1/8. Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas.Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic cytokine that has been implicated in glioma invasion and angiogenesis. The SF/HGF receptor, MET, has been found to be expressed in neoplastic astrocytes as well as in endothelial cells of the tumor vasculature. Both SF/HGF and MET expression have also been described to correlate with the malignancy grade of human gliomas. However, most glioblastoma cell lines lack SF/HGF expression, raising the question of the cellular origin of SF/HGF in vivo. Using in situ hybridization, we analyzed glioblastomas, anaplastic astrocytomas, diffuse astrocytomas, pilocytic astrocytomas, and normal brain for the expression of SF/HGF mRNA. We detected strong SF/HGF expression by the majority of the tumor cells and by vascular endothelial cells in all glioblastoma specimens analyzed. Combined use of in situ hybridization with fluorescence immunohistochemistry confirmed the astrocytic origin of the SF/HGF-expressiong cells. In contrast, CD68-immunoreactive microglia/macrophages, as well as vascular smooth muscle cells reactive to alpha-smooth muscle actin, lacked SF/HGF expression. In anaplastic, diffuse, and pilocytic astrocytomas, SF/HGF expression was confined to a subset of tumor cells, and signals were less intense than in glioblastomas. In addition, we detected SF/HGF mRNA in cortical neurons. SF/HGF expression was not up regulated around necroses or at tumor margins. MET immunoreactivity was observed in GFAP-expressing astrocytic tumor cells and endothelial cells as well as in a subset of microglia/macrophages. We conclude that in vivo, both autocrine and paracrine stimulation of tumor cells and endothelium through the SF/HGF-MET system are likely to contribute to tumor invasion and angiogenesis. Lack of SF/HGF expression by most cultured glioblastoma cells is not representative of the in vivo situation and most likely represents a culture artifact.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
2/8. Long-term survival of a patient with giant cell glioblastoma. Case report.The authors report on a patient who had undergone resection of a left-sided temporal giant cell glioblastoma at the age of 69 years and who survived for more than 17 years. This man had not undergone postoperative radiotherapy or adjuvant chemotherapy. He died at the age of 86 years without clinical evidence of tumor recurrence. Histologically, the lesion was characterized by highly pleomorphic tumor cells (including bizarre multinucleated giant cells) with high mitotic activity, large necroses, and prominent mononuclear infiltration. A point mutation in the TP53 tumor suppressor gene (c.524G>A; R175H) and no epidermal growth factor receptor gene amplification were revealed on molecular genetic analysis. No diagnostic chromosomal imbalances were identified on comparative genomic hybridization, although the average ratio profile for chromosome 10 indicated loss of 10p15 in a subpopulation of tumor cells. This patient is exceptional because tumor resection, probably in conjunction with a marked antitumor immune response, apparently resulted in eradication of the lesion.- - - - - - - - - - ranking = 0.5keywords = hybridization (Clic here for more details about this article) |
3/8. Spatial variability of genomic aberrations in a large glioblastoma resection specimen.In the present study, the distribution of genetic aberrations in a glioblastoma resection specimen of unusually large size (9x8x2 cm) was investigated using comparative genomic hybridization (CGH). CGH was performed on 20 samples taken from the specimen, and the genetic aberrations found were compared with the regional histology. The samples were histopathologically graded according to WHO criteria, and a division in high- and low-grade areas and infiltration rims was made. In high-grade areas, low-grade areas as well as infiltration rims, gains on 10p11.2-pter (14/20), 11q12-q22 (6/20) and losses on 4q13-qter (9/20), 10q22-qter (8/20), 11p14-pter (5/20), 13q12-qter (7/20) were revealed. Gains on 1q21-32 (2/4) and losses on 7p21-pter (3/4) were exclusively found in the high-grade areas. In the low-grade tumor samples and in the infiltration rim, gains on 16p11.2-pter (6/16), 17p11.2-pter (6/16), 17q11.2-qter (5/16), 20q11.2-q13 (3/16) and deletions on 5q31-qter (4/16) were detected. Gains on 7q21-qter (8/11) and 8q11.2-qter (6/11), and loss of chromosome 9 (4/11) and the Y-chromosome (4/11) were found in the high-grade and low-grade samples, not in the infiltration rims. The finding of a set of identical chromosomal aberrations throughout the resection specimen, most of which have been previously reported in gliomas, confirms a mechanism of clonal tumor proliferation operative in gliomas. The previously unreported genetic alterations which were predominantly traced in the tumor rims, might reflect either selection for properties related to infiltrating behavior, or genomic instability of subclones. The findings illustrate the importance of searching for high-grade genetic aberrations in low-grade tumor samples taken from cases in which sampling error is suspected.- - - - - - - - - - ranking = 0.5keywords = hybridization (Clic here for more details about this article) |
4/8. Characterization of chromosomal aberrations in a case of glioblastoma multiforme combining cytogenetic and molecular cytogenetic techniques.A case of glioblastoma multiforme (GBM) that was investigated with a broad spectrum of cytogenetic and molecular cytogenetic techniques is reported. The results of cytogenetic studies, interphase fluorescence in situ hybridization, comparative genomic hybridization, and spectral karyotyping (SKY) are reported. Various structural chromosomal aberrations were identified, among which aberrations involving chromosome arm 2p were especially frequent. Using SKY, six translocations not previously described in GBM are reported.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
5/8. Genetic analysis of a multifocal glioblastoma multiforme: a suitable tool to gain new aspects in glioma development.OBJECTIVE: Multifocal glioblastomas constitute an increasingly diagnosed subgroup of glioblastoma multiforme, the most malignant primary brain tumor in adults. The molecular background of these lesions is unknown. However, the ability to study multiple lesions of one patient simultaneously could provide new aspects in glioma development. methods: Short-term cell cultures were derived from three isolated glioblastoma lesions of one patient. spectral karyotyping and interphase fluorescence in situ hybridization were used for cytogenetic analysis. loss of heterozygosity was assessed in tumor tissues and cell lines for seven gene loci (p73, p21, p16, PTEN, p27, Rb, p53). In addition, sequence analysis of the PTEN and p53 loci was performed, epidermal growth factor receptor protein expression was assessed, and in vitro proliferation was assayed. RESULTS: A balanced translocation [t(1;15)(p3?6;q2?5)] that has not been described previously in glioblastomas was identified in all cell lines. Primarily, the cell lines have a homozygous deletion of the p16 locus and inactivation of the PTEN gene by loss of heterozygosity and an identical mutation in common. Furthermore, the cell lines harbor a hemizygous (R175H) or two heterozygous (R175H, R213Q) mutations of the p53 gene or none at all. The occurrence of p53 mutations correlates with the size of the original tumors and in vitro proliferation. CONCLUSION: The analysis of a multifocal glioma revealed three main aspects: 1) the combined cytogenetic and molecular analysis of this subgroup of glioblastoma multiforme is a suitable tool to gain new perspectives in glioma development, 2) the balanced translocation [t(1;15)(p3?6;q2?5)] might harbor a new genetic marker involved in glioma development, and 3) the pattern of p53 mutation suggests a role of p53 in the progression of malignancy, migration, and growth of this particular primary glioblastoma.- - - - - - - - - - ranking = 0.5keywords = hybridization (Clic here for more details about this article) |
6/8. Independent molecular development of metachronous glioblastomas with extended intervening recurrence-free interval.Two metachronous glioblastomas with different cerebral locations in a 53-year-old long-term survival patient were analyzed by multiple genetic approaches. Using comparative genomic hybridization a different pattern of chromosomal aberrations was observed, with 19 imbalances in the first tumor and only 2 imbalances in the second. sequence analysis revealed a distinct mutation profile in each tumor, with amino acid substitutions in the p53 and PTEN genes only in the first tumor, ie, p53 in codon 273 (CGT-->TGT, Arg-->Cys) and PTEN in codon 336 (TAC-->TTC, Tyr-->Phe). A splicing acceptor site PTEN mutation (IVS8-2A>G) was observed only in the second GBM. EGFR amplification, mutations of p16INK4a/CDKN2A or p14ARF were not observed. According to the results of p53 mutational analysis and EGFR amplification studies, the first tumor is classified as a type 1 GBM, whereas the alterations in the second one are different from those typically encountered in type 1 or type 2 tumors. In conclusion, our data strongly suggest that the metachronous tumors in this patient are exceptional in that they developed independently from each other. Whether the molecular features of the first glioblastoma are associated with the notably extended recurrence-free period of 5 years remains to be elucidated.- - - - - - - - - - ranking = 0.5keywords = hybridization (Clic here for more details about this article) |
7/8. Chromosome breakpoint at 17q11.2 and insertion of dna from three different chromosomes in a glioblastoma with exceptional glial fibrillary acidic protein expression.A glioblastoma that retained glial fibrillary acidic protein (GFAP) in culture has a break in the long arm of chromosome 17 at band 17q11.2. dna inserted at this breakpoint came from chromosome bands 3p21, 3q23, 16q11.2, and 22q11.2. These chromosome fragments were inserted in band 17q11.2 proximal to the neurofibromatosis-1 (NF-1) gene and neu (HER2; erbB2) oncogene loci. The glioblastoma also contained a reciprocal translocation between 16p12 and 20p12. These structural abnormalities, previously undescribed in gliomas, were demonstrated by high-resolution chromosome banding, microdissection, and fluorescence in situ hybridization (FISH). Numerical changes typical of glioblastoma were present: gain of chromosome 7 and losses of chromosomes 10, 13, and 22. The complex chromosome origin of dna inserted in this glioma chromosome is described. The association of two infrequent events in this single glioblastoma line, this complex insertion and retention of GFAP expression, is not likely to be a chance occurrence. It raises the possibility of an association between the two events.- - - - - - - - - - ranking = 0.5keywords = hybridization (Clic here for more details about this article) |
8/8. Translocation 1;19 in two brain tumors.We report two-cases of brain tumors, one childhood medulloblastoma and one adult glioblastoma with an unusual chromosomal abnormality: a t(1;19)(q23;q13). We analyzed these karyotypes using fluorescence in situ hybridization (FISH) and wonder if this chromosomal aberration could represent a particular entity in these brain tumors like t(1;19) in ALL.- - - - - - - - - - ranking = 0.5keywords = hybridization (Clic here for more details about this article) |