ASTROCYTOMA, INCLUDED
GLM1 GLIOMA OF BRAIN, FAMILIAL, INCLUDED
SUBEPENDYMOMA, INCLUDED
EPENDYMOMA, INCLUDED
OLIGODENDROGLIOMA, INCLUDED
GBM, INCLUDED
GLIOBLASTOMA MULTIFORME, INCLUDED
GLM, INCLUDED
Astrocytic tumor
Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, ependymomas, and subependymomas. Glial cells can show various degrees of differentiation even within the same tumor (summary by Kyritsis et al., 2010). ... Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, ependymomas, and subependymomas. Glial cells can show various degrees of differentiation even within the same tumor (summary by Kyritsis et al., 2010). Ependymomas are rare glial tumors of the brain and spinal cord (Yokota et al., 2003). Subependymomas are unusual tumors believed to arise from the bipotential subependymal cell, which normally differentiates into either ependymal cells or astrocytes. They were characterized as a distinct entity by Scheinker (1945). They tend to be slow-growing, noninvasive, and located in the ventricular system, septum pellucidum, cerebral aqueduct, or proximal spinal cord (summary by Ryken et al., 1994). Gliomas are known to occur in association with several other well-defined hereditary tumor syndromes such as mismatch repair cancer syndrome (276300), melanoma-astrocytoma syndrome (155755), neurofibromatosis-1 (NF1; 162200) and NF2 (101000), and tuberous sclerosis (TSC1; 191100). Familial clustering of gliomas may occur in the absence of these tumor syndromes, however. - Genetic Heterogeneity of Susceptibility to Glioma Germline mutations predisposing to glioma have also been identified in the PTEN (601728) gene on chromosome 10q23.31 (GLM2; 613028) and in the BRCA2 gene (600185) on chromosome 13q12.3 (GLM3; 613029). Loci associated with susceptibility to glioma have been identified on chromosomes 15q23-q26.3 (GLM4; 607248), 9p21.3 (GLM5; 613030), 20q13.33 (GLM6; 613031), 8q24.21 (GLM7; 613032), and 5p15.33 (GLM8; 613033). Somatic mutation, disruption, or copy number variation of the following genes or loci may also contribute to the formation of glioma: ERBB (EGFR; 131550), ERBB2 (164870), LGI1 (604619), GAS41 (602116), GLI (165220), DMBT1 (601969), IDH1 (147700), IDH2 (147650), BRAF (164757), PARK2 (602544), TP53 (191170), RB1 (614041), PIK3CA (171834), 10p15, 19q, and 17p13.3.
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 ... 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.
Kyritsis et al. (1994) identified germline mutations in the TP53 gene (see, e.g., 191170.0042) in 6 of 19 patients with multifocal glioma, all of whom had a family history of cancer. In addition, germline TP53 mutations were found ... Kyritsis et al. (1994) identified germline mutations in the TP53 gene (see, e.g., 191170.0042) in 6 of 19 patients with multifocal glioma, all of whom had a family history of cancer. In addition, germline TP53 mutations were found in 3 of 19 patients with unifocal glioma and a family history of cancer. No mutations were detected in a patient with unifocal glioma and another malignancy or in 12 control patients with unifocal glioma and no second malignancies or family history of cancer. Patients with mutations were younger than other patients in the same group. Kyritsis et al. (1994) concluded that germline TP53 mutations are frequent in patients with multifocal glioma, glioma and another primary malignancy, and glioma associated with a family history of cancer, particularly if these factors are combined. Chen et al. (1995) found somatic mutations in the TP53 gene in 8 of 22 adult glioma tissue specimens and germline mutations in 2 of these 8 patients. Both patients with germline mutations developed glioblastoma multiforme before the age of 31, compared to the median age of greater than 50 for glioma patients. Family history was not available for these patients. TP53 mutations were not found in 16 glial tumors occurring in children or in benign meningiomas. The findings suggested that TP53 germline mutations may identify a subset of young adults predisposed to the development of high-grade astrocytic tumors. In a family in which several individuals had glioblastome multiforme and additional family members had multiple cancer types including some consistent with Li-Fraumeni syndrome (151623), Tachibana et al. (2000) identified a germline mutation in the p53 gene (R248Q; 191170.0010). The authors concluded that point mutations of p53 may be responsible for some apparent familial glioma cases. - Modifier Genes Among 254 patients with glioblastoma multiforme, El Hallani et al. (2009) found an association between a pro72 allele in the TP53 gene (191170.0005) and earlier age at onset. The pro/pro genotype was present in 20.6% of patients with onset before age 45 years compared to in 6.5% of those with onset after age 45 years (p = 0.002) and 5.9% among 238 controls (p = 0.001). The findings were confirmed in an additional cohort of 29 patients. The variant did not have any impact on overall patient survival. Analysis of tumor DNA from 73 cases showed an association between the pro allele and a higher rate of somatic TP53 mutations. - Somatic Mutations To identify the genetic alterations in glioblastoma multiforme (GBM), Parsons et al. (2008) sequenced 20,661 protein-coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, Parsons et al. (2008) found recurrent mutations in the active site of isocitrate dehydrogenase-1 (IDH1; 147700) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. Parsons et al. (2008) concluded that their studies demonstrated the value of unbiased genomic analyses in the characterization of human brain cancer and identified a potentially useful genetic alteration for the classification and targeted therapy of GBMs. Parsons et al. (2008) found that the hazard ratio for death among 79 patients with wildtype IDH1, as compared to 11 with mutant IDH1, was 3.7 (95% confidence interval, 2.1 to 6.5; p less than 0.001). The median survival was 3.8 years for patients with mutated IDH1, as compared to 1.1 years for patients with wildtype IDH1. Parsons et al. (2008) found that a majority of tumors analyzed had alterations in genes encoding components of each of the TP53 (191170), RB1 (614041), and PI3K (see 171834) pathways. The Cancer Genome Atlas Research Network (2008) reported the interim integrative analysis of DNA copy number, gene expression, and DNA methylation aberrations in 206 glioblastomas and nucleotide sequence alterations in 91 of the 206 glioblastomas. The authors found that p53 itself showed mutation or homozygous deletion in 35% of tumors and that there was altered p53 signaling in 87% of tumors, as demonstrated by homozygous deletion or mutations in CDKN2A (600160) in 49% of tumors, amplification of MDM2 (164785) in 14%, and amplification of MDM4 (602704) in 7%. The authors also observed that the RTK/RAS/PI3K signaling pathway was altered in 88% of glioblastomas. EGFR (131550) mutation or amplification was present in 45%, PDGFRA (173490) amplification was present in 13%, and MET (164860) amplification was present in 4%. (ERBB2 (164870) mutation was reported in 8%; in an erratum, the group stated that the somatic mutations reported in ERBB2 were actually an artifact of DNA amplification and were not validated in unamplified DNA.) Furthermore, NF1 (613113) was found to be an important gene in glioblastoma as mutation or homozygous deletion of the NF1 gene was present in 18% of tumors. Somatic mutation in the PI3K complex was frequently identified. In particular, novel somatic mutations were identified in the PIK3R1 gene (171833) that result in disruption of the important C2-iSH2 interaction between PIK3R1 and PIK3CA (171834). The RB signaling pathway was found to be altered in 78% of glioblastomas, with RB itself mutated in 11% of tumors. Of note, the Cancer Genome Atlas Research Network (2008) found a link between MGMT (156569) promoter methylation and hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas. The methylation status of MGMT predicts sensitivity to temozolomide, an alkylating agent used to treat glioblastoma patients. In those patients who also have mutation in the mismatch repair pathway, treatment with an alkylating agent was associated with characteristic C-G and A-T transitions in non-CpG sites, raising the possibility that patients who initially respond to treatment with alkylating agents may evolve not only treatment resistance but also a mismatch repair-defective hypermutator phenotype. Bredel et al. (2011) analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA (164008) and EGFR. They further studied the tumor suppressor activity of NFKBIA in tumor cell culture and compared the molecular results with the outcome of glioblastoma in 570 affected individuals. Bredel et al. (2011) found that NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. Bredel et al. (2011) suggested a 2-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase (156569) being strongly associated with the clinical course of the disease, and concluded that deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival. - Mutations in IDH1 and IDH2 Yan et al. (2009) determined the sequence of the IDH1 (147700) gene and related IDH2 (147650) gene in 445 CNS tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Yan et al. (2009) identified mutations that affected amino acid 132 of IDH1 in more than 70% of World Health Organization (WHO) grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wildtype IDH genes. Each of the 4 tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. Yan et al. (2009) concluded that mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas. De Carli et al. (2009) found that IDH1 mutations were more commonly found in adult patients with gliomas (38%; 155 of 404) compared to children with gliomas (5%; 4 of 73). No IDH2 mutations were found in 73 children with gliomas. IDH1 mutations in adults were significantly associated with lower tumor grade, increased survival, and younger age. Children with tumors bearing IDH1 mutations were older than children with mutation-negative tumors. The findings suggested that pediatric and adult gliomas differ biologically. In a retrospective study of 49 progressive astrocytomas, 42 (86%) of which had somatic mutations in the IDH1 gene, Dubbink et al. (2009) found that the presence of IDH1 mutations was significantly associated with increased patient survival (median survival, 48 vs 98 months), but did not affect outcome of treatment with temozolomide. Bralten et al. (2011) found that overexpression of IDH1-R132H in established glioma cell lines resulted in decreased proliferation and more contact-dependent cell migration compared to wildtype. Intracerebral injection of IDH1-R132H in mice, as compared to injection of wildtype, resulted in increased survival and even absence of tumor in 1 mouse. Reduced cellular proliferation was associated with accumulation of D-2-hydroxyglutarate that is produced by the R132H variant protein. The decreased proliferation was not associated with increased apoptosis, but was associated with decreased AKT1 (164730) activity. The findings indicated that R132H dominantly reduces aggressiveness of established glioma cell lines in vitro and in vivo. Bralten et al. (2011) noted that the findings were apparently contradictory because the presence of an IDH1 mutation was thought to contribute to tumorigenesis; the authors suggested that IDH1 mutations may be involved in tumor initiation and not in tumor progression. IDH1-mutant tumors are typically low-grade and often slow-growing. - 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. Using array CGH, Pfister et al. (2008) found that 30 (45%) of 66 low-grade pediatric astrocytomas contained a somatic copy number gain at chromosome 7q34 spanning the BRAF (164757) locus, among others. These changes were associated with increased BRAF mRNA, and further studies showed evidence for activation of the MAPK1 (176948) pathway and downstream targets, such as ERK1/2 (see, e.g., 176872) and CCND1 (168461). Four (6%) of the tumors had an activating BRAF somatic mutation (V600E; 164757.0001). Among 26 adult tumors, 16 (62%) had copy number gains of the BRAF locus. Other changes in the 66 pediatric tumors including large somatic trisomies of chromosomes 5 (6 of 66) and 7 (4 of 66). Initial in vitro pharmacologic studies suggested that inhibition of the MAPK pathway may be possible. Yu et al. (2009) found that 42 (60%) of 70 sporadic pilocytic astrocytomas had rearrangements of the BRAF gene. Two additional tumors with no rearrangement carried a BRAF mutation. Twenty-two of 36 tumors with BRAF rearrangements had corresponding amplification of the neighboring HIPK2 gene (606868). However, 14 of 36 tumors with BRAF rearrangement had no detectable HIPK2 gene amplification. Six of 20 tumors demonstrated HIPK2 amplification without apparent BRAF rearrangement or mutation. Only 12 (17%) of the 70 tumors lacked detectable BRAF or HIPK2 alterations. Yu et al. (2009) concluded that BRAF rearrangement represents the most common genetic alteration in sporadic pilocytic astrocytomas. - 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 (see GLM2, 613028). Nishimoto et al. (2001) mapped a repressor of telomerase expression (608045) to a 2.7-cM region on 10p15.1 by microcell-mediated chromosome transfer (MMCT) into a telomerase-positive cell line. Loss of chromosome 10 is frequent in malignant gliomas. These data prompted Leuraud et al. (2003) to investigate the specific relationship between telomerase reactivation and LOH on 10p15.1 in high-grade gliomas. Leuraud et al. (2003) analyzed a series of 51 high-grade gliomas for LOH on chromosome 10 and for telomerase activity. In univariate analysis, LOH on 10p, found in 59% of the gliomas, and LOH of 10q, found in 61%, were associated with telomerase activity. In the multivariate analysis, only LOH10p remained statistically related to telomerase activity, suggesting that the telomerase repressor gene located on 10p15.1 is inactivated in high-grade gliomas. - 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 (191170) 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. - Chromosomes 19 and 1 Bigner et al. (1988) found chromosome abnormalities in 12 of 54 malignant gliomas. Structural abnormalities of 9p (see GLM5, 613030) and 19q were increased to a statistically significant degree. 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. 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 blot and SSCP analysis, suggesting that ANOVA is not the chromosome 19q glioma tumor suppressor gene. Labussiere et al. (2010) found that 315 (41%) of 764 gliomas had somatic mutations in the IDH1 gene. All mutations were located at residue 132, and nearly 90% resulted in an arg132-to-his (R132H) substitution. Regarding 1p/19q status, 118 IDH1 mutations were found in the group of tumors with a true 1p/19q deletion (118 of 128; 92%). In contrast, only 32% (51 of 159) of the tumors with a false 1p/19q signature harbored an IDH1 mutation. Mutations in codon 172 of IDH2 were found in 16 (2.1%) of the gliomas, and all 10 tumors with a true 1p/19q signature and no IDH1 mutation contained an IDH2 mutation. No tumor had mutations in both IDH1 and IDH2. Patients with IDH1 or IDH2 mutations had better survival than those without these mutations, and those with IDH1 or IDH2 mutations and with complete 1p/19q codeletion had longer survival than those with the mutations alone. The findings indicated that IDH1/IDH2 mutation is a constant feature in gliomas with complete 1p/19q codeletion, suggesting a synergistic effect of these molecular changes. Bettegowda et al. (2011) performed exonic sequencing of 7 oligodendrogliomas. Among other changes, they found that the CIC gene (612082) (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in 6 cases and that the FUBP1 (603444) gene on chromosome 1p was somatically mutated in 2 tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. Bettegowda et al. (2011) concluded that their results suggested a critical role for these genes in the biology and pathology of oligodendrocytes. - 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.