CHROMOSOME 3 MAY HARBOR MULTIPLE TUMOR SUPPRESSOR GENES ASSOCIATED WITH PRIMARY GLIOBLASTOMA MULTIFORME

Glioblastoma multiforme (GBM), the most malignant type of glioma, is the most common primary brainneoplasm. Although comprehensive therapeutic measures are applied, the prognosis of GBM remains dismal with a median post-treatment survival of less than one year.Modern molecular genetics has demonstrated thatabnormal alterations of tumor suppressor genes (TSGs) and oncogenes are the major mechanisms responsible for the initiation and progression of this malignant tumor.Identifying of related…     

Infrequent Genetic Alterations of the PTEN/MMAC1 Gene in Japanese Patients with Primary Cancers of the Breast, Lung, Pancreas, Kidney, and Ovary

In the present study, we searched for genetic alterations of the entire coding region of PTEN/MMACl, a recently isolated candidate tumor suppressor gene, in 178 specimens from Japanese patients with various malignant tumors by the polymerase chain reaction-single strand conformation polymorphism method. The samples consisted of 11 glioblastoma multiformes (GBMs), 14 astrocytomas, 47 breast cancers, 25 non-small cell lung cancers, 9 small cell lung cancers, 8 pancreatic cancers, 24 renal cell carcinomas, 20 ovarian cancers, and 20 metastatic lung tumors from various organs. Only one somatic frameshift mutation at codon 319 was observed in one (9%) of eleven GBMs. Our results suggest that mutation of the PTEN/MMAC1 gene does not play a major role in carcinogenesis, at least in the tumor types from Japanese patients analyzed in this study.     

Analysis of mdm2 and p53 Gene Alterations in Glioblastomas and its Correlation with Clinical Factors

Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with probably prognostic implications. To elucidate the involvement of murine-double-minute (mdm)2 gene amplifications and mutations of the tumor suppressor gene p53 in the tumorigenesis of malignant gliomas we analyzed a series of 75 glioblastomas. The p53 mutations occur in one-third of glioblastomas, mdm2 amplifications were found in 13% of cases. Our analysis revealed a hot spot in the p53 gene locus in codon 156, the same point mutation was detected in 4 tumor samples. None of the mdm2 amplified tumors had p53 mutations, supporting the hypothesis, that mdm2 amplifications are alternative mechanisms for p53 inactivation. Patients with p53 mutated tumors were significantly younger characterized by a mean age of 44 years. Additionally association with longer overall survival could be detected for this subgroup of patients. In our study, survival estimation revealed a significant correlation of mdm2 gene amplification with shorter survival time, and support the hypothesis, that mdm2 oncogene activation appears to occur late in tumor progression and may be characteristic as negative prognostic marker.     

High dose radiation therapy in the treatment of malignant gliomas: final report.

One hundred patients with supratentorial malignant gliomas were prescribed to receive postoperative whole brain irradiation with doses ≥5000 rad; 41 had astrocytoma grade III and 59 had grade IV tumors. The median survival was 91 weeks for patients with grade III tumors and only 42 weeks for those with grade IV (p < 0.01). For both grades, patients who were ≤45 years of age survived significantly better than patients who were older at diagnosis (p < 0.05). Patients with tumors at each grade were divided into three groups depending on the total dose delivered to the tumor; 5000, 6000, 7500 rad (median doses).For patients with grade IV tumors the median survival was 30, 42 and 56 weeks respectively, these differences were significant (p < 0.05) between the extremes but not between consecutive dose groups and were maintained only up to 2 years from the initiation of treatment. For patients with grade III tumors, the median survival was 43, 82 and 204 weeks respectively; these differences were significant (p < 0.05) between consecutive dose groups and between extremes and were maintained up to 4 years from the initiation of treatment. For 22 patients with grade IV who were treated with high-doses (7500 rad), the median time for recurrence was 43 weeks while for six patients with grade III tumors it was 158 weeks.The use of higher radiation doses was well tolerated; it did not compromise the quality of survival, and did not yield normal brain tissue necrosis. However, these doses did not seem to alter the total survival of patients, nor did they seem capable of sterilizing these tumors. Histopathological changes that were observed in normal brain tissue that was irradiated with 7000–8000 rad suggest that increasing total doses beyond this range might attain tumor sterilization, but could also lead to frank radiation necrosis in these patients.     

Giganto-cellular glioblastoma of the lumbosacral spinal cord

Summary A case of giganto-cellular glioblastoma multiforme occurring in the lumbosacral spinal cord is described.Supported in part by US Public Health Grant NS06239 from the National Institute of Neurological Diseases and Stroke     

Glioblastoma in irradiated elderly patients: two case reports

We report our experience with two elderly patients with histologically proven diagnosis of glioblastoma multiforme who were treated 25 and 18 years earlier for tinea capitis and scalp cutaneous hemangioma respectively in the same areas where the glioblastoma multiforme had grown. These pathologies were benign, and nowadays can be treated with alternative approaches rather than radiotherapy. Radiotherapeutic treatment should be carefully considered before using it in young patients with benign pathologies who have a long life expectancy and subsequently a higher risk of developing radio-induced malignant lesions. Radio-induced gliomas are typical of patients younger than the ones with spontaneous glioblastomas; however, the subjects of our study were elderly (78 and 72 years).     

Super fractionation in glioblastoma multiforme-results of a phase II study

A suquential series of 30 patients who were referred to a cancer treatment hospital with glioblastoma multiforme were treated with superfractionated cobalt 60 y radiation, three treatments per day, 100 rad per fraction. Their survival was compared to that of a historical group of 90 patients who had been referred for the same disease. Survival of the study patients was significantly longer than the historical patients, both for those who underwent resection (48.6 weeks median survival vs. 35.1 weeks), and for those who did not (35.1 weeks vs. 11.7 weeks). A retrospective survey of the historical group led to the following conclusions about this group: 1. Survival for patients who were well enough to be referred was unchanged after steroids came into general use; 2. Younger patients (under 50 years) did not have a longer survival than older patients; 3. The size of the dose of irradiation did not affect survival over the range of doses employed; 4. The size of the treatment volume employed did not affect survival over the range of treatment volumes employed.     

Amplification and overexpression of epidermal growth factor receptor gene in glioblastomas of Chinese patients correlates with patient’s age but not with tumor’s clinicopathological pathway

It is believed that there are two distinct pathological pathways leading to the development of human glioblastomas (GBM) in Caucasian populations. Primary (de novo) GBM most often occurs in older individuals, and is characterized by the overexpression/amplification of epidermal growth factor receptor gene (EGFR), whereas secondary GBM, which progresses from a low-grade astrocytoma, often affects younger individuals and frequently contains the TP53 mutation. We and others have previously found that the age of onset of GBM in Chinese patients tends to be younger than that in Caucasian patients. To identify whether GBMs from Chinese patients share this common pattern of genetic alterations, expression levels of EGFR and TP53 and TP53 mutation were analyzed in 56 randomly selected Chinese GBMs (30 primary and 26 secondary), including 47 adult-onset and 9 pediatric GBMs. Consistent with other studies, overexpression/mutation of TP53 and aneuploid DNA content were more frequently detected in secondary GBMs of Chinese adult patients. In contrast to that observed in Caucasian patients, no significant difference was observed in the age distribution and the frequency of EGFR overexpression/amplification between primary and secondary GBMs in adult Chinese patients. Furthermore, the overexpression of EGFR was much higher in late-onset (age >45 years) GBMs (73%) than that in both early-onset (age 18–45 years) (17%) and pediatric (age <18 years) GBMs (11%), suggesting that overexpression of EGFR in Chinese GBMs may be associated closely with the patients age but not with the tumors pathological pathway.     

Mutation analysis of B-RAF gene in human gliomas

The RAS/RAF/MEK/ERK kinase pathway is pivotal in the transduction of mitogenic stimuli from activated growth factor receptors, which regulates cell proliferation, survival, and differentiation. Up-regulation of this pathway due to RAS mutations is found in approximately 30% of human tumors. Recently, activating mutations of B-RAF were identified in a large proportion of human cancers. Gliomas are the most frequent primary central nervous system tumors and the molecular mechanisms that underlie the development and progression of these tumors are far from being completely understood. The purpose of this study was to clarify the incidence of B-RAF mutations and their possible relation with tumor progression in a series of 82 human gliomas, including 49 astrocytic and 33 oligodendroglial tumors. The analysis of B-RAF hotspot regions, exons 11 and 15, showed presence of B-RAF mutations in only 2 out of 34 (6%) glioblastomas, and absence in the remaining histological types. Both mutations were located in the hotspot residue 600 (V600E) at exon 15, which leads to constitutive B-RAF kinase activity. These data suggest that activating mutations of B-RAF are not a frequent event in gliomas; nevertheless, when present they are associated with high-grade malignant lesions.The first two authors contributed equally to the present study     

Sudden unexpected death due to undiagnosed glioblastoma

Although glioblastomas are among the most common primary cerebral neoplasms, sudden death due to these tumors is an uncommon event. Due to the usual rapid increase in intracranial pressure, patients develop symptoms rather early, leading to medical attention in time. A search for cases of sudden unexpected death due to undiagnosed glioblastoma from a total of 14,482 cases from the archives of the Institute of Legal Medicine in Hamburg in the period of 1991–2003 revealed only one such case. Out of a total of 5,432 cases from the Institute of Neuropathology, Hamburg, during the same period, two further cases were found. A comprehensive literature review on cases of sudden death due to primary cerebral neoplasms published so far revealed a total of 83 cases with only ten cases of glioblastoma (12%), whereas 55 of these cases were due to histological benign tumors (66%).