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H Ohgaki

Publications and source records attributed to H Ohgaki.

At least 37 records · Page 2Linked to original sources
PubMed2000

Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays.

Diffuse astrocytoma WHO grade II is a well-differentiated, slowly growing tumor that has an inherent tendency to progress to anaplastic astrocytoma (WHO grade III) and, eventually, to glioblastoma (WHO grade IV). Little is known about its molecular basis, except for p53 mutations that are found in >60% of cases. In a search for additional genetic alterations, we carried out gene expression profiling of 11 diffuse astrocytomas using cDNA expression arrays. Expression of six genes (TIMP3, c-myc, EGFR, DR-nm23, nm23-H4, and GDNPF) was detected in 64-100% of diffuse astrocytomas, but not in nontumorous brain tissue. Seven genes (AAD14, SPARC, LRP, PDGFR-alpha, 60S ribosomal protein L5, PTN, and hBAP) were found to be up-regulated more than 2-fold in 20-60% of cases, whereas 11 genes (IFI 9-27, protein kinase CLK, TDGF1, BIN1, GAB1, TYRO3, LDH-A, adducin 3, GUK1, CDC10, and KRT8) were down-regulated to less than 50% of normal levels in 64-100% of cases. Semiquantitative conventional reverse transcription-PCR was performed for 11 genes, 9 of which showed an expression profile similar to that obtained with cDNA expression arrays. Immunohistochemical staining for SPARC showed cytoplasmic immunoreactivity of neoplastic cells in all diffuse astrocytomas analyzed. These results indicate significant changes in gene expression in diffuse astrocytomas, but it remains to be shown which of these are causally related to the transformation of glial cells.

Adult↗
PubMed2000

Effect of intragastric application of N-methylnitrosourea in p53 knockout mice.

Nullizygous p53 knockout (p53(-/-)) mice are highly susceptible to spontaneous tumorigenesis, in particular malignant lymphomas at an early age. Heterozygous p53 knockout (p53(+/-)) mice develop spontaneous tumors less frequently but may show increased susceptibility to chemical carcinogens. In this study, p53(-/-), p53(+/-), and p53 wild-type (p53(+/+)) mice were treated with N-methylnitrosourea (MNU) by gastric intubation (5 microg/g body weight) three times per week for 5 wk, starting at 5-6 wk of age. The surviving mice were killed when they were 56-57 wk old. All eight p53(-/-) mice treated with MNU developed malignant lymphomas with a shorter latent period (mean age = 16.4+/-0.5 wk) than their spontaneous tumors (61%, at age 23.3+/-1.4 wk). In p53(+/-) mice treated with MNU, malignant lymphomas developed at a higher frequency (eight of 27, 30%) than did spontaneous lymphomas (5%). Development of sarcomas in p53(-/-) and p53(+/-) mice was also significantly enhanced by treatment with MNU. All eight thymic lymphomas and three sarcomas in the p53(+/-) mice showed a loss of the remaining wild-type p53 allele. These results indicate that intragastric MNU treatment significantly enhanced spontaneous development of malignant lymphomas and sarcomas in both p53(-/-) and p53(+/-) mice. In the stomachs of 12 p53(+/-) mice, that were killed at the end of the experiment, two adenomas, one carcinoma in situ, and four adenocarcinomas were observed. In the stomachs of 31 p53(+/+) mice, eight adenomas and one carcinoma in situ were detected. The overall incidence of tumorous changes in the stomachs of p53(+/-) (seven of 12, 58%) and p53(+/+) (nine of 31, 29%) mice were not significantly different (P = 0.090). However, adenocarcinomas invading the submucosa were observed in p53(+/-) mice (four of 12, 33%) but not in p53(+/+) mice (zero of 31; P = 0. 004), suggesting a slightly higher susceptibility to gastric carcinogenesis induced by MNU in p53(+/-) mice. Mol. Carcinog. 28:97-101, 2000.

Adenocarcinoma↗
PubMed2000

APO2L/TRAIL expression in human brain tumors.

APO2 ligand (APO2L)/TRAIL is a novel member of the tumor necrosis factor cytokine family and a potent inducer of apoptosis in tumor cell lines. We recently reported that APO2L is consistently expressed in low-grade astrocytomas, anaplastic astrocytomas, glioblastomas, and cell lines derived thereof, and that malignant glioma cell lines are susceptible to APO2L-induced apoptosis. In this study, we investigated whether APO2L is expressed in medulloblastoma or neuroblastoma cell lines and whether these cells are sensitive to APO2L-induced apoptosis. Immunoblot analyses revealed full-length APO2L protein expression in one (DAOY) of three medulloblastoma cell lines but not in two neuroblastoma cell lines (SKN-BE and SKN-LE). Viability assay performed after exposure to soluble APO2L for 16 h showed that DAOY medulloblastoma cells were the most sensitive and that apoptosis induced by APO2L was greatly enhanced when protein synthesis was inhibited by cycloheximide. Neuroblastoma cell lines were almost completely resistant to APO2L-induced apoptosis. We also carried out APO2L immunohistochemistry in a total of 115 tumors of the nervous system with different histogenesis and biological behavior. In all 9 pilocytic astrocytomas, the areas of dense fibrillary network showed diffuse and strong APO2L expression. In oligodendrogliomas, APO2L expression was observed in areas with a significant admixture of astrocytic cells, but was absent in neoplastic oligodendrocytes. In 13 of 14 ependymomas, APO2L was expressed in perivascular pseudorosettes. In all 12 medulloblastomas, strong APO2L expression was observed in intra-tumoral-reactive astrocytes, but neoplastic cells did not show APO2L immunoreactivity. Thus, the pattern of APO2L expression was largely similar to that of glial fibrillary acidic protein (GFAP), except for choroid plexus tumors and 3 of 8 anaplastic meningiomas, in which APO2L was focally expressed without concomitant GFAP expression. APO2L expression was absent in meningiomas, neurocytomas, and schwannomas. Thus, there is considerable heterogeneity of APO2L expression and susceptibility to APO2L-induced apoptosis among human brain tumors.

Apoptosis↗
PubMed2000

Genetic profile of gliosarcomas.

There are distinct genetic pathways leading to the glioblastoma, the most malignant astrocytic brain tumor. Primary (de novo) glioblastomas develop in older patients and are characterized by epidermal growth factor (EGF) receptor amplification/overexpression, p16 deletion, and PTEN mutations, whereas secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma develop in younger patients and frequently contain p53 mutations. In this study, we assessed the genetic profile of gliosarcoma, a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. Single-strand conformation polymorphism followed by direct DNA sequencing revealed p53 mutations in five of 19 gliosarcomas (26%) and PTEN mutations in seven cases (37%). Homozygous p16 deletion was detected by differential polymerase chain reaction in seven (37%) gliosarcomas. The overall incidence of alterations in the Rb pathway (p16 deletion, CDK4 amplification, or loss of pRb immunoreactivity) was 53%, and these changes were mutually exclusive. Coamplification of CDK4 and MDM2 was detected in one gliosarcoma. None of the gliosarcomas showed amplification or overexpression of the EGF receptor. Thus gliosarcomas exhibit a genetic profile similar to that of primary (de novo) glioblastomas, except for the absence of EGFR amplification/overexpression. Identical PTEN mutations in the gliomatous and sarcomatous tumor components were found in two cases. Other biopsies contained p16 deletions, an identical p53 mutation, or coamplification of MDM2 and CDK4 in both tumor areas. This strongly supports the concept of a monoclonal origin of gliosarcomas and an evolution of the sarcomatous component due to aberrant mesenchymal differentiation in a highly malignant astrocytic neoplasm.

Adult↗
PubMed2000

APC mutations in sporadic medulloblastomas.

The cerebellar medulloblastoma (WHO Grade IV) is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Several molecular alterations appear to be involved, including isochromosome 17q and the p53, PTCH, and beta-catenin gene mutations. In this study, 46 sporadic medulloblastomas were screened for the presence of mutations in genes of the Wnt signaling pathway (APC and beta-catenin). Single-strand conformational polymorphism (SSCP) analysis followed by direct DNA sequencing revealed 3 miscoding APC mutations in 2 (4.3%) medulloblastomas. One case contained a GCA-->GTA mutation at codon 1296 (Ala-->Val), and another case had double point mutations at codons 1472 (GTA-->ATA, Val-->Ile) and 1495 (AGT-->GGT, Ser-->Gly). Miscoding beta-catenin mutations were detected in 4 tumors (8.7%). Three of these were located at codon 33 (TCT -->TTT, Ser-->Phe) and another at codon 37 (TCT-->GCT, Ser-->Ala). Adenomatous polyposis coli (APC) gene and beta-catenin mutations were mutually exclusive and occurred in a total of 6 of 46 cases (13%). Although germline APC mutations are a well established cause of familial colon and brain tumors (Turcot syndrome), this study provides the first evidence that APC mutations are also operative in a subset of sporadic medulloblastomas.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas.

Glioblastomas develop de novo (primary glioblastomas) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastomas). There is increasing evidence that these glioblastoma subtypes develop through different genetic pathways. Primary glioblastomas are characterized by EGFR and MDM2 amplification/overexpression, PTEN mutations, and p16 deletions, whereas secondary glioblastomas frequently contain p53 mutations. Loss of heterozygosity (LOH) on chromosome 10 (LOH#10) is the most frequent genetic alteration in glioblastomas; the involvement of tumor suppressor genes, other than PTEN, has been suggested. We carried out deletion mappings on chromosome 10, using PCR-based microsatellite analysis. LOH#10 was detected at similar frequencies in primary (8/17; 47%) and secondary glioblastomas (7/13; 54%). The majority (88%) of primary glioblastomas with LOH#10 showed LOH at all informative markers, suggesting loss of the entire chromosome 10. In contrast, secondary glioblastomas with LOH#10 showed partial or complete loss of chromosome 10q but no loss of 10p. These results are in accordance with the view that LOH on 10q is a major factor in the evolution of glioblastoma multiform as the common phenotypic end point of both genetic pathways, whereas LOH on 10p is largely restricted to the primary (de novo) glioblastoma.

Adult↗
PubMed2000

p53 knockout mice (-/-) are more susceptible than (+/-) or (+/+) mice to N-methyl-N-nitrosourea stomach carcinogenesis.

Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers. Mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this study we have investigated the susceptibility of p53 nullizygote (-/-), heterozygote (+/-) and wild-type (+/+) mice to N:-methyl-N:-nitrosourea (MNU) gastric carcinogenesis. p53 knockout mice were treated with 30 p.p.m. MNU in the drinking water 1 week on and 1 week off and killed after 5 weeks. The numbers of pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were 1.8, 1.7 and 22.6 in p53 (+/+), (+/-) and (-/-) mice, respectively. In a 15 week experiment, adenomas were found in 0 of 19 (+/+) (0%), 2 of 21 (+/-) (9.5%) and 6 of 10 (-/-) (60.0%) animals. Also, one well-differentiated adenocarcinoma was observed in a p53 (-/-) mouse. After 40 weeks treatment with 120 or 30 p.p.m. MNU there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/-) mice. However, mortality from carcinogen-induced lymphomas, leukemias and sarcomas was very much greater in the latter group. Homozygous knockout animals could not be maintained long term. PCR-single strand conformation polymorphism analysis of exons 5-8 of the p53 gene of DNA extracts from 68 gastric tumors consisting of 16 and 20 30 p.p.m. MNU-treated p53 (+/+) and (+/-) mice and 14 and 18 120 p.p.m. MNU-treated p53 (+/+) and (+/-) mice demonstrated no mutations. These results suggest that p53 may not be a direct target of MNU but rather play an important role as a gatekeeper in mouse stomach carcinogenesis induced by this direct acting agent.

Animals↗
PubMed2000

Loss of heterozygosity on chromosome 19 in secondary glioblastomas.

Glioblastomas develop rapidly de novo (primary glioblastomas) or slowly through progression from low-grade or anaplastic astrocytoma (secondary glioblastomas). Recent studies have shown that these glioblastoma subtypes develop through different genetic pathways. Primary glioblastomas are characterized by EGFR amplification/overexpression, PTEN mutation, homozygous p16 deletion, and loss of heterozygosity (LOH) on entire chromosome 10, whereas secondary glioblastomas frequently contain p53 mutations and show LOH on chromosome 10q. In this study, we analyzed LOH on chromosomes 19q, 1p, and 13q, using polymorphic microsatellite markers in 17 primary glioblastomas and in 13 secondary glioblastomas that progressed from low-grade astrocytomas. LOH on chromosome 19q was frequently found in secondary glioblastomas (7 of 13, 54%) but rarely detected in primary glioblastomas (1 of 17, 6%, p = 0.0094). The common deletion was 19q13.3 (between D19S219 and D19S902). These results suggest that tumor suppressor gene(s) located on chromosome 19q are frequently involved in the progression from low-grade astrocytoma to secondary glioblastoma, but do not play a major role in the evolution of primary glioblastomas. LOH on chromosome 1p was detected in 12% of primary and 15% of secondary glioblastomas. LOH on 13q was detected in 12% of primary and in 38% of secondary glioblastomas and typically included the RB locus. Except for 1 case, LOH 13q and 19q were mutually exclusive.

Astrocytoma↗
PubMed1999

Molecular analysis of glioma and skin-tumour alterations in a xeroderma-pigmentosum child.

Xeroderma pigmentosum (XP) is a rare hereditary disease characterized by a very high frequency of skin tumours due to a defect in the nucleotide-excision-repair process. Some of these patients have also been reported to develop internal tumours with higher frequency than the normal population. Reported here are the clinical features and molecular analysis of an XP patient who developed multiple skin cancers as well as a thalamic glioma. Complementation analysis with recombinant retrovirus, cloning efficiency and unscheduled DNA synthesis after UV-C indicate that the patient belongs to the C group. Characterization of the p53 mutations in the 2 tumours of the patient leads to speculation on the aetiological agents involved in tumour initiation. The skin tumour is clearly induced by the presence of unrepaired UVB-induced DNA damage on the non-transcribed strand of the p53 gene, while the glioma may be induced by unrepaired DNA lesions produced by free radicals.

Brain Neoplasms↗
PubMed1999

Human astrocytic brain tumors express AP02L/TRAIL.

AP02 ligand (APO2L) is a CD95 ligand (CD95L)-related cytokine of the tumor necrosis factor family that interacts with agonistic (DR4, DR5) and antagonistic (DcR1, DcR2) receptors. Cultured malignant glioma cells preferentially express agonistic receptors and are susceptible to APO2L-induced apoptosis. Here, we report that 8 of 8 human glioma cell lines expressed APO2L mRNA and protein in vitro. Immunohistochemistry using a monoclonal antibody to APO2L revealed that all 23 primary astrocytic brain tumors analyzed, including low-grade astrocytomas and glioblastomas, express APO2L in vivo. With the exception of reactive astrocytes, non-neoplastic glia and neurons in the cerebrum lacked immunoreactivity of APO2L. Thus, in addition to the CD95/CD95L system, a second death ligand/death receptor pair may regulate susceptibility to apoptosis in human glial neoplasms.

Adult↗
PubMed1999

A case history of glioma progression.

Low-grade diffuse astrocytomas have an intrinsic tendency for malignant progression but the factors determining the kinetics of this process are still poorly understood. We report here the case of a male patient who developed a fibrillary astrocytoma at the age of 33 years and who underwent six surgical interventions over a period of 17 years without radiotherapy or chemotherapy. The first three biopsies spanned a period of 11 years and led to the diagnosis of low-grade, diffuse astrocytoma (WHO grade II), with a growth fraction (MIB-1 labeling index) of 2.3-3.7%. The fourth to sixth biopsies showed histological features of anaplastic astrocytoma (WHO grade III), with growth fractions between 5.0 and 10.5%. The fraction of gemistocytic neoplastic astrocytes also increased, from 0.3% in the first biopsy to 17.5% in the last biopsy and preceded the increase in proliferative activity and transition to anaplastic astrocytoma. The fraction of tumor cells immunoreactive to BCL-2 increased from 0.3% to 8.2%. A p53 mutation in codon 273 (CGT-->TGT, Arg-->Cys) was identified in the first biopsy and persisted throughout the course of the disease. However, the fraction of cells with p53 protein accumulation increased significantly during progression, from 3.2% in the first biopsy to 13.7% in the last. The absence of additional genetic alterations (PTEN mutations, loss of chromosome 10 and 19q) may be responsible for the slow progression and lack of glioblastoma features even after a 17-year disease duration.

Adult↗
PubMed1999

Acquisition of the glioblastoma phenotype during astrocytoma progression is associated with loss of heterozygosity on 10q25-qter.

Loss of heterozygosity on chromosome 10 (LOH#10) is the most frequent genetic alteration in glioblastomas and occurs in more than 80% of cases. We recently reported that PTEN (MMAC1) on 10q23.3 is mutated in approximately 30% of primary (de novo) glioblastomas but rarely in secondary glioblastomas that progressed from low-grade or anaplastic astrocytomas. Because secondary glioblastomas also show LOH#10, tumor suppressor genes other than PTEN are likely to be involved. We analyzed LOH on chromosomes 10 and 19, using polymorphic microsatellite markers in microdissected foci showing histologically an abrupt transition from low-grade or anaplastic astrocytoma to glioblastoma, suggestive of the emergence of a new tumor clone. When compared to the respective low-grade or anaplastic astrocytoma of the same biopsy, deletions were detected in 7 of 8 glioblastoma foci on 10q25-qter distal to D10S597, covering the DMBT1 and FGFR2 loci. Six of 8 foci showed LOH at one or two flanking markers of PTEN but did not contain PTEN mutations. LOH on 10p and 19q was found in only one case each. These data indicate that acquisition of a highly anaplastic glioblastoma phenotype with marked proliferative activity and lack of glial fibrillary acidic protein expression is associated with loss of a putative tumor suppressor gene on 10q25-qter.

Adult↗
PubMed1999

Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection.

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide. Hepatitis B virus and hepatitis C virus infections, exposure to aflatoxin, and excessive intake of alcohol have been identified as major risk factors. However, the molecular mechanisms underlying their development are still poorly understood. Recently, beta-catenin, one of the key components of the Wnt signaling pathway, has been found to be mutated in about 20% of HCCs, suggesting a role of the Wnt pathway in their development. In this study, we examined beta-catenin and APC mutations in 22 HCCs associated with HCV infection, using single-strand conformation polymorphism (SSCP) followed by direct DNA sequencing. beta-Catenin mutations were found in nine (41%) cases, but no APC mutations were found. beta-Catenin immunohistochemistry revealed nuclear accumulation of beta-catenin protein in all nine tumors with a beta-catenin mutation and two additional tumors without a mutation. These results suggest that activation of the Wnt signaling pathway by beta-catenin mutation contributes significantly to the hepatocellular carcinogenesis associated with HCV infection.

Adenomatous Polyposis Coli Protein↗
PubMed1999

Primary and secondary glioblastomas: from concept to clinical diagnosis.

Glioblastomas may develop de novo (primary glioblastomas) or through progression from low-grade or anaplastic astrocytomas, (secondary glioblastomas). These subtypes of glioblastoma constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and are likely to differ in prognosis and response to therapy. Primary glioblastomas develop in older patients and typically show EGFR overexpression, PTEN (MMAC1) mutations, CDKN2A (p16) deletions, and less frequently, MDM2 amplification. Secondary glioblastomas develop in younger patients and often contain TP53 mutations as the earliest detectable alteration. These characteristics are derived largely from patients selected on the basis of clinical history and sequential biopsies. Currently available data are insufficient for a substitution of histologic classification and grading of astrocytic tumors by genetic typing alone. More subtypes of glioblastomas may exist with intermediate clinical and genetic profiles, a factor exemplified by the giant-cell glioblastoma that clinically and genetically occupies a hybrid position between primary (de novo) and secondary glioblastomas. Future research should aim at the identification of criteria for a combined clinical, histologic, and genetic classification of astrocytic tumors.

Adult↗
PubMed1999

Altered expression of hepatic carcinogen metabolizing enzymes with liver injury in HBV transgenic mouse lineages expressing various amounts of hepatitis B surface antigen.

AIMS/BACKGROUND: The objective of this work was to evaluate the possible modulation of carcinogen metabolizing enzymes in relation to chronic infection by hepatitis B virus (HBV). This was to test whether enzyme level is altered in association with HBV gene expression per se or only when that expression was associated with an induction of liver injury. METHODS: For this purpose, we studied four different HBV transgenic mouse lineages (23.3, 45.2, 50.4 and 107.5) that express the transgene encoding for the large envelope protein (HBsAg) at different levels. These lineages exhibit an associated liver injury which progresses with age and is positively correlated with the degree of accumulation of HBsAg in the hepatocytes. The modulation of levels of cytochrome P450 (1a, 2a-5, 2b, 2c, 3A4 and 2E1) and glutathione S-transferases (GST alpha and pi) involved in carcinogen metabolism was examined by immunohistochemistry in these lineages. RESULTS: While we observed an increase in staining intensity of P450s 1-a and 2a-5 in lineages expressing cytopathic amounts of HBsAg (lineages 50.4 and 45.2), we only observed minor changes or no changes at all for the other lineages (23.3 and 107.5). Staining with antibodies to cytosolic pi class GST demonstrated an increase in older mice, although no major alterations were observed for GST alpha. CONCLUSIONS: These results suggest that liver cell injury induced by accumulation of HBV antigens can result in the induction of some carcinogen metabolizing enzymes and this may be one mechanism of chemical-viral interaction in hepatocarcinogenesis.

Animals↗
PubMed1999

Identification in human brain tumors of DNA sequences specific for SV40 large T antigen.

Simian virus 40 (SV40) sequences have recently been identified in a variety of human neoplasms, including mesothelioma, osteosarcoma, and brain tumors, but significant discrepancies exist regarding the frequency at which this occurs. The SV40 genome is 70% homologous to JC and BK, two related polyomaviruses that are highly prevalent in humans and which may cause in immune-compromised patients progressive multifocal leukoencephalopathy (PML) and cystitis, respectively. We have established a specific and sensitive method to identify SV40 sequence in DNA extracted from histological sections, using PCR followed by Southern hybridization to probes specific to the large T region. We found SV40 large T antigen sequences in all brain tumor types investigated. High frequencies were found in low-grade astrocytomas, anaplastic astrocytomas and secondary glioblastomas derived thereof (13/22, 59%) while somewhat lower frequencies were found in gemistocytic astrocytomas (9/28, 32%) and oligodendrogliomas (3/12, 25%). Primary glioblastomas, giant cell glioblastomas, and gliosarcomas, which clinically develop de novo, contained SV40 sequences in 11-25% of cases. Presence of viral DNA was also observed in pediatric brain tumors, including ependymomas (9/16, 56%), choroid plexus papillomas (6/16, 38%), and medulloblastomas (5/17, 29%). In 8 tumor biopsies with SV40 sequences, the adjacent normal brain tissue was also analyzed but was devoid of viral DNA in all but one case. BK and JC virus sequences were rarely detected, the overall frequencies being 3% and 2%, respectively. It remains to be shown whether the presence of SV40 contributes significantly to malignant transformation or whether certain human neoplasms provide a microenvironment that favors viral replication in humans with latent SV40 infection.

Adolescent↗
PubMed1999

Genetic profile of the giant cell glioblastoma.

Giant cell glioblastoma is a rare glioblastoma variant characterized by the presence of large, bizarre, multinucleated giant cells. This glioblastoma subtype develops clinically de novo after a short clinical history and contains a high frequency of p53 mutations. In this study, we screened a series of 18 giant cell glioblastomas for additional genetic alterations. PCR-SSCP followed by DNA sequencing revealed PTEN mutations in 5 of 15 tumors (33%). Of these, two mutations were located in exon 5, two mutations in exon 6, and one mutation each in exons 1 and 9. Four mutations were point mutations and two mutations were deletions. One neoplasm contained two PTEN mutations (exons 5 and 6). None of the giant cell glioblastomas showed a homozygous deletion of PTEN orp16, or amplification of MDM2. Immunohistochemically, MDM2 overexpression was either not observed or detected in only a minor fraction of tumor cells. Differential PCR revealed EGFR amplification in only one of 17 tumors (6%). These results indicate that giant cell glioblastomas occupy a hybrid position, sharing with primary (de novo) glioblastomas a short clinical history, the absence of a less malignant precursor lesion and a 30% frequency of PTEN mutations. With secondary glioblastomas that develop through progression from low-grade astrocytomas, they have in common a younger patient age at manifestation and a high frequency (>70%) of p53 mutations.

Adult↗