Molecular genetic studies on gliomas and capillary hemangioblastomas of the central nervous system
Author: Reifenberger, Guido
Date: 1996-05-10
Location: Radiumhemmets föreläsningssal, Karolinska sjukhuset
Time: 9.15
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
Abstract
The molecular genetic alterations associated with the initiation and progression of central nervous system tumors are complex and poorly understood at present. This thesis aims at the further elucidation of the molecular genetics of two important types of central nervous system tumors: gliomas and capillary hemangioblastomas. Gliomas are the most common primary central nervous system tumors and comprise astrocytic tumors (including the glioblastoma), oligodendroglial tumors, mixed gliomas, and ependymomas. The vast majority of gliomas cannot be cured by the presently available therapeutic options. Thus the prognosis for most glioma patients is still poor. In contrast, capillary hemangioblastomas are generally benign tumors of uncertain histogenesis. They occur either in patients with von Hippel-Lindau syndrome or, more frequently, as solitary sporadic lesions without any hereditary predisposition. In spite of their biologically benign nature, both sporadic and hereditary capillary hemangioblastomas are associated with a significant mortality rate.
The first part of the molecular studies on gliomas consists of the analysis of 157 primary brain tumors (150 gliomas and 7 primitive neuroectodermal tumors) for amplification and expression of the MDM2 (murine double minute 2) gene. MDM2 codes for a protein that can complex the p53 tumor suppressor gene product and inhibit its function. We found MDM2 amplification and overexpression in 8 - 10% of glioblastomas and anaplastic astrocytomas. Sequencing of the p53 transcripts from exon 2 to 10 in the cases with MDM2 amplification revealed no mutations and restriction fragment length polymorphism analysis showed, with one exception, no losses of alleles on chromosome 17. Thus, MDM2 amplification appears to be an alternative mechanism to p53 mutation by which a subset of human malignant gliomas escapes from p53-regulated growth control.
We then analyzed an extended series of 234 brain tumors, including 218 gliomas, for amplification and overexpression of 9 different gene loci located close to MDM2 at 12ql3-ql5. Amplification of one or more of these loci was found in about 15% of anaplastic astrocytomas and glioblastomas. Detailed mapping of the individual amplicons combined with mRNA expression analysis of the amplified genes showed that CDK4 (cyclin dependent kinase 4) and SAS (sarcoma amplified sequence) were the most frequently amplified genes (18/19 cases). MDM2 was co-amplified in 11 tumors and was the only amplified gene in one glioblastoma. Our data implicate CDK4, SAS and MDM2 as the targets for the amplification events at 12ql3-ql5 in malignant gliomas.
In a further study, 136 gliomas were analyzed for loss of heterozygosity at 16 polymorphic loci from both arms of chromosome 12. Allelic loss on 12 was found in only 16% of the tumors. However, a significant association between amplification of genes from 12ql3-ql5 and loss of alleles from 12q was found. This finding supports a model considering chromosome breakage and deletion as important events in the development of gene amplification.
In order to characterize the genetic alterations in oligodendroglial tumors and mixed gliomas, a comprehensive allelotyping and amplification screening was performed on a series of 37 cases (21oligodendroglial tumors and 16 mixed gliomas). All chromosomal arms were examined for allelic loss by restriction fragment length polymorphism analysis and/or densitometric evaluation of l 85loci. These studies showed that initial alterations in oligodendroglial tumors differ from astrocytomas and typically consist of loss of genetic information from l9q and lp. Anaplastic oligodendrogliomas showed an increased incidence of additional allelic losses, most frequently including loci on 9p and 10, and in individual cases amplification of proto-oncogenes. A further abnormality frequently found in both low-grade and anaplastic oligodendroglial tumors was overexpression of the epidermal growth factor receptor (EGFR) in the absence of EGFR gene amplification.
Molecular analysis of capillary hemangioblastomas revealed mutations of the von Hippel-Lindau tumor suppressor gene (VHL) in 10 of 20 tumors. In addition, we found a consistent co-expression of transforming growth factor alpha and epidermal growth factor receptor in capillary hemangioblastomas. Thus, our data implicate mutational inactivation of VHL as well as autocrine and/or juxtacrine growth stimulation via the epidermal growth factor receptor as molecular mechanisms involved in the growth of capillary hemangioblastomas.
The first part of the molecular studies on gliomas consists of the analysis of 157 primary brain tumors (150 gliomas and 7 primitive neuroectodermal tumors) for amplification and expression of the MDM2 (murine double minute 2) gene. MDM2 codes for a protein that can complex the p53 tumor suppressor gene product and inhibit its function. We found MDM2 amplification and overexpression in 8 - 10% of glioblastomas and anaplastic astrocytomas. Sequencing of the p53 transcripts from exon 2 to 10 in the cases with MDM2 amplification revealed no mutations and restriction fragment length polymorphism analysis showed, with one exception, no losses of alleles on chromosome 17. Thus, MDM2 amplification appears to be an alternative mechanism to p53 mutation by which a subset of human malignant gliomas escapes from p53-regulated growth control.
We then analyzed an extended series of 234 brain tumors, including 218 gliomas, for amplification and overexpression of 9 different gene loci located close to MDM2 at 12ql3-ql5. Amplification of one or more of these loci was found in about 15% of anaplastic astrocytomas and glioblastomas. Detailed mapping of the individual amplicons combined with mRNA expression analysis of the amplified genes showed that CDK4 (cyclin dependent kinase 4) and SAS (sarcoma amplified sequence) were the most frequently amplified genes (18/19 cases). MDM2 was co-amplified in 11 tumors and was the only amplified gene in one glioblastoma. Our data implicate CDK4, SAS and MDM2 as the targets for the amplification events at 12ql3-ql5 in malignant gliomas.
In a further study, 136 gliomas were analyzed for loss of heterozygosity at 16 polymorphic loci from both arms of chromosome 12. Allelic loss on 12 was found in only 16% of the tumors. However, a significant association between amplification of genes from 12ql3-ql5 and loss of alleles from 12q was found. This finding supports a model considering chromosome breakage and deletion as important events in the development of gene amplification.
In order to characterize the genetic alterations in oligodendroglial tumors and mixed gliomas, a comprehensive allelotyping and amplification screening was performed on a series of 37 cases (21oligodendroglial tumors and 16 mixed gliomas). All chromosomal arms were examined for allelic loss by restriction fragment length polymorphism analysis and/or densitometric evaluation of l 85loci. These studies showed that initial alterations in oligodendroglial tumors differ from astrocytomas and typically consist of loss of genetic information from l9q and lp. Anaplastic oligodendrogliomas showed an increased incidence of additional allelic losses, most frequently including loci on 9p and 10, and in individual cases amplification of proto-oncogenes. A further abnormality frequently found in both low-grade and anaplastic oligodendroglial tumors was overexpression of the epidermal growth factor receptor (EGFR) in the absence of EGFR gene amplification.
Molecular analysis of capillary hemangioblastomas revealed mutations of the von Hippel-Lindau tumor suppressor gene (VHL) in 10 of 20 tumors. In addition, we found a consistent co-expression of transforming growth factor alpha and epidermal growth factor receptor in capillary hemangioblastomas. Thus, our data implicate mutational inactivation of VHL as well as autocrine and/or juxtacrine growth stimulation via the epidermal growth factor receptor as molecular mechanisms involved in the growth of capillary hemangioblastomas.
Issue date: 1996-04-19
Publication year: 1996
ISBN: 91-628-2019-2
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