Thema: Genveränderungen bei Gliomen

GLIOMA OF BRAIN, FAMILIAL

Victor A. McKusick

A number sign (#) is used with this entry because gliomas have been associated with abnormalities in several chromosomal regions or individual genes, including GAC1 (605492) on 1q32.1, PPARG (601487) on 3p25, EGFR (131550) on 7p12.3-p12.1, LGI1 (604619) on 10q24, PTEN (601728) on 10q23.31, GLTSCR1 (605690) and GLTSCR2 (605691) on 19q13.3, GAS41 (602116) on 12q13-q15, GLI (165220) on 12q13.2-13.3, p15 (600431) and p16/p14 (600160) on 9p, and loci at 15q23-q26.3 (607248), 17p13.3, and 14q.

DESCRIPTION
Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas (131445). See also subependymomas (600139).

Gliomas are known to occur in association with several well-defined hereditary tumor syndromes such as neurofibromatosis-1 (NF1; 162200) and NF2 (101000), tuberous sclerosis (TS; 191100), Li-Fraumeni syndrome (151623), and Turcot syndrome (276300). Familial clustering of gliomas often occurs in the absence of these tumor syndromes, however.

Large germline deletions at the INK4 (600160) tumor suppressor region involving the p16, p15, and p14 genes have been found in some families featuring both gliomas and skin melanomas (155755).

INHERITANCE
King and Eisinger (1966) described glioma multiforme of the frontal lobes in father and daughter with development of symptoms at age 50 and 34 years, respectively. Armstrong and Hanson (1969) described 3 sibs who died of brain glioma in adulthood. In a study of cancer mortality during childhood in sibs, Miller (1971) found 8 pairs of nontwin sibs with brain tumor versus 0.9 expected. There were 8 other families versus 0.9 expected in which 1 child died of brain tumor and another died of cancer of bone or muscle. Thuwe et al. (1979) observed 6 cases of brain glioma and a possible seventh on an isolated Swedish coastal island. The affected persons were related as cousins, all in different sibships. One instance of parental consanguinity, the lack of parent-child transmission, and the longtime isolation of the population suggest recessive inheritance. In further studies in this island community, Thuwe (1984) reported 4 closely related cases of brain tumor. It was found that 30 probands with brain tumor were more often the product of a consanguineous marriage than were controls and a higher proportion could be traced to a common ancestor living in the 1600s. It was concluded that genetic factors play a role, although a single major gene seemed unlikely. Schianchi and Kraus-Ruppert (1980) described affected father and son.

In a highly inbred Arab family in Israel, Chemke et al. (1985) observed 5 cases of glioblastoma multiforme in 2 sibships. Curiously, all were male and in all the tumor was located on the right side of the brain. The ages of presentation ranged from 4 to 11 years. ´Astrocytoma type 3´ was the histologic diagnosis.

Leblanc et al. (1986) described father and son operated on at ages 26 and 37 years, respectively, for mixed oligodendrocytic-astrocytic glioma. Heuch and Blom (1986) reported glioblastoma multiforme in 2 brothers, aged 65 and 68 years, and in their paternal aunt, aged 81. The father had died of tuberculosis before age 40. True multicentric origin, consistent with a hereditary basis, was observed in 1 of the 3 cases.

Tijssen (1987) referred to an international register of familial brain tumors maintained in Leyden. Vieregge et al. (1987) gave an extensive review of reported cases of familial glioma with or without other malformations. They reported a family in which members of several generations had one or another abnormality: father and son had glioma; another man and his daughter had colonic polyps; and skeletal abnormalities in the form of short stature and exostoses were present in some members. Munoz et al. (1988) described a brother and sister without a history of phacomatosis or cerebral tumors who developed malignant tumors with ependymal and choroidal differentiation. The girl presented at 28 months with a tumor of the posterior fossa, and the boy presented at 15 months with a tumor of the left cerebral hemisphere. Duhaime et al. (1989) reported histologically identical glioblastoma multiforme in 2 sibs, aged 2 and 5 years old, whose symptoms developed simultaneously.

On the basis of segregation analyses in families with multiple glioma patients, autosomal recessive and multifactorial mendelian models have been suggested (Malmer et al., 2001; de Andrade et al., 2001).

DIAGNOSIS
Marie et al. (2001) found that OLIG2 (606386) expression was upregulated in neoplastic oligodendrocytes, but not in neoplastic astrocytes or in other brain tumor cells, and suggested its use as a specific marker in the diagnosis of oligodendroglial tumors.

Prenatal Diagnosis
The case of prenatal diagnosis ascertained via ultrasound reported by Geraghty et al. (1989) illustrated the occurrence of glioblastoma multiforme in the fetus.

MAPPING
Chromosome 7
In a series of human glioblastoma cell lines, Henn et al. (1986) found that the most striking and consistent chromosomal finding was an increase in copy number of chromosome 7. In all of the cell lines, ERBB-specific mRNA (EGFR; 131550) was increased to levels even higher than expected from the number of chromosomes 7 present. These changes were not found in benign astrocytomas. Previously, Downward et al. (1984) presented evidence that oncogene ERBB may be derived from the gene coding for EGFR.

Bigner et al. (1988) determined that double minute chromosomes, indicating the presence of gene amplification, are found in about 50% of malignant gliomas. Most tumors with double minute chromosomes contain 1 of 5 amplified genes, most often the EGFR gene on chromosome 7. Following up on the observation that the EGFR gene is amplified in 40% of malignant gliomas, Wong et al. (1992) characterized the rearrangements in 5 malignant gliomas. In one they found deletion of most of the extracytoplasmic domain of the receptor. The 4 other tumors had internal deletions of the gene.

Chromosome 10
Bigner et al. (1988) concluded that the most frequent chromosomal changes in malignant gliomas are gains of chromosome 7 and losses of chromosome 10. Loss of 1 copy of chromosome 10 is a common event in high-grade gliomas. Rearrangement and loss of at least some parts of the second copy, especially in the 10q23-q26 region, has been demonstrated in approximately 80% of glioblastoma multiforme tumors (Bigner and Vogelstein, 1990).

Chromosome 10 was implicated in glioblastoma multiforme by Fujimoto et al. (1989), who found loss of constitutional heterozygosity in tumor samples from 10 of 13 patients in whom paired tumor and lymphocyte DNA samples were screened. In a search for submicroscopic deletions in chromosome 10, Fults and Pedone (1993) performed a RFLP analysis in 30 patients, using markers that had been mapped accurately on chromosome 10 by genetic linkage studies. Loss of heterozygosity (LOH) at one or more loci was found in 15 of the 30 patients. In 7 cases, LOH was found at every informative locus. LOH was confined to a portion of the long arm in 6 patients; the smallest region of overlap among these 6 deletions was flanked by markers D10S12 proximally and D10S6 distally, a 33.4-cM region mapped physically near the telomere, 10q25.1-qter.

Karlbom et al. (1993) analyzed a panel of glial tumors consisting of 11 low-grade gliomas, 9 anaplastic gliomas, and 29 glioblastomas for loss of heterozygosity by examining at least one locus for each chromosome. The frequency of allele loss was highest among the glioblastomas, suggesting that genetic alterations accumulate during glial tumor development. The most common genetic alteration was found to involve allele losses of chromosome 10 loci, these being found in all glioblastomas and in 3 anaplastic tumors. Deletion mapping analysis revealed partial loss of chromosome 10 in 8 glioblastomas and 2 anaplastic tumors in 3 distinct regions: one telomeric region on 1p and both telomeric and centromeric locations on 10q. These data suggested to Karlbom et al. (1993) the existence of multiple chromosome 10 tumor suppressor gene loci whose inactivation is involved in the malignant progression of glioma. In studies of 20 gliomas with microsatellite markers from chromosome 10, the locus that exhibited the most loss (69%) was the region bordered by D10S249 and D10S558 and inclusive of D10S594, with a linkage distance of 3 cM (Kimmelman et al., 1996). This region was known to be deleted in various grades of tumor, including low- and high-grade tumors. Kimmelman et al. (1996) suggested that chromosome region 10p15 is involved in human gliomas of diverse grades and that this region may harbor genes important in the development of and progression to the malignant phenotype.

See the DMBT1 gene (601969), so designated for ´deleted in malignant brain tumors,´ for a discussion of a gene on 10q25.3-q26.1 that showed intragenic homozygous deletions in medulloblastoma and glioblastoma multiforme tumor tissue and in brain tumor cell lines (Mollenhauer et al., 1997). Chernova et al. (1998) isolated a novel gene on 10q24, ´leucine-rich gene, glioma-inactivated-1´ (LGI1; 604619), which was rearranged as a result of a t(10;19)(q24;q13) balanced translocation in a glioblastoma cell line. See also the PTEN gene (601728) on 10q23.31 in which Staal et al. (2002) identified a mutation in a patient with oligodendroglioma.

Chromosome 17p
El-Azouzi et al. (1989) described loss of constitutional heterozygosity for markers on the short arm of chromosome 17 in both low-grade and high-grade malignant astrocytomas, suggesting that this region may contain a tumor suppressor gene associated with the early events in tumorigenesis. Chattopadhyay et al. (1997) identified a locus at 17p13.3, independent of the p53 locus, as a genetic link in glioma tumor progression. Jin et al. (2000) provided further evidence of a glioma tumor suppressor gene distinct from p53 at 17p.

Chromosome 9p
Bigner et al. (1988) found chromosome abnormalities in 12 of 54 malignant gliomas. Structural abnormalities of 9p and 19q were increased to a statistically significant degree. Olopade et al. (1992) found molecular evidence of deletion in 9p in 10 of 15 glioma-derived cell lines and 13 of 35 primary gliomas. The shortest region of overlap of these deletions mapped to the interval between the centromeric end of the interferon gene cluster and the methylthioadenosine phosphorylase locus (156540). Simons et al. (1999) used representational difference analysis (RDA) of a human glioblastoma xenograft to isolate 5 tumor-associated homozygously deleted DNA fragments, all originating from the 9p21 region. Subsequent analysis of a series of 10 glioblastomas using the newly isolated RDA fragments in conjunction with a series of known 9p21 DNA markers revealed homozygous deletions in 9 of the 10 tumors. These deletions encompassed the p15 (CDKN2B; 600431) and p14/p16 (CDKN2A; 600160) complex and 2 additional putative tumor suppressor loci. The RDA fragments corresponded to the latter 2 loci. Taken together, these results suggested the involvement of multiple tumor suppressor genes from the 9p21 region in glioblastoma tumorigenesis.

Chromosomes 19 and 1
To evaluate whether loss of chromosome 19 alleles is common in glial tumors of different types and grades, von Deimling et al. (1992) performed Southern blot RFLP analysis for multiple chromosome 19 loci in 122 gliomas from 116 patients. In 29 tumors, loss of constitutional heterozygosity of 19q was demonstrated; 4 tumors had partial deletion of 19q. The results were interpreted as indicating the presence of a glial tumor suppressor gene on 19q.

Smith et al. (2000) generated a complete transcript map of a 150-kb interval of chromosome 19q13.3, in which allelic loss is a frequent event in human diffuse gliomas, and identified 2 novel transcripts, designated GLTSCR1 (605690) and GLTSCR2 (605691). Mutation analysis of the transcripts in this region in diffuse gliomas with 19q deletions revealed no tumor-specific mutations.

Hoang-Xuan et al. (2001) examined the molecular profile of 26 oligodendrogliomas (10 WHO grade II and 16 WHO grade III) and found that the most frequent alterations were loss of heterozygosity on 1p and 19q. These 2 alterations were closely associated, suggesting that the 2 loci are involved in the same pathway of tumorigenesis. Hoang-Xuan et al. (2001) also found that the combination of homozygous deletion of the P16/CDKN2A tumor suppressor gene, LOH on chromosome 10, and amplification of the EGFR oncogene was present at a higher rate than previously reported. A statistically significant exclusion was noted between these 3 alterations and the LOH on 1p/19q, suggesting that there are at least 2 distinct genetic subsets of oligodendroglioma. EGFR amplification and LOH on 10q were significant predictors of shorter progression-free survival (PFS), characterizing a more aggressive form of tumor, whereas LOH on 1p was associated with longer PFS.

Chromosome 14q
Hu et al. (2002) performed allelotype analysis on 17 fibrillary astrocytomas and 21 de novo glioblastoma multiforme and identified 2 common regions of deletions on 14q22.3-32.1 and 14q32.1-qter, suggesting the presence of 2 putative tumor suppressor genes.

PATHOGENESIS
Von Deimling et al. (1995) proposed a simplified model for the pathogenesis of human gliomas. Reviewing their work and that of others, they suggested 3 distinct pathways. The first pathway, which leads to pilocytic astrocytomas (WHO grade I), is caused by loss of heterozygosity for chromosome 17q, presumably unmasking mutations in the NF1 (162200) gene. The second pathway begins with LOH at 17p, unmasking mutations in p53 (191170) and leading to astrocytoma (WHO grade II). Further LOH at 13q, 19q and 9p, unmasking mutations in RB1, p16 and p15, provides a further step on the second pathway, giving rise to grade III astrocytomas. The final step on the second pathway, LOH on chromosome 10 and perhaps other chromosomes, culminates in glioblastoma multiforme type 1 (WHO grade IV). The third independent pathway begins with LOH at chromosomes 10 and 9p, followed by gene amplification of EGFR, CDK4 (123829), MDM2 (164785), and SAS (181035), and culminating in glioblastoma multiforme type 2 (WHO grade IV).

MOLECULAR GENETICS
Ueki et al. (1997) studied gliomas for tumor-specific alterations in the ANOVA gene (601991), which they cloned from the glioma candidate region at 19q13.3. They found no alterations of ANOVA in gliomas by Southern blotting and SSCP analysis, suggesting that ANOVA is not the chromosome 19q glioma tumor suppressor gene.

Bogler et al. (1995) reviewed the role of the p53 tumor protein gene (191170) in the initiation and progression of human gliomas. Tachibana et al. (2000) examined genomic DNA from 15 glioma patients with a family history of brain tumors for mutations in the p53, PTEN (601728), p16/CDKN2A (600160), and CDK4 (123829) genes, using direct sequencing and FISH analysis. Mutations were identified in 2 cases. A p53 germline point mutation was identified in 1 family with some findings of Li-Fraumeni syndrome (151623), and a hemizygous germline deletion of the p16/CDKN2A tumor suppressor region was demonstrated in 1 family with a history of both astrocytoma and melanoma. The authors concluded that point mutations of p53 and hemizygous deletions and other rearrangements of the p16/CDKN2A tumor suppressor region may be responsible for some familial glioma cases. Pollack et al. (2002) found that overexpression of p53 in malignant gliomas during childhood is strongly associated with an adverse outcome, independently of clinical prognostic factors and histologic findings.

Zhou et al. (2000) sought to determine if somatic high penetrance mutations in the PPAR-gamma gene (601487) play a role in glioblastoma multiforme. No somatic high penetrance mutations were found in 96 patients with sporadic glioblastoma. However, polymorphisms in this gene (601487.0002 and 601487.0010) were overrepresented in American patients with glioblastoma, but not in German patients.

Staal et al. (2002) described a 38-year-old male who presented with focal seizures of the right arm and dysphasia in 1981. In 1985, he was found to have a meningioma (607174), which was removed completely. A low-grade glioma of the left frontal lobe was detected in 1990 and operated on in 1993 with subsequent radiotherapy. The tumor was classified as an anaplastic oligodendroglioma. By 1998, regrowth of the tumor had occurred and the diagnosis was again anaplastic oligodendroglioma. In the patient, Staal et al. (2002) identified a heterozygous germline mutation of the PTEN gene (601728) that resulted in an arg234-to-gln (R234Q; 601728.0029) substitution, without loss of heterozygosity in tumor DNA. The patient did not show any of the clinical signs of Cowden disease (CD; 158350) or other hereditary diseases typically associated with PTEN germline mutations.

Hamilton et al. (1995) found that glioblastoma multiforme is a feature of the form of Turcot syndrome (276300) due to defects in the mismatch repair genes MLH1 (120436) or PMS2 (600259).

OTHER FEATURES
Cartron et al. (2002) examined the expression of BAX (600040) in 55 patients with glioblastoma multiforme. The authors identified a novel form of BAX, designated BAX-psi, which was present in 24% of the patients. BAX-psi is an N-terminal truncated form of BAX which results from a partial deletion of exon 1 of the BAX gene. BAX-psi and the wildtype form, BAX-alpha, are encoded by distinct mRNAs, both of which are present in normal tissues. Glial tumors expressed either BAX-alpha or BAX-psi proteins, an apparent consequence of an exclusive transcription of the corresponding mRNAs. The BAX-psi protein was preferentially localized to mitochondria and was a more powerful inducer of apoptosis than BAX-alpha. BAX-psi tumors exhibited slower proliferation in Swiss nude mice, and this feature could be circumvented by the coexpression of the BCL2 (151430) transgene, the functional antagonist of BAX. The expression of BAX-psi correlated with a longer survival in patients (18 months versus 10 months for BAX-alpha patients). The authors hypothesized a beneficial involvement of the psi variant of BAX in tumor progression.

ANIMAL MODEL
Holland et al. (2000) transferred, in a tissue-specific manner, genes encoding activated forms of Ras (190070) and Akt (164730) to astrocytes and neural progenitors in mice. They found that although neither activated Ras nor Akt alone was sufficient to induce glioblastoma multiforme formation, the combination of activated Ras and Akt induced high-grade gliomas with the histologic features of human GBMs. These tumors appeared to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs, and Holland et al. (2000) demonstrated that AKT activity is increased in most of these tumors, implying that combined activation of these 2 pathways accurately models the biology of this disease.

Gutmann et al. (2002) generated a transgenic mouse model that targeted an activated Ras molecule to astrocytes, resulting in high-grade astrocytoma development in 3 to 4 months. They used high-density oligonucleotide arrays to perform gene expression profiling on cultured wildtype mouse astrocytes, non-neoplastic transgenic astrocytes, and neoplastic astrocytes. The authors identified changes in different groups of genes, including those associated with cell adhesion and cytoskeleton-mediated processes, astroglial-specific genes, growth regulation and, in particular, a reduced expression of GAP43 (162060), suggesting that it regulates growth in astrocytes.

SEE ALSO
Bigner et al. (1988); de Tribolet et al. (1979); Haley et al. (1969); Isamat et al. (1974); Kjellin et al. (1960); Koch and Waldbaur (1981); Parkinson and Hall (1962); Reese et al. (1944); Von Motz et al. (1977)

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CONTRIBUTORS
Cassandra L. Kniffin - updated : 12/6/2002
Cassandra L. Kniffin - updated : 11/13/2002
George E. Tiller - updated : 10/17/2002
Cassandra L. Kniffin - reorganized : 9/26/2002
Cassandra L. Kniffin - updated : 9/26/2002
Victor A. McKusick - updated : 8/23/2002
Cassandra L. Kniffin - updated : 5/29/2002
Victor A. McKusick - updated : 2/28/2002
Michael J. Wright - updated : 7/23/2001
Sonja A. Rasmussen - updated : 10/12/2000
Ada Hamosh - updated : 4/28/2000
Victor A. McKusick - updated : 1/19/2000
Orest Hurko - updated : 4/6/1998
Victor A. McKusick - updated : 9/12/1997
Victor A. McKusick - updated : 9/2/1997

CREATION DATE
Victor A. McKusick : 6/4/1986

EDIT HISTORY
carol : 5/16/2003
cwells : 12/9/2002
ckniffin : 12/6/2002
tkritzer : 12/2/2002
cwells : 11/26/2002
ckniffin : 11/13/2002
cwells : 10/17/2002
ckniffin : 10/3/2002
carol : 9/26/2002
carol : 9/26/2002
ckniffin : 9/20/2002
mgross : 8/23/2002
carol : 6/3/2002
ckniffin : 5/29/2002
cwells : 5/29/2002
cwells : 3/1/2002
terry : 2/28/2002
alopez : 7/27/2001
terry : 7/23/2001
terry : 6/4/2001
mcapotos : 10/13/2000
mcapotos : 10/12/2000
alopez : 5/1/2000
terry : 4/28/2000
mcapotos : 1/21/2000
terry : 1/19/2000
carol : 12/17/1998
carol : 6/22/1998
terry : 4/6/1998
terry : 9/12/1997
jenny : 9/3/1997
terry : 9/2/1997
mark : 2/18/1997
terry : 2/6/1997
terry : 6/26/1996
terry : 6/21/1996
mark : 3/26/1996
terry : 3/21/1996
mark : 5/15/1995
mimadm : 9/24/1994
terry : 4/27/1994
pfoster : 2/18/1994
carol : 11/12/1993
carol : 10/29/1993

Copyright © 1966-2003 Johns Hopkins University

Hallo Tom,
die Ausführungen in diesem Artikel sind sehr interessant
(zumindest so weit ich sie verstanden habe).
Aus welcher Quelle stammt der Artikel?
Ich selbst gehöre ja zu so einem siblings-Fall.
Über eine Antwort würde ich mich freuen.

Grüße aus Köln

Christine