2005

Copy number gains on 22q13 in adenoid cystic carcinoma of the salivary gland revealed by comparative genomic hybridization and tissue microarray analysis.

Adenoid cystic carcinoma (ACC) of the salivary gland is a neoplasm characterized by slow but inevitable local progression and terminal hematogenous metastasis. To detect novel imbalanced chromosomal regions associated with tumorigenesis, we used chromosomal comparative genomic hybridization to screen 27 ACC. The most common aberration was copy number gain of 22q13 (nine cases) followed by gains of 16p (seven cases) and 17q (four cases) and copy number losses on 6q (six cases). To further delineate the prevalence of 22q13 copy number gains in ACC, fluorescence in situ hybridization was performed for five bacterial/phage artificial chromosome (BAC/PAC) probes from the 22q13 consensus region with 57 ACC on a tissue microarray. The overall prevalence of copy number gains on 22q13 was 30% of the tumors in the fluorescence in situ hybridization analysis, irrespective of histologic differentiation (cribriform/tubular vs. solid) or tumor event (primary vs. recurrent). We therefore assume that copy number gain of 22q13 is a novel frequent finding in ACC that may be involved in the initial pathogenesis of this neoplasm by proto-oncogene activation.

Adult↗

PubMed2005

Differential KIT expression in histological subtypes of adenoid cystic carcinoma (ACC) of the salivary gland.

Adenoid cystic carcinoma (ACC) of the salivary gland is characterized by a prolonged but inevitably unfavorable clinical course. Recent studies suggested the transmembrane tyrosine kinase KIT to be involved in ACC pathogenesis. To investigate KIT expression in histologically defined subgroups of ACC and to clarify whether KIT gene copy number gain contributes to KIT overexpression, tumor tissue microarray sections including 55 ACC tumors were analyzed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). The prevalence of positive KIT immunostaining was 89% (49/55). Strong immunostaining of KIT was only found in cribriform and tubular but never in solid subtypes (p=0.02). Average KIT staining intensity was higher in cribriform and tubular (n=37) compared to solid (n=18) ACC subtypes (p=0.005). FISH analysis revealed copy number gains of the KIT gene in 6.1% (3/49) of tumors analyzed. Our results implicate that specific KIT tyrosine kinase inhibitors such as imatinib, might be used in future therapeutic approaches against subgroups of ACC.

Carcinoma, Adenoid Cystic↗

PubMed2004

Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival.

Medulloblastoma, a primitive neuroectodermal tumor of the cerebellum, is one of the most common central nervous system malignancies of childhood. Despite aggressive multimodal therapy, including surgery, irradiation, and chemotherapy, 5-year survival rates have only approached 50-60%. To identify potential candidate genes that predict for overall survival (OS), we performed a gene expression profiling analysis in 35 newly diagnosed medulloblastoma neoplasms. Subsequently, the nine most promising candidate genes were analyzed by immunohistochemistry and fluorescence in situ hybridization on tumor tissue microarrays representing a series of 180 tumors. We found 54 genes in which expression levels predicted for unfavorable survival in medulloblastoma. In line with the gene expression profiling analysis, a positive staining for STK15 (P = 0.0006), stathmin 1 (P = 0.001), and cyclin D1 (P = 0.03) was associated with an unfavorable OS, whereas cyclin B1, DAXX, Ki-67, MYC, NRAS, and p53 showed no statistical significant effect. In comparison to clinically defined parameters such as gender, age, metastatic stage, extent of tumor resection, application of chemotherapy, and tumor grade, positive staining for STK15 was identified as an independent prognostic factor for OS (P = 0.026). Moreover, additional gene copy numbers of MYC (P = 0.003) and STK15 (P = 0.05) predicted for poor survival. The combination of gene expression profiling with tissue microarray experiments allowed the identification of a series of candidate genes that predicts for survival in medulloblastoma. Of the results highlighted by the various data analysis procedures, genes associated with cell proliferation (cyclin D1), transcription (MYC), and especially mitosis (stathmin 1, STK15) appear particularly intriguing with respect to medulloblastoma pathomechanism.

Adolescent↗

PubMed2004

The role of Bcl-2 family members in tumorigenesis.

The Bcl-2 family consists of about 20 homologues of important pro- and anti-apoptotic regulators of programmed cell death. The established mode of function of the individual members is to either preserve or disturb mitochondrial integrity, thereby inducing or preventing release of apoptogenic factors like Cytochrome c (Cyt c) from mitochondria. Recent findings also indicate further Bcl-2-controlled mitochondria-independent apoptosis pathways. Bcl-2 represents the founding member of the new and growing class of cell death inhibiting oncoproteins. In this review, we try to briefly summarize current models of Bcl-2 family function and to outline the work demonstrating the influence of deregulated Bcl-2 family member expression on tumorigenesis and cancer therapy. Since several Bcl-2 homologues, in addition to influencing apoptotic behaviour, also impinge on cell cycle progression, we discuss possible implications of this additional role for the expression of Bcl-2 family members in tumor cells.

Animals↗

PubMed2003

HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma.

Apoptosis is a fundamental biological process used to eliminate unwanted cells in a multicellular organism. An increasing number of regulatory proteins have been identified that either promote or inhibit apoptosis. For tumors to arise, apoptosis must be blocked in the transformed cells, for example by mutational overexpression of anti-apoptotic proteins, which represent attractive target proteins for molecular therapy strategies. In a functional yeast survival screen designed to select new anti-apoptotic mammalian genes, we have identified the chromosomal high-mobility group box-1 protein (HMGB1) as an inhibitor of yeast cell death induced by the pro-apoptotic Bcl-2 family member Bak. The C-terminal 33 amino acids of HMGB1 are dispensable for this inhibitory function. HMGB1 is also able to protect mammalian cells against different death stimuli including ultraviolet radiation, CD95-, TRAIL-, Casp-8-, and Bax-induced apoptosis. We found high HMGB1 protein levels in human primary breast carcinoma. Hmgb1 RNA levels are changing during different stages of mouse mammary gland development and are particularly low during lactation and involution. These data suggest that HMGB1 may participate in the regulation of mammary gland apoptosis and that its high expression level promotes tumor growth because of its anti-apoptotic properties.

Animals↗

PubMed2003

Tissue microarray analysis reveals site-specific prevalence of oncogene amplifications in head and neck squamous cell carcinoma.

Fluorescence in situ hybridization was applied on a collection of 609 squamous cell carcinomas of the head and neck (HNSCCs),including 511 primary carcinomas of different clinical stage and anatomical localization and 98 recurrent carcinomas, second primary carcinomas, and regional metastases on a tissue microarray. The overall prevalence of amplifications of five oncogenes analyzed was 34.5% for CCND1, 12.7% for EGFR, 8.8% for MYC, 6.2% for ZNF217, and 3.6% for ERBB2. CCND1 amplifications were associated with the pharyngeal site in primary carcinomas (P < 0.001), whereas amplifications of ZNF217 were less frequent in pharyngeal carcinomas as compared with primary oral and laryngeal carcinomas (P = 0.02). The amplification pattern of these oncogenes suggests that different molecular pathways are involved in HNSCCs of different localizations.

Carcinoma, Squamous Cell↗