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Hiroko Ohgaki

Publications and source records attributed to Hiroko Ohgaki.

At least 19 recordsLinked to original sources
PubMed2006

Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53+/- mice.

Chronic inflammation is a recognized risk factor for human cancer at various sites because of persistent oxidative and nitrative tissue damage. Trp53+/- mice show the predisposition to tumor development, such as sarcomas and lymphomas, compared with Trp53+/+ mice. We investigated the effects of chronic inflammation, especially oxidative and nitrative stress, induced by subcutaneous implantation of a plastic plate (10 x 5 x 1 mm) as a foreign body on tumorigenesis in Trp53+/- and Trp53+/+ mice. The plastic plates were implanted at the age of about 11 weeks. Thirty out of 38 Trp53+/- mice (79%) developed sarcomas around the implant (mean time of tumor appearance was 45.8 +/- 12.0 weeks of age), whereas only one of 10 Trp53+/+ mice with an implant (10%) developed a tumor, at 56 weeks. No sarcomas developed at a sham-operation site. Two of 10 Trp53+/- mice with no implant (20%) also developed three sarcomas spontaneously at 77, 81 and 84 weeks. Increased immunostaining for markers of oxidative and nitrative stress (8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-nitroguanine and 3-nitrotyrosine) and expression of inducible nitric oxide synthase in tumor cells and inflammatory cells were detected in implant-induced sarcomas compared with spontaneous sarcomas in Trp53+/- mice. Furthermore, p53 loss of heterozygosity was observed in 26 out of 29 implant-induced sarcomas (90%). These results indicate that implanted foreign bodies significantly enhanced sarcoma development in Trp53+/- mice, and this may be associated with increased oxidaive and nitrative stress. Loss of the remaining wild-type p53 allele and loss of p53 function appears to be, at least in part, underlying molecular mechanisms during the development of sarcomas at the implantation site in Trp53+/- mice. Such implant-induced sarcoma development in Trp53+/- mice could be useful for studying molecular mechanisms and developing new strategies for chemoprevention in human carcinogenesis induced by chronic inflammation and/or foreign bodies.

Animals↗
PubMed2006

Stratification of medulloblastoma on the basis of histopathological grading.

Medulloblastoma (WHO grade IV) is an embryonal tumour of the cerebellum and the most common malignant central nervous system tumour in children. Despite significant advances in treatment, 5-year survival rates are still less than 70%, suggesting the presence of subgroups with different response to radio/chemotherapy. In the present study, we re-evaluated a series of 347 medulloblastomas from the SIOP II clinical trial of the International Society of Paediatric Oncology to identify features predictive of clinical outcome. Relapse free survival for medulloblastomas with severe anaplasia [5-year rate: S(60)=49.5%], was significantly shorter than for tumours with moderate or mild anaplasia S(60)=65.4%; P=0.001). The difference between both groups was even larger when the presence or absence of extensive apoptosis was included (46.5 vs. 66.7%; P=0.0216). Other histological features including nodularity, necrosis, vascular proliferation and the presence of beta-catenin mutations (7% of cases) were not predictive for relapse free survival. These findings indicate that degree of anaplasia is the most significant histologic feature predictive of the survival of medulloblastoma patients.

Adolescent↗
PubMed2006

Correlation among pathology, genotype, and patient outcomes in glioblastoma.

Glioblastomas are histologically and genetically heterogeneous. We have investigated to what extent histologic features reflect the genetic profile and whether they are predictive of clinical outcome. Key histologic characteristics, including major cell types (small cell, nonsmall cell), other components such as oligodendroglial components, gemistocytes, multinucleated giant cells, as well as necrosis and microvascular proliferation, of 420 cases of glioblastoma within a population-based study (1) were reassessed and correlated with patients' clinical outcome and key genetic alterations. EGFR amplification and p16 homozygous deletion were significantly more frequent in small cell glioblastomas than in nonsmall cell glioblastomas (EGFR, 46% vs 26%, p = 0.0002; p16 39% vs 25%, p = 0.0167). Multivariate analyses with adjustment for age and gender showed that small cell glioblastomas had frequent EGFR amplification and p16 deletion but infrequent PTEN mutations. An oligodendroglial component was detected in 20% of glioblastomas; these patients were significantly younger (54.4 +/- 13.6 vs 59.2 +/- 13.8 years; p = 0.0049) and survived longer (10.3 +/- 8.3 vs 8.2 +/- 8.4 months; p = 0.0647). However, multivariate analyses with adjustment for age and gender did not show the presence of an oligodendroglial component to be predictive of longer survival. After adjustment for age and gender, LOH 1p was associated with longer survival (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0), whereas LOH 10q was associated with shorter survival (hazard ratio, 1.4; 95% CI, 1.0-1.8) of patients with glioblastoma. Glioblastomas containing >or=5% multinucleated giant cells showed more frequent TP53 mutation and infrequent EGFR amplification than those containing <5% multinucleated giant cells (TP53, 45% vs 24%, p = 0.0001; EGFR, 24% vs 42%, p = 0.0005). Vascular proliferation was observed in all glioblastomas, whereas large ischemic and/or pseudopalisading necrosis was observed in 366 of 420 (87%) cases. Glioblastomas with necrosis were associated with older age (59.2 +/- 13.3 vs 51.6 +/- 15.3 years; p = 0.0001) and shorter survival (7.9 +/- 6.8 vs 12.9 +/- 14.2 months; p = 0.0017). Multivariate analyses with adjustment for age and gender confirmed this observation (hazard ratio, 1.5; 95% CI, 1.1-2.0). Multivariate analysis with adjustment for age and gender showed that necrosis was significantly associated with wild-type TP53 and absence of an oligodendroglial component. These results suggest that some histologic features in glioblastomas are associated with specific genetic alterations and with clinical outcome.

Adult↗
PubMed2006

Brain tumors in S100beta-v-erbB transgenic rats.

We have established a line of transgenic rats expressing v-erbB, the viral form of epidermal growth factor receptor (EGFR), under transcriptional regulation of the S100beta promoter. Reverse transcriptase-polymerase chain reaction revealed highest transgene expression in the cerebellum followed by the cerebrum, ovary, and testis. Other organs, including the lung, heart, salivary gland, colon, liver, kidney, and spleen, did not show detectable transgene expression. Of 23 homozygous rats that died or were killed because they became moribund between 25 and 91 weeks of age, 15 (65%) showed the presence of brain tumors (mean age, 59 weeks). Of the 10 heterozygous rats killed between 61 and 91 weeks of age, 4 (40%) showed the presence of brain tumors (mean, 77 weeks). With 3 exceptions, all tumors were located within or near the cerebellum (83%). There were 2 major histologic types; one type displayed a solid growth pattern with predominantly perivascular infiltration of adjacent central nervous system tissue and the meninges. Tumors showed histologic features of malignancy with occasional lung metastases. There was a consistent, strong immunoreactivity for S100 protein but no significant expression of glial, neuronal, or meningothelial markers. These tumors were classified as malignant gliomas. A second tumor type was less invasive and characterized by isomorphic cells with round to ovoid nuclei and clear perinuclear halos expressing S100 but no neuronal or glial marker proteins. They were diagnosed as oligodendrogliomas. This is the first transgenic rat model that spontaneously develops brain tumors. Because v-erbB is structurally and functionally similar to the truncated form of EGFR amplified and overexpressed in human glioblastomas, S100beta-v-erbB transgenic rats may serve as a useful animal model for the identification of EGFR-related molecular targets and as a tool for the assessment of novel therapeutic approaches.

Animals↗
PubMed2005

TP53 promoter methylation in human gliomas.

Methylation of the promoter region of tumor suppressor genes may be associated with transcriptional silencing and tumor progression. The 5' region of the TP53 gene does not contain a CpG island, but a basal promoter region of 85 bp is essential for its full promoter activity. In the present study, we assessed whether TP53 promoter methylation is present in malignant glioma cells and whether this is associated with reduced TP53 expression. Methylation-specific PCR revealed TP53 promoter methylation in three (U87MG, LNT-229, T98G) out of six malignant glioma cell lines studied. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC) led to up-regulated expression of TP53 mRNA and protein in U87MG and T98G cells, suggesting that promoter methylation is associated with reduced expression in some malignant glioma cells. We then assessed TP53 promoter methylation in primary tissue of low-grade gliomas, and observed TP53 promoter methylation in 29/48 (60%) low-grade astrocytomas, 11/18 (61%) oligoastrocytomas, and 31/42 (74%) oligodendrogliomas. Promoter methylation of the p14ARF gene, another gene involved in the TP53 pathway, was detected by methylation-specific PCR in 5/49 (10%) low-grade astrocytomas, 7/18 (39%) oligoastrocytomas, and 15/41 (37%) oligodendrogliomas. Our previous and present data show alterations of at least one of TP53 promoter methylation, p14ARF promoter methylation, and TP53 mutations in 43/49 (88%) of low-grade astrocytomas, 15/18 (83%) of oligoastrocytomas, and 35/42 (83%) oligodendrogliomas, suggesting that disruption of the TP53/p14ARF pathway is frequent in all histological types of low-grade glioma.

Base Sequence↗
PubMed2005

Epidemiology and etiology of gliomas.

Gliomas of astrocytic, oligodendroglial and ependymal origin account for more than 70% of all brain tumors. The most frequent (65%) and most malignant histological type is the glioblastoma. Since the introduction of computerized tomography and magnetic resonance imaging, the incidence rates of brain tumors have been rather stable, with a tendency of higher rates in highly developed, industrialized countries. Some reports indicate that Caucasians have higher incidence than black or Asian populations, but to some extent, this may reflect socio-economic differences and under-ascertainment in some regions, rather than a significant difference in genetic susceptibility. With the exception of pilocytic astrocytomas, the prognosis of glioma patients is still poor. Less than 3% of glioblastoma patients are still alive at 5 years after diagnosis, higher age being the most significant predictor of poor outcome. Brain tumors are a component of several inherited tumor syndromes, but the prevalence of these syndromes is very low. Several occupations, environmental carcinogens, and diet (N-nitroso compounds) have been reported to be associated with an elevated glioma risk, but the only environmental factor unequivocally associated with an increased risk of brain tumors, including gliomas, is therapeutic X-irradiation. In particular, children treated with X-irradiation for acute lymphoblastic leukemia show a significantly elevated risk of developing gliomas and primitive neuroectodermal tumor (PNET), often within 10 years after therapy. TP53 mutations are frequent in low-grade gliomas and secondary glioblastomas derived therefrom. Approximately 60% of mutations are located in the hot spot codons 248 and 273, and the majority of these are G:C-->A:T transitions at CpG sites. TP53 mutations are significantly more frequent in low-grade astrocytomas with promoter methylation of the O(6)-methylguanine-DNA methyltransferase repair gene, suggesting that, in addition to deamination of 5-methylcytosine, exogenous or endogenous alkylation in the O(6) position of guanine may contribute to the formation of these mutations.

Age Factors↗
PubMed2005

Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas.

Published data on prognostic and predictive factors in patients with gliomas are largely based on clinical trials and hospital-based studies. This review summarizes data on incidence rates, survival, and genetic alterations from population-based studies of astrocytic and oligodendrogliomas that were carried out in the Canton of Zurich, Switzerland (approximately 1.16 million inhabitants). A total of 987 cases were diagnosed between 1980 and 1994 and patients were followed up at least until 1999. While survival rates for pilocytic astrocytomas were excellent (96% at 10 years), the prognosis of diffusely infiltrating gliomas was poorer, with median survival times (MST) of 5.6 years for low-grade astrocytoma WHO grade II, 1.6 years for anaplastic astrocytoma grade III, and 0.4 years for glioblastoma. For oligodendrogliomas the MSTwas 11.6 years for grade II and 3.5 years for grade III. TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but infrequent (13%) in oligodendrogliomas. LOH 1p/19q typically occurred in tumors without TP53 mutations and were most frequent in oligodendrogliomas (69%), followed by oligoastrocytomas (45%), but were rare in fibrillary astrocytomas (7%) and absent in gemistocytic astrocytomas. Glioblastomas were most frequent (3.55 cases per 100,000 persons per year) adjusted to the European Standard Population, amounting to 69% of total incident cases. Observed survival rates were 42.4% at 6 months, 17.7% at one year, and 3.3% at 2 years. For all age groups, survival was inversely correlated with age, ranging from an MST of 8.8 months (<50 years) to 1.6 months (>80 years). In glioblastomas, LOH 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations, and was the only alteration associated with shorter survival of glioblastoma patients. Primary (de novo) glioblastomas prevailed (95%), while secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hot-spot codons 248 and 273, while in primary glioblastomas, mutations were more evenly distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas, suggesting that the acquisition of TP53 mutations in these glioblastoma subtypes may occur through different mechanisms.

Age Distribution↗
PubMed2005

Altered expression of immune defense genes in pilocytic astrocytomas.

Pilocytic astrocytoma (WHO grade I) is a circumscribed, slowly growing, benign astrocytoma that most frequently develops in the cerebellar hemispheres and in midline structures and occurs predominantly in childhood and adolescence. In contrast to diffusely infiltrating gliomas in adults (e.g. grade II astrocytomas, oligodendrogliomas), survival of patients with pilocytic astrocytoma is excellent after surgical intervention. To search for potential molecular mechanisms underlying its benign biologic behavior, we compared gene expression profiles of pilocytic astrocytomas (8 cases) with those of normal cerebellum (4 cases), low-grade astrocytomas (WHO grade II; 15 cases), and oligodendrogliomas (WHO grade II; 17 cases) by cDNA array analysis. A number of immune system-related genes such as HLA-DRalpha, HLA-DPB1, HLA-DQB1, IgG3, IgGK, FCER1G, A2M, FCRN, IFI-56K, and DAP12 were upregulated in pilocytic astrocytomas relative to normal cerebellum, grade II astrocytomas, and oligodendrogliomas. Genes expressed at higher levels in pilocytic astrocytomas than in grade II astrocytomas and oligodendrogliomas include HLA-DRalpha, HLA-DPA1, HLA-DPB1, HLA-DQB1, A2M, TIMP1, TIMP2, CDKN1A, and SOCS3 and those expressed at lower levels include EGFR and PDGFRA. Hierarchical clustering analysis using the entire set of 1176 genes distinguished pilocytic astrocytomas from grade II astrocytomas and oligodendrogliomas. Clustering analysis using selected subgroups of genes based on their molecular functions revealed that immune system-related genes (75 genes) or cell adhesion, migration, and angiogenesis-related genes (69 genes) showed similar power to the entire gene set for separation of pilocytic astrocytomas from diffusely infiltrating low-grade gliomas. Immunohistochemistry revealed that HLA-DRalpha is expressed diffusely in neoplastic cells in pilocytic astrocytomas, whereas in oligodendrogliomas, expression was limited to scattered reactive astrocytes. These results suggest that gene expression profiles of pilocytic astrocytomas differ significantly from those of diffusely infiltrating low-grade gliomas and that their benign biologic behavior may be related to upregulation of immune defense-associated genes.

Adolescent↗
PubMed2005

Genetic pathways to glioblastomas.

Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). These glioblastoma subtypes constitute distinct disease entities that affect patients of different ages and develop through different genetic pathways. Our recent population-based study in the Canton of Zürich, Switzerland, shows that primary glioblastomas develop in older patients (mean age, 62 years) and typically show LOH on chromosome 10q (69%) and other genetic alterations (EGFR amplification, TP53 mutations, p16INK4a deletion, and PTEN mutations) at frequencies of 24-34%. Secondary glioblastomas develop in younger patients (mean, 45 years) and frequently show TP53 mutations (65%) and LOH 10q (63%). Common to both primary and secondary glioblastoma is LOH on 10q, distal to the PTEN locus; a putative suppressor gene at 10q25-qter may be responsible for the glioblastoma phenotype. Of the TP53 point mutations in secondary glioblastomas, 57% were located in hotspot codons 248 and 273, while in primary glioblastomas, mutations were more widely distributed. Furthermore, G:C-->A:T mutations at CpG sites were more frequent in secondary than in primary glioblastomas (56% vs 30%). These data suggest that the TP53 mutations in these glioblastoma subtypes arise through different mechanisms. There is evidence that G:C-->A:T transition mutations at CpG sites in the TP53 gene are significantly more frequent in low-grade astrocytomas with promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene than in those without methylation. This suggests that, in addition to deamination of 5-methylcytosine (the best known mechanism of formation of G:C-->A:T transitions at CpG sites), involvement of alkylating agents that produce O6-methylguanine or related adducts recognized by MGMT cannot be excluded in the pathway leading to secondary glioblastomas.

Age Factors↗
PubMed2004

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53-deficient mice lacking inducible nitric oxide synthase gene.

Trp53-deficient mice spontaneously develop lymphomas, mainly of thymic origin, although the molecular mechanism remains largely unknown. As several interaction effects between p53 and iNOS have been reported, we hypothesized that iNOS activity in the thymus is causally linked to lymphomagenesis in Trp53-deficient mice. We therefore created mouse strains with different combinations of the Trp53 and iNOS genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of Trp53 status and its expression was enhanced in Trp53+/- and Trp53-/- mice compared to Trp53+/+ mice. Homozygous disruption of iNOS decreased the incidence of thymic lymphomas by almost 40% (p=0.087) and 90% (p<0.05) in Trp53-/- and Trp53+/- mice, respectively, compared to the respective iNOS wild-type mice but significantly (p<0.05) increased the development of nonthymic lymphomas in Trp53-/- and Trp53+/- mice. Although iNOS gene disruption did not affect the phenotype of thymic lymphomas, absence of the iNOS gene shifted the spectrum of nonthymic lymphoma from the B-cell to the T-cell lineage. RT-PCR analysis revealed enhanced expression of IL-10, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations Trp53-/-iNOS-/- and Trp53+/-iNOS-/- but not Trp53-/-iNOS+/+ or Trp53+/-iNOS+/+. These results suggest that iNOS could increase the development of thymic lymphomas in Trp53-deficient mice. While iNOS may have protective effects against nonthymic lymphomagenesis, the regulation of cytokine production by iNOS may be involved in the underlying mechanism of antilymphomagenesis effects in the peripheral lymphoid organ.

Animals↗
PubMed2004

Genetic pathways to glioblastoma: a population-based study.

We conducted a population-based study on glioblastomas in the Canton of Zurich, Switzerland (population, 1.16 million) to determine the frequency of major genetic alterations and their effect on patient survival. Between 1980 and 1994, 715 glioblastomas were diagnosed. The incidence rate per 100,000 population/year, adjusted to the World Standard Population, was 3.32 in males and 2.24 in females. Observed survival rates were 42.4% at 6 months, 17.7% at 1 year, and 3.3% at 2 years. For all of the age groups, younger patients survived significantly longer, ranging from a median of 8.8 months (<50 years) to 1.6 months (>80 years). Loss of heterozygosity (LOH) 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16(INK4a) deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations and was predictive of shorter survival. Primary (de novo) glioblastomas prevailed (95%), whereas secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hotspot codons 248 and 273, whereas in primary glioblastomas, mutations were more equally distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas (56% versus 30%; P = 0.0208). This suggests that the acquisition of TP53 mutations in these glioblastoma subtypes occurs through different mechanisms.

Adult↗
PubMed2004

Gene expression profiling and subgroup identification of oligodendrogliomas.

The histological diagnosis of low-grade astrocytomas and oligodendrogliomas (WHO grade II) is often challenging, particularly in cases that show both astrocytic and oligodendroglial differentiation. We carried out gene expression profiling on 17 oligodendrogliomas (93% with LOH 1p and/or 19q) and 15 low-grade astrocytomas (71% with a TP53 mutation), using a cDNA array containing 1176 cancer-related genes. In oligodendrogliomas, 40 genes showed on average higher expression (at least a two-fold increase) than in astrocytomas, including DES, TDGF1, TGF-beta, GABA-BR1A, Histone H4, CDKN1A, PCDH43, Rho7 and Jun-D, while 39 genes were expressed at lower levels (at least a two-fold decrease), including JNK2, ITGB4, JNK3A2, RhoC, IFI-56K, AAD14 and EGFR. Immunohistochemistry revealed nuclear staining of Jun-D in oligodendrogliomas, in contrast to the immunoreactivity of cytoplasm and cell processes in low-grade astrocytomas. Partial least-squares analysis of the 79 genes at least two-fold differentially expressed between oligodendrogliomas and low-grade astrocytomas demonstrated perfect separation of oligodendrogliomas from low-grade astrocytomas and normal cerebral white matter. Clustering analysis based on the entire gene set divided the 17 subjects with oligodendrogliomas into two subgroups with significantly different survival (log-rank test, P=0.0305; survival to 5-years, 80 vs 0%, P=0.048). These results demonstrate that oligodendrogliomas and low-grade astrocytomas differ in their gene expression profiles, and that there are subgroups of oligodendroglioma with distinct expression profiles related to clinical outcome.

Adult↗
PubMed2004

APC mutations are infrequent but present in human lung cancer.

Recent studies have revealed the presence of beta-catenin mutations in a small subset of human and rat lung carcinomas, suggesting the involvement of the Wnt pathway in pulmonary carcinogenesis. LOH on chromosome 5q (APC locus) is frequent in lung cancer, but previous studies have found no adenomatous polyposis coli (APC) mutations. In this study, we screened 114 human lung cancer specimens for alterations in the mutation cluster region of the APC gene and in exon 3 of the beta-catenin gene. SSCP followed by direct DNA sequencing revealed APC mutations in 2/44 (5%) squamous cell carcinomas, a 2-bp deletion in codon 1465 (AGT-->A), and a GAA-->CAA (Glu-->Gln) mutation at codon 1317. One of 32 (3%) small cell lung carcinomas contained a GAA-->AAA (Glu-->Lys) mutation at codon 1284. Two cases with an APC mutation showed focal nuclear beta-catenin staining. These results suggest that disruption of the Wnt pathway through APC mutations is infrequent, but may be involved in the pathogenesis of a small subset of human lung carcinomas.

Adenocarcinoma↗
PubMed2004

Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas.

We carried out a population-based study on low-grade diffuse gliomas in the Canton of Zurich, Switzerland (population 1.16 million). From 1980 to 1994, 987 astrocytic and oligodendroglial tumors were diagnosed, of which 122 (12.4%) were low-grade (WHO grade II). The incidence rates adjusted to the World Standard Population, per million population per year, were 2.28 for low-grade diffuse astrocytomas, 0.89 for oligoastrocytomas, and 2.45 for oligodendrogliomas. The survival rate (mean follow-up 7.5+/-4.8 years) was highest for patients with oligodendroglioma (78% at 5 years, 51% at 10 years), followed by those with oligoastrocytoma (70% at 5 years, 49% at 10 years) and fibrillary astrocytoma (65% at 5 years, 31% at 10 years). Survival of patients with gemistocytic astrocytoma was poor, with survival rates of 16% at 5 years and 0% at 10 years. Younger patients (<50 years) survived significantly longer than older patients (>50 years; P=0.013). DNA sequencing, performed in 84% of cases, revealed that TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but were infrequent (13%) in oligodendrogliomas. The presence of TP53 mutations was associated with shorter survival of patients with low-grade diffuse gliomas (log-rank test; P=0.047), but when each histological type was analyzed separately, an association was observed only for oligoastrocytoma ( P=0.05). Loss on 1p and 19q were assessed by quantitative microsatellite analysis in 67% of cases. These alterations were frequent in oligodendrogliomas (1p, 57%; 19q, 69%), less common in oligoastrocytomas (1p, 27%; 19q, 45%), rare in fibrillary astrocytomas (1p, 7%; 19q, 7%), and absent in gemistocytic astrocytomas. None of these alterations were predictive of survival. These results establish the frequency of key genetic alterations in low-grade diffuse gliomas at a population-based level. Multivariate Cox's regression analysis indicates that only age and histological type, but not genetic alterations, are significant predictive factors.

Age Factors↗
PubMed2004

Molecular pathogenesis of astrocytic tumours.

Our current knowledge of the molecular pathogenesis of the diffuse adult astrocytic tumours is vast if compared to 20 years ago, yet we are far from understanding the details of this process at the molecular level and using such an understanding to logically and specifically treat patients' tumours. In other astrocytic tumours we have little or no knowledge of the molecular processes. This article will attempt to summarise the histological classification criteria and genetic data for all the astrocytic tumours. The current World Health Organisation classification lists six entities, some with subgroups. Common problems associated with the diagnosis of these tumours are outlined. While the molecular findings are not as yet used clinically, we are approaching a time when the histological investigation will have to be supplemented with molecular data to ensure the best choice of treatment for the patient and as an accurate indicator of prognosis.

Adult↗
PubMed2004

Predominant expression of mutant EGFR (EGFRvIII) is rare in primary glioblastomas.

EGFR amplification is a frequent genetic alteration in primary (de novo) glioblastomas, and is often associated with structural alterations. Most common is variant III (EGFRvIII), which results from a non-random 801 bp in-frame deletion of exons 2 to 7 of the EGFR gene. We assessed amplification and overexpression of EGFRvIII and wild-type EGFR in 30 glioblastoma biopsies. Immunohistochemically, EGFR overexpression was observed in 20 (67%) of 30 glioblastomas. Eight (27%) cases also showed immunoreactivity to an EGFRvIII antibody. In 6 of these cases, the pattern of EGFR and EGFRvIII overexpression was compared in serial sections: In 4 cases, areas with immunoreactivity to EGFRvIII largely coincided with wild-type EGFR expression. In the other 2 cases, the areas immunoreactive to EGFRvIII were significantly less extensive than EGFR-positive areas. To assess whether EGFRvIII is predominantly amplified in tumors with concurrent wild-type EGFR amplification, we carried our real-time quantitative PCR using 2 sets of primers located in exon 2 and intron 15 of the EGFR gene. A > 5-fold ratio of relative copy numbers between intron 15 (present both in wild-type EGFR and EGFRvIII) and exon 2 (present only in wild-type EGFR, but missing in EGFRvIII) suggested predominant amplification of EGFRvIII in only 3 (10%) of 30 glioblastomas. The observation that intratumoral wild-type EGFR overexpression is often more extensive and that predominant amplification of EGFRvIII is a rare event would limit the effectiveness of therapeutic approaches based on selective targeting of EGFRvIII.

Adult↗
PubMed2004

Genetic and expression profiles of cerebellar liponeurocytomas.

Cerebellar liponeurocytoma, a rare, newly identified CNS neoplasm of adults, is characterized by advanced neuronal/neurocytic and focal lipomatous differentiation, low proliferative potential and a favorable clinical prognosis. Despite the different age distribution and benign biological behavior, the cerebellar liponeurocytoma shares several features with the cerebellar medulloblastoma, which may include an origin from the periventricular matrix of the fourth ventricle or the external granular layer of the cerebellum. To establish the genetic profile of cerebellar liponeurocytomas, we have formed an international consortium and collected tumor samples from 20 patients. DNA sequencing revealed TP53 missense mutations in 4 (20%) of 20 cerebellar liponeurocytomas, a frequency higher than in medulloblastomas. There was no case with PTCH, APC, or beta-catenin mutations, each of which may be present in subsets of medulloblastomas. Isochromosome 17q, a genetic hallmark of classic medulloblastomas, was not observed in any of the cases investigated by FISH analysis. cDNA array analyses were carried out on 4 cerebellar liponeurocytomas, 4 central neurocytomas, and 4 classic medulloblastomas. Cluster analysis of the cDNA expression data of 1176 genes grouped cerebellar liponeurocytomas close to central neurocytomas, but distinct from medulloblastomas. These results suggest cerebellar liponeurocytoma as a distinct tumor entity that is genetically different from medulloblastoma. Furthermore, the cDNA expression array data suggest a relationship to central neurocytomas, but the presence of TP53 mutations, which are absent in central neurocytomas, suggests that their genetic pathways are different.

Adult↗
PubMed2003

Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype.

A database has been created to collect information on families carrying a germ-line mutation in the TP53 gene and on families affected with Li-Fraumeni syndromes [Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL)]. Data from the published literature have been included. The database is available online at http://www.iarc.fr/p53, as part of the IARC TP53 Database. The analysis of the 265 families/individuals that have been included thus far has revealed several new findings. In classical LFS families with a germ-line TP53 mutation (83 families), the mean age of onset of breast cancer was significantly lower than in LFS families (16 families) without a TP53 mutation (34.6 versus 42.5 years; P = 0.0035). In individuals with a TP53 mutation, a correlation between the genotype and phenotype was found. Brain tumors were associated with missense TP53 mutations located in the DNA-binding loop that contact the minor groove of DNA (P = 0.01), whereas adrenal gland carcinomas were associated with missense mutations located in the loops opposing the protein-DNA contact surface (P = 0.003). Finally, mutations likely to result in a null phenotype (absence of the protein or loss of function) were associated with earlier onset brain tumors (P = 0.004). These observations have clinical implications for genetic testing and tumor surveillance in LFS/LFL families.

Adolescent↗