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Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886 EISSN: 1998-4022
Vol. 53, Num. 2, 2005, pp. 140-148

Neurology India, Vol. 53, No. 2, April-June, 2005, pp. 140-148

Review Article

Oligodendrogliomas: Impact of molecular genetics on treatment

Department of Neuropathology, Charité University Medicine Berlin

Correspondence Address: Department of Neuropathology, Charité University Medicine Berlin, andreas.von_deimling@charite.de

Date of Acceptance: 21-Jan-2005

Code Number: ni05043

ABSTRACT

The interest in oligodendrogliomas has increased since it became evident that a subset of these tumors respond to chemotherapy or radiation. This interest was augmented when the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 was identified as a powerful prediction factor for response. Lack of stringent morphological criteria allow high-interobserver variation with regard to classification and grading of oligodendroglial tumors. The prospect of beneficial chemotherapy prompted neuropathologists to diagnose more 'oligodendroglioma' than before. Therefore, there is great demand for unambiguous classification of oligodendroglial tumors. Supplementary analysis of the integrity of chromosomal arms 1p and 19q may greatly assist diagnostic characterization of tumors with oligodendroglial phenotype. The underlying mechanisms for these deletions are not known. Tumor suppressor genes on 1p and 19q relevant for oligodendroglioma have not yet been identified. Knowledge of these genes and the mechanisms of their inactivation might help to understand why oligodendroglial tumors do respond better to chemotherapy and radiotherapy than astrocytomas. This review compiles clinical, pathological and molecular genetic findings on oligodendrogliomas and oligoastrocytomas of WHO Grades II and III to present a brief overview on recent developments.

Keywords: Oligodendroglioma, oligoastrocytoma, pathology, proto-oncogene, suppressor gene, tumor

Bailey et al . first described oligodendrogliomas and proposed a link between oligodendroglioma cells and oligodendrocytes based on morphologic similarities.[1],[2]

According to the WHO classification, oligodendrogliomas are diffusely infiltrating tumors and are divided into Grade II and anaplastic Grade III tumors.[3] Mixed gliomas or oligoastrocytomas are defined by the presence of both oligodendroglial and astrocytic components in the tumor tissue. Ambiguous data regarding the incidence of oligodendrogliomas have been published ranging between 5 and 19% of all intracranial gliomas.[4],[5],[6] Interestingly, the incidences of oligodendrogliomas seem to have increased over the last years reaching levels of up to 25% of all gliomas.[7] This is likely to be due to improvements in treatment for oligodendroglioma prompting neuropathologists to favor this diagnosis. The fraction of anaplastic tumors among oligodendrogliomas varies in the literature between 3.5[8] and 50%.[3],[9] The typical age of onset of oligodendroglioma is between 35 and 55 years peaking at 45 years.[4],[6] Oligodendrogliomas WHO Grade II often occurs in patients younger than 40 years, and anaplastic oligodendrogliomas WHO Grade III typically are seen in patients older then 40 years.[10] The ratio between men and women varies from 1.5 to 2.1.[4],[6]

The incidence of oligoastrocytomas differs in published studies between 23 and 19%[11] of intracranial gliomas.

The etiology of oligodendrogliomas is not clear. In single instances, oligodendrogliomas followed previous irradiation of pituitary adenoma,[12] cerebral contusions[13] or were observed in combination with multiple sclerosis.[14] Familial oligodendroglioma was reported in a few cases.[15],[16]

Neuropathology of oligodendroglial tumors

Morphology

The distribution between frontal, parietal, temporal, and occipital lobe approximates 3:2:2:1.[17] Rarely, oligodendroglial tumors affect the cerebellum, brain stem and spinal cord.[18] Oligodendrogliomas impose as soft, gelatinous grayish-pink colored masses with well-delineated borders. Calcification may appear as gritty texture in unfixed tissue. Hemorrhages are not uncommon in oligodendrogliomas. Necrosis occurs only in anaplastic oligodendrogliomas WHO Grade III.

Microscopically, oligodendrogliomas WHO Grade II are moderately cellular, monomorphous gliomas with rounded nuclei [Figure - 1]A: H&E. A characteristic artifact is clear cytoplasm (′honeycomb′appearance) following standard tissue preparation [Figure - 1]A: H&E. Calcification is frequent [Figure - 1]B - arrow. Typical are numerous delicate branching vessels with a ′chicken wire′ or ′retiform′appearance [Figure - 1]C: CD31. Perineuronal satellitosis, subpial, and perivascular tumor cell accumulation are frequent findings. GFAP-positive minigemistocytes can be found [Figure - 1]D: GFAP.

Diagnostic criterions for anaplasia are ill defined. Cell density is either focally or diffusely increased [Figure - 1]E: H&E. Cytology descriptions of the tumor cells range from atypical to frankly pleomorphic cells or even multinucleated giant cells [Figure - 1]F: H&E. Mitotic activity may be brisk [Figure - 1]F - arrow. Intratumoral vascular changes range from increased density of branching vessels to glomeruloid microvascular proliferation [Figure - 1]G: H&E and H: CD31. Both geographic necrosis and necrosis with perinecrotic pseudopallisading may occur.

Oligoastrocytomas or mixed gliomas exhibit oligodendrocytic and astrocytic components [Figure - 1]I: H&E - 1: oligodendroglial component, 2: astrocytic component]. Cut-off levels for the astrocytic tumor component have been suggested, ranging from 1 to 50%.[19],[20],[21] In general, the diagnosis of oligoastrocytoma strongly relies on personal thresholds for typing individual cells as astrocytic or oligodendroglial. A common problem is that the material seen by the neuropathologist is not representative of the entire tumor. Therefore, the diagnosis of oligoastrocytoma has one of the highest interobserver variations.

Immunohistochemical characteristics

There are no routine antibodies to positively identify oligodendrogliomas. Immunohistochemical examinations are useful for exclusion of other glioma entities. Specific proteins of mature and developing oligodendrocytes like myelin basic protein (MBP), galactocerebroside (GaLC), or Myelin-associated glycoprotein (MAG) are only inconsistently expressed in oligodendroglial tumor cells.[17] Recently, high-transcriptional activity of the oligodendrocyte lineage genes Olig-1 and Olig-2 encoding transcription factors expressed in early developmental and mature stages of oligodendrocytes was suggested for oligodendrogliomas, but not for astrocytomas by in situ hybridization.[22],[23] Meanwhile, multiple studies showed the expression of these transcription factors in both entities.[22],[24],[25],[26] Other oligodendrocytic linage markers like PDGF-R, PLP and NG2 failed to specifically label oligodendrogliomas.[17] Antibodies targeting glial fibrillary acid protein (GFAP) usually do not bind to oligodendroglial cells. However, so-called ′mini gemistocytes′seen in a fraction of oligodendrogliomas strongly express GFAP [Figure - 1]E. The antibody Mib1 that binds to Ki67 antigen is very useful in the assessment of proliferation. In many cases, less than 5% of tumor cells in oligodendroglioma WHO Grade II express Ki67.[3]

Therapy of oligodendroglial tumors

Surgery

The traditional treatment of oligodendroglioma was of gross total resection. This approach decompresses mass effect and prolongs survival. In addition, surgical specimens allow neuropathological evaluation with classification and grading of the tumor.

In most series, the outcome of patients with low-grade oligodendroglioma correlates with the extent of surgery.[4],[9],[27],[28],[29] However, one study found no difference in outcome between partial and gross total resection.[30] This notion may be supported by a recent study on patients with anaplastic oligodendroglioma treated with PCV (Procarbazine-Vincristine-CCNU) chemotherapy with no difference in outcome regardless of partial or gross total resection or biopsy only approach.[31]

Radiation therapy

Postsurgery radiation with 45-65 Gy is a common standard for anaplastic oligodendroglioma WHO Grade III.[32] Most authors found a clear benefit from radiation therapy.[33],[34],[35],[36],[37],[38] On the other hand, some investigators failed to demonstrate a significant effect of radiation on survival rate.[9],[39],[40],[41],[42] These differences may be due to the inclusion of patients with oligodendrogliomas regardless of histological tumor grading. In oligodendroglial tumors WHO Grade II, no major benefit by radiation therapy was reported by most studies.[9],[30],[43],[44],[45],[46],[47] However, a few series detected a moderate benefit for patients,[48],[49],[50] particularly in cases with subtotal surgical resection.[29],[51] It should be kept in mind that patients with oligodendroglial tumors do have a life expectancy of several years warranting great care to avoid radiation-induced lesions such as leukencephalopathy.[43] Therefore, it was recommended to delay radiation therapy in low-grade oligodendrogliomas until anaplastic transformation or tumor recurrence occurs.[52]

Chemotherapy

In 1988, Cairncross et al . reported the response of anaplastic oligodendroglioma to chemotherapy.[53] Later, PCV was identified as the most effective combination.[54] Approximately 75% of patients with anaplastic oligodendroglioma responded to PCV while 25% of patients did not benefit from this treatment.[55]

Oligoastrocytomas seem to respond to PCV therapy, too.[56],[57] Meanwhile, chemotherapy with PCV prior to irradiation therapy has been recommended for newly diagnosed and recurrent oligodendroglioma.[43] A novel drug introduced for treatment is Temozolomide, generally well tolerated and not associated with cumulative myelosuppression. However, up to now no phase III study compared the outcome of patients randomized for PCV or Temozolomide treatment.[58],[59],[60] Recently, it was recommended to use Temozolomide as the last option in patients with recurrent anaplastic oligodendrogliomas.[61] A recent report suggested treatment with Temozolomide for patients with oligodendroglioma WHO Grade II.[62]

Successful chemotherapy and prolonged survival are associated with an increased incidence of secondary leukemia.[63]

Up to now, no clinical or morphological features are known for identification of patients likely to respond to chemotherapy.[43]

Prognosis of oligodendroglial tumors

The prognosis of patients with oligodendroglial tumors varies due to different inclusion criteria for patients. The median postoperative survival time of oligodendrogliomas WHO Grade II ranged from 3.5[40] to 16.7 years.[64] The 5-year survival rate varies between 38[65] and 83%.[49] Progression to anaplasia does occur, but at lower frequency than in astrocytomas.[3]

The median postoperative survival of anaplastic oligodendrogliomas WHO Grade III ranged from 0.9[40] to 7.3 years.[28] The 5-year survival rate ranged from 23[40] to 66%.[66] Chemotherapy of anaplastic oligodendrogliomas has prolonged the median time to progression to 25 months for responders.[55],[66] The largest series reported that 50 of 93 patients with anaplastic oligodendrogliomas treated either by chemotherapy or radiation showed tumor progression after a median of 48 months.[28]

Only few data are available for low-grade oligoastrocytomas. The median postoperative survival times ranged from 3.9[11] to 6.3 years[9] with a 5-year survival rate of 58%.[9]

One study reported a median time of survival in anaplastic oligoastrocytomas similar to anaplastic astrocytomas and less of that in anaplastic oligodendrogliomas.[8]

Among the most exciting observations in oligodendrogliomas was the recognition of an association of allelic losses on chromosomal arms 1p and 19q and good response to chemotherapy.[66] In a series of 39 patients with anaplastic oligodendroglioma, nearly all of those 70% with positive response to PCV chemotherapy exhibited loss of heterozygosity (LOH) 1p/19q. A significant association between a poor outcome and homozygous loss of CDKN2Ap16 was observed.

Another study confirmed the association of LOH 1p/19q and prolonged overall survival in oligodendrogliomas WHO Grade II. No survival advantage for patients with oligoastrocytomas (19 cases) and glioblastomas with LOH 1p/19q were seen.[67] In contrast, two studies with low number of cases reported a positive association between LOH 1p/19q and response to chemotherapy in oligoastrocytomas[68] or oligoastrocytomas and glioblastomas.[69]

Oligodendrogliomas WHO Grade II can be separated in tumors with a more classical oligodendroglial and in tumors with a more astrocytic histological appearance. Indeed, genetic analyses demonstrated 1p loss in 19 of 22 classic oligodendrogliomas (86%) and maintenance of both 1p alleles in 16 of 22 gliomas with astrocytic features (73%).

Interestingly, the predictive quality regarding response to chemotherapy was lower for the two histologically defined groups than genetic analysis of LOH 1p.[70] Later, another study reported similar results by correlating histological features with the 1p/19q genotype and demonstrated an association between anaplastic features and loss of 9p or CDKN2A alterations.[71]

Further, LOH 1p was shown to be a predictor of progression-free survival for patients with oligodendrogliomas WHO Grades II and III that received both, PCV chemotherapy and radiotherapy.[72] Recently published data indicate a similar outcome for patients with 1p/19q LOH that were treated at the time of diagnosis with both PCV chemotherapy and radiotherapy, or only with chemotherapy.[73] To avoid neurotoxic side effects, the authors suggested delaying radiation therapy until tumor recurrence. Other studies support this positive correlation between LOH 1p/19q and survival.[60],[74],[75],[76],[77] In general, it was recommended to use PCV chemotherapy for patients with oligodendrogliomas exhibiting LOH 1p and to use radiation treatment for patients that retain both copies of chromosome 1p.[78] Negative molecular predictors for overall survival in anaplastic oligodendrogliomas were found to be CDKN2Ap16 deletions and LOH 10q.[66],[79],[80] In fact, these genetic alterations are typically seen in glioblastoma. However, only small groups of patients were analyzed.

Molecular pathology of oligodendroglial tumors

Allelic loss of chromosome 1p and 19q

The hallmark of oligodendrogliomas WHO Grade II is the combined allelic losses on the short arm of chromosome 1 (1p) and on the long arm of 19 (19q). These chromosomal alterations [Figure - 2] were found in up to 90% of oligodendrogliomas.[81],[82],[83],[84],[85] The high frequency of losses raises the possibility classifying oligodendrogliomas WHO Grade II by molecular alterations rather than by morphology. In anaplastic oligodendroglioma WHO Grade III, the frequency of LOH 1p/19q is lower. This might indicate either a broader spectrum of genetic alterations that induces these tumors or point toward more difficulties distinguishing anaplastic gliomas.[86] Usually a combined loss of both chromosomal arms is observed but LOH 1p alone is also seen in oligodendroglial tumors.[66] On the other hand, LOH 19q alone is a chromosomal alteration associated with the progression of astrocytic tumors.[87] No sequential pattern of losses can be seen (unpublished own data).

Recently, an association between 1p/19q LOH and extra-temporal location of anaplastic oligodendroglioma has been described. Tumors that retained both alleles predominantly localize to the temporal lobe. Bilateral growth of anaplastic oligodendrogliomas was linked to LOH 1p/19q.[88] In a larger series of tumors consisting of oligodendrogliomas and Oligoastrocytomas, a similar distribution was identified. In contrast, TP53 mutations were seen mostly in temporal oligoastrocytomas but not in extra-temporal tumors. In astrocytic tumors, no link between mutational spectrum and location was observed.[89]

Classical tumor suppressor genes map to chromosomal regions with frequent allelic losses.[90] Therefore, multiple deletions studies on both chromosomal locations were performed and candidate regions were identified. Deletion mapping of candidate regions on chromosome 1p was performed on those rare oligodendrogliomas with interstitial deletions. Three different candidate regions were identified on 1p, indicating the involvement of multiple tumor suppressor genes in oligodendroglial tumors: 1p36.3 [Figure - 3], I, 1p36.1-2 [Figure - 3], II and 1p34-35 [Figure - 3], III. [74, 91-96] Candidate genes like TP73 (1p36.3), CDKN2C ( p18INK4c , 1p32), and hRAD54 (1p32) already have been excluded as major tumor suppressor gene candidates.[91],[92],[93],[94],[95],[96],[97]

Deletion studies face the problem of complete loss of 19q in oligodendroglioma.

Therefore, most fine mapping studies were based on astrocytic tumors, which frequently exhibit interstitial deletions on 19q.[85],[98],[99],[100] Initially a common region of overlap was found between 19q13.11 and 19q13.4,[85] which consecutively was narrowed down to 150 kb of genomic sequence.[98],[101],[102],[103],[104] However, none of the genes within these 150 kb, GLTSCR1 , EDH , GLTSR2, and SW , carried mutations or were obviously deregulated.[105],[106] Therefore, based on meta-analysis of multiple studies and employing physical sequence data from the human genome project, the candidate region was re-expanded to 3.7 Mb between D19S219 and D19S112.[107] Up to now, several attractive tumor suppressor genes like BAX , CRX, or STD have been screened for mutations but no genetic alterations were identified.[107]

Alternative mechanisms of inactivation have been suggested. Haploinsufficiency by LOH may cause reduced expression of one or multiple putative tumor suppressors by gene dosage effects.[107],[108],[109] Hypermethylation as a potential mechanism of gene inactivation appears possible: the density of CpG-islands within the 19q candidate region is higher than at any other genomic site.[107] This theory has become more attractive by observation of exclusive losses of the paternal allele in oligodendrogliomas (six of six cases), suggesting germ-line imprinting of the maternal copy of the gene.[110] However, two follow-up studies based on larger sets of samples clearly showed an equal distribution of losses of parental alleles.[111],[112]

Other chromosomal alterations were detected at a lower frequency. LOH studies, CGH, and karyotyping identified chromosomes 4, 6, 11p, 14q, and 22q as potential targets.[84],[113],[114],[115],[116],[117] LOH 14q was observed in up to 30% of two candidate regions and an association with LOH 1p was identified.[117] So far, for the other locations neither deletion mapping was performed nor associations with LOH1p/19q have been reported. LOH 17p and TP53 mutations were found rarely in oligodendrogliomas WHO Grade II with a frequency of 10-15% and usually inversely associated with LOH 1p/19q.[89],[118],[119],[120],[121],[122]

However, epigenetic silencing of the p14ARF gene that stabilizes the p53/MDM2 complex suggests a disruption of the p53 pathway in up to 20% of analyzed cases.[119],[121]

Progression-associated alterations in oligodendrogliomas

Progression-associated alterations similar to those seen in malignant astrocytomas can be found in anaplastic oligodendrogliomas. Multiple genes in the RB1 pathway are altered: CDKN2A on 9p21 was identified as a major target of homozygous deletions in anaplastic oligodendrogliomas.[66],[73],[115],[123],[124] Usually, these deletions include CDKN2B and the splice variant p14ARF.[124] In addition, these genes are frequently silenced by promoter hypermethylation.[121],[124] Further, CDK4 amplifications and RB1 alterations were described.[124]

Deletions of chromosome 10 were found in up to 58% of anaplastic oligodendrogliomas.[80],[114],[125] An association between allelic loss of 10q and a poorer outcome, similar to astrocytic tumors, was described.[80],[126],[127] However, another study failed to detect such association.[66] This may point to the diagnostic problem of distinguishing anaplastic oligoastrocytoma from glioblastoma typically exhibiting LOH 10. Frequently, an inverse association between LOH 10q and LOH 1p/19q was reported.[73],[75],[79],[120],[128] The tumor suppressor gene PTEN on 10q23.31 is mutated only in 3-10% of oligodendroglial tumors.[80],[128],[129],[130],[131] Those patients with PTEN mutations exhibited a poor outcome.[131] However, the high frequency of LOH 10q, the low number of PTEN mutations and observation of interstitial deletions on 10q25-q26 telomere to PTEN indicate the existence of another, yet not identified, tumor suppressor gene on this chromosomal arm.[132] Recently, point mutations in the oncogene PIK3CA on 3q26.3 that antagonizes PTEN were described in 14% of anaplastic oligodendrogliomas WHO Grade III.[133] Promoter Hypermethylation of MGMT on 10q26.3 was found in 60-80% of oligodendrogliomas. Only in a few samples, amplification of EGFR and PDGFRA was seen in anaplastic oligodendrogliomas.[79],[115],[134],[135],[136],[137]

Promoter hypermethylation in oligodendrogliomas

Epigenetic silencing may play an important role in the induction and progression of oligodendrogliomas.[86],[138] In fact, a high throughput approach identified large numbers of hypermethylated genes. However, most of these genes do not map to the 1p and 19q candidate regions.[138] It should be kept in mind that methylation studies in oligodendrogliomas suffer the problem of insufficient comparison methods: differences in methylation status are based on the comparison of oligodendrogliomas with normal brain tissue containing mixed cell populations. Specific genes were further characterized: CDKN2A , CDKN2B , p14ARF, RB1 , TP73 , DAPK1 , ESR1, GSTP1 , THBS1 , TIMP3 , HIC, and MGMT were found to be epigenetically silenced.[119],[121],[124],[139],[140],[141],[142],[143] p14ARF, an alternative splice variant of CDKN2A, binds to Mdm2, thereby blocking complex formation of p53 with Mdm2, resulting in a reduced degradation of p53.[144] TP53 mutations and MDM2 amplifications are rare in anaplastic oligodendrogliomas[84],[121],[124],[145],[146] but epigenetic silencing of p14ARF was reported in up to 50%.[121],[124]

Promoter Hypermethylation of MGMT ( O6-methylguanine-DNA methyltransferase ) on 10q26.3 was found in 60-80% of oligodendrogliomas. An association with 1p/19q status and tumor grade has been described.[141],[143]

Oncogenes


There is little information available on proto-oncogenes in human oligodendrogliomas. Activating mutations of oncogenes are rare in these tumors. On the other hand, strong expression of receptor tyrosine kinases that activate PI3K/AKT-, RAS/MAP-, and PLC/PKC-pathways are frequently encountered. Analysis of these tumor-promoting pathways are of major importance. EGFR (epithelial growth factor receptor) is frequently amplified and over expressed in high-grade astrocytic tumors.[3] In oligodendrogliomas, increased mRNA and protein expression was observed in up to 80%.[134],[135], [147],[148],[149],[150],[151],[152],[153] Similar expression levels for EGFR were found in Grades II and III oligodendrogliomas, indicating that this alteration is an early event in tumorigenesis. However, in contrast to high-grade astrocytomas, most studies reported only EGFR amplification in a few samples of anaplastic oligodendroglioma.[79],[115],[134],[135],[136]

The ligand PDGF-AA (platelet-derived growth factor) is a major mitogen for oligodendrocyte O2A progenitors, indicating a role in oligodendrocyte differentiation.[154] Increased expression of PDGF-A and the receptor PDGFR-α was found in up to 94% of Grades II and III oligodendrogliomas, suggesting autocrine and paracrine stimulation.[155],[156],[157],[158],[159],[160] In 4 of 41 anaplastic oligodendrogliomas, PDGFR-α amplification were identified.[137] However, another study failed to detect such mutations.[159] Our own analysis for PDGFRA point mutations in oligodendrogliomas failed to detect alterations.[161] PTEN protein antagonizes the activity of phosphatidylinositol-3¢-kinases (Pi3k) that convert PIP2 to PIP3. PIP3 activates the oncoprotein Akt that regulates other multiple proteins involved in cell cycle progression, cell growth and survival, cell migration, invasion, and angiogenesis. Recently, mutations in PIK3CA , a Pi3k family member, were observed in 3 of 21 (14%) anaplastic oligodendrogliomas WHO Grade III.[133] Effects on O2A progenitor cells are also induced by other growth factors such as bFGF, IGF-1, TGF-β, CNTF, NT-3, IL-2, and IL-6, which are frequently over expressed in oligodendroglial tumors.[17] Genetic alterations have not been not described. Amplification of other oncogenes like CDK4 and MDM4 were observed only in a low frequency in anaplastic oligodendrogliomas.[124],[162] Recently, point mutations in the gene coding for the oncogenic PTEN antagonist PIK3CA have been described in 16% of anaplastic oligodendrogliomas WHO Grade III133 but no amplification of the gene was found.[163]

CONCLUSION

No particular gene mutations have been identified in low-grade oligodendroglial tumors so far. The putative tumor suppressors on 1p and 19q still await identification. This paucity of knowledge about mutations on the gene level contrasts that on astrocytoma with many well-established mutations. However, analysis of LOH 1p/19q in oligodendroglial tumors is developing toward a valuable tool for therapeutic decisions in oligodendroglial tumors while molecular examinations do not yet play a major role in the management of astrocytic tumors.


REFERENCES

1.Bailey P, Cushing H. A Classification of Tumors of the Glioma Group on a Histogenetic basis with a Correlation Study of Prognosis. Philadelphia: Lippincott; 1926.  Back to cited text no. 1    
2.Bailey P, Bucy P. Oligodendrogliomas of the brain . J Pathol Bacteriol 1929;32:735-54  Back to cited text no. 2    
3.Kleihues P, Cavenee WK. Pathology and genetics of tumours of the nervous system. 2nd edition ed. Lyon; IARC Press; 2000.  Back to cited text no. 3    
4.Mork SJ, Lindegaard KF, Halvorsen TB, Lehmann EH, Solgaard T, Hatlevoll R, et al . Oligodendroglioma: incidence and biological behavior in a defined population . J Neurosurg 1985;63:881-9.  Back to cited text no. 4    
5.Helseth A, Mork SJ. Neoplasms of the central nervous system in Norway. III. Epidemiological characteristics of intracranial gliomas according to histology . Apmis 1989;97:547-55.  Back to cited text no. 5    
6.Zulch K. Brain tumours. Their biology and pathology. 3rd ed. Berlin: Springer; 1986.  Back to cited text no. 6    
7.Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK. Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas . Cancer 1997;79:1381-93.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Winger MJ, Macdonald DR, Cairncross JG. Supratentorial anaplastic gliomas in adults. The prognostic importance of extent of resection and prior low-grade glioma . J Neurosurg 1989;71:487-93.  Back to cited text no. 8  [PUBMED]  
9.Shaw EG, Scheithauer BW, O'Fallon JR, Tazelaar HD, Davis DH. Oligodendrogliomas: the Mayo Clinic experience . J Neurosurg 1992;76:428-34.  Back to cited text no. 9  [PUBMED]  
10.Ludwig CL, Smith MT, Godfrey AD, Armbrustmacher VW. A clinicopathological study of 323 patients with oligodendrogliomas . Ann Neurol 1986;19:15-21.  Back to cited text no. 10  [PUBMED]  
11.Jaskolsky D, Zawirski M, Papierz W, Kotwica Z. Mixed gliomas. Their clinical course and results of surgery . Zentralbl Neurochir 1987;48:120-3.  Back to cited text no. 11  [PUBMED]  
12.Huang CI, Chiou WH, Ho DM. Oligodendroglioma occurring after radiation therapy for pituitary adenoma . J Neurol Neurosurg Psychiatry 1987;50:1619-24.  Back to cited text no. 12  [PUBMED]  
13.Perez-Diaz C, Cabello A, Lobato RD, Rivas JJ, Cabrera A. Oligodendrogliomas arising in the scar of a brain contusion. Report of two surgically verified cases . Surg Neurol 1985;24:581-6.  Back to cited text no. 13  [PUBMED]  
14.Giordana MT, Mauro A, Soffietti R, Leone M. Association between multiple sclerosis and oligodendroglioma. Case report . Ital J Neurol Sci 1981;2:403-9.  Back to cited text no. 14    
15.Kros JM, Lie ST, Stefanko SZ. Familial occurrence of polymorphous oligodendroglioma . Neurosurgery 1994;34:732-6.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Ferraresi S, Servello D, De Lorenzi L, Allegranza A. Familial frontal lobe oligodendroglioma. Case report . J Neurosurg Sci 1989;33:317-8.  Back to cited text no. 16  [PUBMED]  
17.Graham DI, Lantos PL. Greenfield's Neuropathology. 6th ed. London: Arnold; 1997.  Back to cited text no. 17    
18.Ironside JW, Moss TH, Louis DN, Lowe JS, Well RO. Diagnostic Pathology of Nervous System Tumours. London: Churchill Livingstone; 2002.  Back to cited text no. 18    
19.Kim L, Hochberg FH, Thornton AF, Harsh GRt, Patel H, Finkelstein D, et al . Procarbazine, lomustine, and vincristine (PCV) chemotherapy for grade III and grade IV oligoastrocytomas . J Neurosurg 1996;85:602-7.  Back to cited text no. 19    
20.Mork SJ, Halvorsen TB, Lindegaard KF, Eide GE. Oligodendroglioma. Histologic evaluation and prognosis . J Neuropathol Exp Neurol 1986;45:65-78.  Back to cited text no. 20  [PUBMED]  
21.Hart MN, Petito CK, Earle KM. Mixed gliomas . Cancer 1974;33:134-40.  Back to cited text no. 21  [PUBMED]  
22.Lu QR, Park JK, Noll E, Chan JA, Alberta J, Yuk D, et al . Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors . Proc Natl Acad Sci U S A 2001;98:10851-6.  Back to cited text no. 22    
23.Marie Y, Sanson M, Mokhtari K, Leuraud P, Kujas M, Delattre JY, et al . OLIG2 as a specific marker of oligodendroglial tumour cells . Lancet 2001;358:298-300.  Back to cited text no. 23    
24.Ohnishi A, Sawa H, Tsuda M, Sawamura Y, Itoh T, Iwasaki Y, et al . Expression of the oligodendroglial lineage-associated markers Olig1 and Olig2 in different types of human gliomas . J Neuropathol Exp Neurol 2003;62:1052-9.  Back to cited text no. 24    
25.Aguirre-Cruz L, Mokhtari K, Hoang-Xuan K, Marie Y, Criniere E, Taillibert S, et al . Analysis of the bHLH transcription factors Olig1 and Olig2 in brain tumors . J Neurooncol 2004;67:265-71.  Back to cited text no. 25    
26.Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL, et al . The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas . J Neuropathol Exp Neurol 2004;63:499-509.  Back to cited text no. 26    
27.Whitton AC, Bloom HJ. Low grade glioma of the cerebral hemispheres in adults: a retrospective analysis of 88 cases . Int J Radiat Oncol Biol Phys 1990;18:783-6.  Back to cited text no. 27  [PUBMED]  
28.Puduvalli VK, Hashmi M, McAllister LD, Levin VA, Hess KR, Prados M, et al . Anaplastic oligodendrogliomas: prognostic factors for tumor recurrence and survival . Oncology 2003;65:259-66.  Back to cited text no. 28    
29.Lindegaard KF, Mork SJ, Eide GE, Halvorsen TB, Hatlevoll R, Solgaard T, et al . Statistical analysis of clinicopathological features, radiotherapy, and survival in 170 cases of oligodendroglioma . J Neurosurg 1987;67:224-30.  Back to cited text no. 29    
30.Sun ZM, Genka S, Shitara N, Akanuma A, Takakura K. Factors possibly influencing the prognosis of oligodendroglioma . Neurosurgery 1988;22:886-91.  Back to cited text no. 30  [PUBMED]  
31.Fortin D, Macdonald DR, Stitt L, Cairncross JG. PCV for oligodendroglial tumors: in search of prognostic factors for response and survival . Can J Neurol Sci 2001;28:215-23.  Back to cited text no. 31  [PUBMED]  
32.Henderson KH, Shaw EG. Randomized trials of radiation therapy in adult low-grade gliomas . Semin Radiat Oncol 2001;11:145-51.  Back to cited text no. 32  [PUBMED]  
33.Wallner KE, Gonzales M, Sheline GE. Treatment of oligodendrogliomas with or without postoperative irradiation . J Neurosurg 1988;68:684-8.  Back to cited text no. 33  [PUBMED]  
34.Sheline GE. Radiation therapy of brain tumors . Cancer 1977;39:873-81.  Back to cited text no. 34  [PUBMED]  
35.Allison RR, Schulsinger A, Vongtama V, Barry T, Shin KH. Radiation and chemotherapy improve outcome in oligodendroglioma . Int J Radiat Oncol Biol Phys 1997;37:399-403.  Back to cited text no. 35  [PUBMED]  [FULLTEXT]
36.Macdonald DR. Low-grade gliomas, mixed gliomas, and oligodendrogliomas . Semin Oncol 1994;21:236-48.  Back to cited text no. 36  [PUBMED]  
37.Leonardi MA, Lumenta CB. Oligodendrogliomas in the CT/MR-era . Acta Neurochir (Wien) 2001;143:1195-203.  Back to cited text no. 37  [PUBMED]  [FULLTEXT]
38.Jeremic B, Shibamoto Y, Gruijicic D, Milicic B, Stojanovic M, Nikolic N, et al . Combined treatment modality for anaplastic oligodendroglioma: a phase II study . J Neurooncol 1999;43:179-85.  Back to cited text no. 38    
39.Bullard DE, Rawlings CE, 3rd, Phillips B, Cox EB, Schold SC, Jr., Burger P, et al . Oligodendroglioma. An analysis of the value of radiation therapy . Cancer 1987;60:2179-88.  Back to cited text no. 39    
40.Dehghani F, Schachenmayr W, Laun A, Korf HW. Prognostic implication of histopathological, immunohistochemical and clinical features of oligodendrogliomas: a study of 89 cases . Acta Neuropathol (Berl) 1998;95:493-504.  Back to cited text no. 40  [PUBMED]  [FULLTEXT]
41.Kirby S, Macdonald D, Fisher B, Gaspar L, Cairncross G. Pre-radiation chemotherapy for malignant glioma in adults . Can J Neurol Sci 1996l23:123-7.  Back to cited text no. 41  [PUBMED]  
42.Kros JM, Pieterman H, van Eden CG, Avezaat CJ. Oligodendroglioma: the Rotterdam-Dijkzigt experience . Neurosurgery 1994l34:959-66.  Back to cited text no. 42  [PUBMED]  [FULLTEXT]
43.Fortin D, Cairncross GJ, Hammond RR. Oligodendroglioma: an appraisal of recent data pertaining to diagnosis and treatment . Neurosurgery 1999;45:1279-91.  Back to cited text no. 43  [PUBMED]  [FULLTEXT]
44.Reedy DP, Bay JW, Hahn JF. Role of radiation therapy in the treatment of cerebral oligodendroglioma: an analysis of 57 cases and a literature review . Neurosurgery 1983;13:499-503;  Back to cited text no. 44  [PUBMED]  
45.Westergaard L, Gjerris F, Klinken L. Prognostic factors in oligodendrogliomas . Acta Neurochir (Wien) 1997;139:600-5.  Back to cited text no. 45  [PUBMED]  
46.Nijjar TS, Simpson WJ, Gadalla T, McCartney M. Oligodendroglioma. The Princess Margaret Hospital experience (1958-1984) . Cancer 1993;71:4002-6.  Back to cited text no. 46  [PUBMED]  
47.Kros JM, Troost D, van Eden CG, van der Werf AJ, Uylings HB. Oligodendroglioma. A comparison of two grading systems . Cancer 1988;61:2251-9.  Back to cited text no. 47  [PUBMED]  
48.Yeh SA, Lee TC, Chen HJ, Lui CC, Sun LM, Wang CJ, et al . Treatment outcomes and prognostic factors of patients with supratentorial low-grade oligodendroglioma . Int J Radiat Oncol Biol Phys 2002;54:1405-9.  Back to cited text no. 48    
49.Gannett DE, Wisbeck WM, Silbergeld DL, Berger MS. The role of postoperative irradiation in the treatment of oligodendroglioma . Int J Radiat Oncol Biol Phys 1994;30:567-73.  Back to cited text no. 49  [PUBMED]  
50.Celli P, Nofrone I, Palma L, Cantore G, Fortuna A. Cerebral oligodendroglioma: prognostic factors and life history . Neurosurgery 1994;35:1018-34.  Back to cited text no. 50  [PUBMED]  [FULLTEXT]
51.Shimizu KT, Tran LM, Mark RJ, Selch MT. Management of oligodendrogliomas . Radiology 1993;186:569-72.  Back to cited text no. 51  [PUBMED]  
52.Walker DG, Kaye AH. Diagnosis and management of astrocytomas, oligodendrogliomas and mixed gliomas: a review . Australas Radiol 2001;45:472-82.  Back to cited text no. 52  [PUBMED]  [FULLTEXT]
53.Cairncross JG, Macdonald DR. Successful chemotherapy for recurrent malignant oligodendroglioma . Ann Neurol 1988;23:360-4.  Back to cited text no. 53  [PUBMED]  
54.Levin VA, Edwards MS, Wright DC, Seager ML, Schimberg TP, Townsend JJ, et al . Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors . Cancer Treat Rep 1980;64:237-44.  Back to cited text no. 54    
55.Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J, et al . Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group . J Clin Oncol 1994;12:2013-21.  Back to cited text no. 55    
56.Kyritsis AP, Yung WK, Bruner J, Gleason MJ, Levin VA. The treatment of anaplastic oligodendrogliomas and mixed gliomas . Neurosurgery 1993;32:365-70.  Back to cited text no. 56  [PUBMED]  [FULLTEXT]
57.Glass J, Hochberg FH, Gruber ML, Louis DN, Smith D, Rattner B. The treatment of oligodendrogliomas and mixed oligodendroglioma-astrocytomas with PCV chemotherapy . J Neurosurg 1992;76:741-5.  Back to cited text no. 57  [PUBMED]  
58.van den Bent MJ, Taphoorn MJ, Brandes AA, Menten J, Stupp R, Frenay M, et al . Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971 . J Clin Oncol 2003;21:2525-8.  Back to cited text no. 58    
59.Brada M, Viviers L, Abson C, Hines F, Britton J, Ashley S, et al . Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas . Ann Oncol 2003;14:1715-21.  Back to cited text no. 59    
60.Chahlavi A, Kanner A, Peereboom D, Staugaitis SM, Elson P, Barnett G. Impact of chromosome 1p status in response of oligodendroglioma to temozolomide: preliminary results . J Neurooncol 2003;61:267-73.  Back to cited text no. 60  [PUBMED]  [FULLTEXT]
61.Engelhard HH, Stelea A, Mundt A. Oligodendroglioma and anaplastic oligodendroglioma: clinical features, treatment, and prognosis . Surg Neurol 2003;60: 443-56.  Back to cited text no. 61  [PUBMED]  [FULLTEXT]
62.Hoang-Xuan K, Capelle L, Kujas M, Taillibert S, Duffau H, Lejeune J, et al . Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions . J Clin Oncol 2004;22:3133-8.  Back to cited text no. 62    
63.Perry JR, Brown MT, Gockerman JP. Acute leukemia following treatment of malignant glioma . J Neurooncol 1998;40:39-46.  Back to cited text no. 63  [PUBMED]  [FULLTEXT]
64.Olson JD, Riedel E, DeAngelis LM. Long-term outcome of low-grade oligodendroglioma and mixed glioma . Neurology 2000;54:1442-8.  Back to cited text no. 64    
65.Heegaard S, Sommer HM, Broholm H, Broendstrup O. Proliferating cell nuclear antigen and Ki-67 immunohistochemistry of oligodendrogliomas with special reference to prognosis . Cancer 1995;76:1809-13.  Back to cited text no. 65  [PUBMED]  
66.Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, et al . Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas . J Natl Cancer Inst 1998;90:1473-9.  Back to cited text no. 66    
67.Smith JS, Perry A, Borell TJ, Lee HK, O'Fallon J, Hosek SM, et al . Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas . J Clin Oncol 2000;18:636-45.  Back to cited text no. 67    
68.Ino Y, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, Jhung S, et al . Long survival and therapeutic responses in patients with histologically disparate high-grade gliomas demonstrating chromosome 1p loss . J Neurosurg 2000;92:983-90.  Back to cited text no. 68    
69.Schmidt MC, Antweiler S, Urban N, Mueller W, Kuklik A, Meyer-Puttlitz B, et al . Impact of genotype and morphology on the prognosis of glioblastoma . J Neuropathol Exp Neurol 2002;61:321-8.  Back to cited text no. 69    
70.Sasaki H, Zlatescu MC, Betensky RA, Johnk LB, Cutone AN, Cairncross JG, et al . Histopathological-molecular genetic correlations in referral pathologist-diagnosed low-grade "oligodendroglioma" . J Neuropathol Exp Neurol 2002;61:58-63.  Back to cited text no. 70    
71.Godfraind C, Rousseau E, Ruchoux MM, Scaravilli F, Vikkula M. Tumour necrosisand microvascular proliferation are associated with 9p deletion and CDKN2A alterations in 1p/19q-deleted oligodendrogliomas . Neuropathol Appl Neurobiol 2003;29:462-71.  Back to cited text no. 71  [PUBMED]  [FULLTEXT]
72.Bauman GS, Ino Y, Ueki K, Zlatescu MC, Fisher BJ, Macdonald DR, et al . Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas . Int J Radiat Oncol Biol Phys 2000;48:825-30.  Back to cited text no. 72    
73.Ino Y, Betensky RA, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, et al . Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis . Clin Cancer Res 2001;7: 839-45.  Back to cited text no. 73    
74.Hashimoto N, Murakami M, Takahashi Y, Fujimoto M, Inazawa J, Mineura K. Correlation between genetic alteration and long-term clinical outcome of patients with oligodendroglial tumors, with identification of a consistent region of deletion on chromosome arm 1p . Cancer 2003;97:2254-61.  Back to cited text no. 74    
75.Thiessen B, Maguire JA, McNeil K, Huntsman D, Martin MA, Horsman D. Loss of heterozygosity for loci on chromosome arms 1p and 10q in oligodendroglial tumors: relationship to outcome and chemosensitivity . J Neurooncol 2003;64:271-8.  Back to cited text no. 75  [PUBMED]  [FULLTEXT]
76.Van Den Bent MJ, Looijenga LH, Langenberg K, Dinjens W, Graveland W, Uytdewilligen L, et al . Chromosomal anomalies in oligodendroglial tumors are correlated with clinical features . Cancer 2003;97:1276-84.  Back to cited text no. 76    
77.Buckner JC, Gesme D, Jr., O'Fallon JR, Hammack JE, Stafford S, Brown PD, et al . Phase II trial of procarbazine, lomustine, and vincristine as initial therapy for patients with low-grade oligodendroglioma or oligoastrocytoma: efficacy and associations with chromosomal abnormalities . J Clin Oncol 2003;21:251-5.  Back to cited text no. 77    
78.Louis DN, Pomeroy SL, Cairncross JG. Focus on central nervous system neoplasia . Cancer Cell 2002;1:125-8.  Back to cited text no. 78    
79.Hoang-Xuan K, He J, Huguet S, Mokhtari K, Marie Y, Kujas M, et al . Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression . Neurology 2001; 57:1278-81.  Back to cited text no. 79    
80.Sanson M, Leuraud P, Aguirre-Cruz L, He J, Marie Y, Cartalat-Carel S, et al . Analysis of loss of chromosome 10q, DMBT1 homozygous deletions, and PTEN mutations in oligodendrogliomas . J Neurosurg 2002;97:1397-401.  Back to cited text no. 80    
81.Bello MJ, Vaquero J, de Campos JM, Kusak ME, Sarasa JL, Saez-Castresana J, et al . Molecular analysis of chromosome 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors . Int J Cancer 1994 ;57:172-5.  Back to cited text no. 81    
82.Bello MJ, Leone PE, Vaquero J, de Campos JM, Kusak ME, Sarasa JL, et al . Allelic loss at 1p and 19q frequently occurs in association and may represent early oncogenic events in oligodendroglial tumors . Int J Cancer 1995;64:207-10.  Back to cited text no. 82    
83.Kraus JA, Koopmann J, Kaskel P, Maintz D, Brandner S, Schramm J, et al . Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and oligoastrocytoma . J Neuropathol Exp Neurol 1995;54:91-5.  Back to cited text no. 83    
84.Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p . Am J Pathol 1994;145:1175-90.  Back to cited text no. 84    
85.von Deimling A, Louis DN, von Ammon K, Petersen I, Wiestler OD, Seizinger BR. Evidence for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas . Cancer Res 1992;52:4277-9.  Back to cited text no. 85    
86.Reifenberger G, Louis DN. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology . J Neuropathol Exp Neurol 2003;62:111-26.  Back to cited text no. 86    
87.Kleihues P, Lubbe J, Watanabe K, von Ammon K, Ohgaki H. Genetic alterations associated with glioma progression . Verh Dtsch Ges Pathol 1994;78:43-7.  Back to cited text no. 87    
88.Zlatescu MC, TehraniYazdi A, Sasaki H, Megyesi JF, Betensky RA, Louis DN, et al . Tumor location and growth pattern correlate with genetic signature in oligodendroglial neoplasms . Cancer Res 2001;61:6713-5.  Back to cited text no. 88    
89.Mueller W, Hartmann C, Hoffmann A, Lanksch W, Kiwit J, Tonn J, et al . Genetic signature of oligoastrocytomas correlates with tumor location and denotes distinct molecular subsets . Am J Pathol 2002;161:313-9.  Back to cited text no. 89    
90.Knudson AG, Jr. Mutation and cancer: statistical study of retinoblastoma . Proc Natl Acad Sci U S A 1971;68:820-3.  Back to cited text no. 90    
91.Husemann K, Wolter M, Buschges R, Bostrom J, Sabel M, Reifenberger G. Identification of two distinct deleted regions on the short arm of chromosome 1 and rare mutation of the CDKN2C gene from 1p32 in oligodendroglial tumors . J Neuropathol Exp Neurol 1999;58:1041-50.  Back to cited text no. 91    
92.Alonso ME, Bello MJ, Gonzalez-Gomez P, Lomas J, Arjona D, de Campos JM, et al . Mutation analysis of the p73 gene in nonastrocytic brain tumours . Br J Cancer 2001;85:204-8.  Back to cited text no. 92    
93.Mai M, Huang H, Reed C, Qian C, Smith JS, Alderete B, et al . Genomic organization and mutation analysis of p73 in oligodendrogliomas with chromosome 1 p-arm deletions . Genomics 1998;51:359-63.  Back to cited text no. 93    
94.Tsujimoto T, Mochizuchi S, Iwadate Y, Namba H, Nagai M, Kawamoto T, et al . The p73 gene is not mutated in oligodendrogliomas which frequently have a deleted region at chromosome 1p36.3 . Anticancer Res 2000;20:2495-7.  Back to cited text no. 94    
95.Bello MJ, de Campos JM, Vaquero J, Ruiz-Barnes P, Kusak ME, Sarasa JL, et al . hRAD54 gene and 1p high-resolution deletion-mapping analyses in oligodendrogliomas . Cancer Genet Cytogenet 2000;116:142-7.  Back to cited text no. 95    
96.He J, Hoang-Xuan K, Marie Y, Leuraud P, Mokhtari K, Kujas M, et al . P18 tumor suppressor gene and progression of oligodendrogliomas to anaplasia . Neurology 2000;55:867-9.  Back to cited text no. 96    
97.Pohl U, Cairncross JG, Louis DN. Homozygous deletions of the CDKN2C/p18INK4C gene on the short arm of chromosome 1 in anaplastic oligodendrogliomas . Brain Pathol 1999;9:639-43.  Back to cited text no. 97    
98.Rosenberg JE, Lisle DK, Burwick JA, Ueki K, von Deimling A, Mohrenweiser HW, et al . Refined deletion mapping of the chromosome 19q glioma tumor suppressor gene to the D19S412-STD interval . Oncogene 1996;13:2483-5.  Back to cited text no. 98    
99.Nakamura M, Yang F, Fujisawa H, Yonekawa Y, Kleihues P, Ohgaki H. Loss of heterozygosity on chromosome 19 in secondary glioblastomas . J Neuropathol Exp Neurol 2000;59:539-43.  Back to cited text no. 99    
100.von Deimling A, Bender B, Jahnke R, Waha A, Kraus J, Albrecht S, et al . Loci associated with malignant progression in astrocytomas: a candidate on chromosome 19q . Cancer Res 1994;54:1397-401.  Back to cited text no. 100    
101.von Deimling A, Nagel J, Bender B, Lenartz D, Schramm J, Louis DN, et al . Deletion mapping of chromosome 19 in human gliomas . Int J Cancer 1994;57:676-80.  Back to cited text no. 101    
102.Rubio MP, Correa KM, Ueki K, Mohrenweiser HW, Gusella JF, von Deimling A, et al . The putative glioma tumor suppressor gene on chromosome 19q maps between APOχ2 and HRC . Cancer Res 1994;54:4760-3.  Back to cited text no. 102    
103.Yong WH, Chou D, Ueki K, Harsh GRt, von Deimling A, Gusella JF, et al . Chromosome 19q deletions in human gliomas overlap telomeric to D19S219 and may target a 425 kb region centromeric to D19S112 . J Neuropathol Exp Neurol 1995;54:622-6.  Back to cited text no. 103    
104.Smith JS, Tachibana I, Lee HK, Qian J, Pohl U, Mohrenweiser HW, et al . Mapping of the chromosome 19 q-arm glioma tumor suppressor gene using fluorescence in situ hybridization and novel microsatellite markers . Genes Chromosomes Cancer 2000;29:16-25.  Back to cited text no. 104    
105.Smith JS, Tachibana I, Pohl U, Lee HK, Thanarajasingam U, Portier BP, et al . A transcript map of the chromosome 19q-arm glioma tumor suppressor region . Genomics 2000;64:44-50.   Back to cited text no. 105    
106.Pohl U, Smith JS, Tachibana I, Ueki K, Lee HK, Ramaswamy S, et al . EHD2, EHD3, and EHD4 encode novel members of a highly conserved family of EH domaincontaining proteins . Genomics 2000;63:255-62.  Back to cited text no. 106    
107.Hartmann C, Johnk L, Kitange G, Wu Y, Ashworth LK, Jenkins RB, et al . Transcript map of the 3.7-Mb D19S112-D19S246 candidate tumor suppressor region on the long arm of chromosome 19 . Cancer Res 2002;62:4100-8.  Back to cited text no. 107    
108.Mukasa A, Ueki K, Matsumoto S, Tsutsumi S, Nishikawa R, Fujimaki T, et al . Distinction in gene expression profiles of oligodendrogliomas with and without allelic loss of 1p . Oncogene 2002;21:3961-8.  Back to cited text no. 108    
109.Wolf RM, Draghi N, Liang X, Dai C, Uhrbom L, Eklof C, et al . p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3 . Genes Dev 2003;17:476-87.  Back to cited text no. 109    
110.Sanson M, Leuraud P, Marie Y, Delattre JY, Hoang-Xuan K. Preferential loss ofpaternal 19q, but not 1p, alleles in oligodendrogliomas . Ann Neurol 2002;52:105-7.  Back to cited text no. 110    
111.Hartmann C, Mueller W, Lass U, Stockhammer F, von Eckardstein K, Veelken J, et al . No preferential loss of paternal 19q alleles in oligodendroglial tumors . Ann Neurol 2003;54:256-8.  Back to cited text no. 111    
112.Trouillard O, Aguirre-Cruz L, Hoang-Xuan K, Marie Y, Delattre JY, Sanson M. Parental 19q loss and PEG3 expression in oligodendrogliomas . Cancer Genet Cytogenet 2004;151:182-3.  Back to cited text no. 112    
113.Zhu JJ, Santarius T, Wu X, Tsong J, Guha A, Wu JK, et al . Screening for loss of heterozygosity and microsatellite instability in oligodendrogliomas . Genes Chromosomes Cancer 1998;21:207-16.  Back to cited text no. 113    
114.Kros JM, van Run PR, Alers JC, Beverloo HB, van den Bent MJ, Avezaat CJ, et al . Genetic aberrations in oligodendroglial tumours: an analysis using comparative genomic hybridization (CGH) . J Pathol 1999;188:282-8.  Back to cited text no. 114    
115.Bigner SH, Matthews MR, Rasheed BK, Wiltshire RN, Friedman HS, Friedman AH, et al . Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization . Am J Pathol 1999;155:375-86.  Back to cited text no. 115    
116.Weber RG, Sabel M, Reifenberger J, Sommer C, Oberstrass J, Reifenberger G, et al . Characterization of genomic alterations associated with glioma progression by comparative genomic hybridization . Oncogene 1996 ;13:983-94.  Back to cited text no. 116    
117.Dichamp C, Taillibert S, Aguirre-Cruz L, Lejeune J, Marie Y, Kujas M, et al . Loss of 14q chromosome in oligodendroglial and astrocytic tumors . J Neurooncol 2004;67:281-5.  Back to cited text no. 117    
118.Ohgaki H, Eibl RH, Wiestler OD, Yasargil MG, Newcomb EW, Kleihues P. p53 mutations in nonastrocytic human brain tumors . Cancer Res 1991;51:6202-5.  Back to cited text no. 118    
119.Watanabe T, Nakamura M, Kros JM, Burkhard C, Yonekawa Y, Kleihues P, et al . Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas . Acta Neuropathol (Berl) 2002;103:267-75.  Back to cited text no. 119    
120.Ueki K, Nishikawa R, Nakazato Y, Hirose T, Hirato J, Funada N, et al . Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors . Clin Cancer Res 2002;8:196-201.  Back to cited text no. 120    
121.Wolter M, Reifenberger J, Blaschke B, Ichimura K, Schmidt EE, Collins VP, et al . Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes . J Neuropathol Exp Neurol 2001;60:1170-80.  Back to cited text no. 121    
122.Burger PC, Minn AY, Smith JS, Borell TJ, Jedlicka AE, Huntley BK, et al . Losses of chromosomal arms 1p and 19q in the diagnosis of oligodendroglioma. A study of paraffin-embedded sections . Mod Pathol 2001;14:842-53.  Back to cited text no. 122    
123.Bortolotto S, Chiado-Piat L, Cavalla P, Bosone I, Chio A, Mauro A, et al . CDKN2A/p16 inactivation in the prognosis of oligodendrogliomas . Int J Cancer 2000;88:554-7.  Back to cited text no. 123    
124.Watanabe T, Yokoo H, Yokoo M, Yonekawa Y, Kleihues P, Ohgaki H. Concurrent inactivation of RB1 and TP53 pathways in anaplastic oligodendrogliomas . J Neuropathol Exp Neurol 2001;60:1181-9.  Back to cited text no. 124    
125.von Deimling A, Fimmers R, Schmidt MC, Bender B, Fassbender F, Nagel J, et al . Comprehensive allelotype and genetic analysis of 466 human nervous system tumors . J Neuropathol Exp Neurol 2000 ;59:544-58.  Back to cited text no. 125    
126.Bissola L, Eoli M, Pollo B, Merciai BM, Silvani A, Salsano E, et al . Association of chromosome 10 losses and negative prognosis in oligoastrocytomas . Ann Neurol 2002;52:842-5.  Back to cited text no. 126    
127.Jeuken JW, Sprenger SH, Vermeer H, Kappelle AC, Boerman RH, Wesseling P. Chromosomal imbalances in primary oligodendroglial tumors and their recurrences: clues about malignant progression detected using comparative genomic hybridization . J Neurosurg 2002;96:559-64.  Back to cited text no. 127    
128.Jeuken JW, Sprenger SH, Wesseling P, Macville MV, von Deimling A, Teepen HL, et al . Identification of subgroups of high-grade oligodendroglial tumors by comparative genomic hybridization . J Neuropathol Exp Neurol 1999;58:606-12.  Back to cited text no. 128    
129.Duerr EM, Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis DN, et al . PTEN mutations in gliomas and glioneuronal tumors . Oncogene 1998;16:2259-64.  Back to cited text no. 129    
130.Jeuken JW, Nelen MR, Vermeer H, van Staveren WC, Kremer H, van Overbeeke JJ, et al . PTEN mutation analysis in two genetic subtypes of high-grade oligodendroglial tumors. PTEN is only occasionally mutated in one of the two genetic subtypes . Cancer Genet Cytogenet 2000;119:42-7.  Back to cited text no. 130    
131.Sasaki H, Zlatescu MC, Betensky RA, Ino Y, Cairncross JG, Louis DN. PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis . Am J Pathol 2001;159:359-67.  Back to cited text no. 131    
132.Maier D, Comparone D, Taylor E, Zhang Z, Gratzl O, Van Meir EG, et al . New deletion in low-grade oligodendroglioma at the glioblastoma suppressor locus on chromosome 10q25-26 . Oncogene 1997;15:997-1000.  Back to cited text no. 132    
133.Broderick DK, Di C, Parrett TJ, Samuels YR, Cummins JM, McLendon RE, et al . Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas . Cancer Res 2004;64:5048-50.  Back to cited text no. 133    
134.Diedrich U, Soja S, Behnke J, Zoll B. Amplification of the c-erbB oncogene is associated with malignancy in primary tumours of neuroepithelial tissue . J Neurol 1991;238:221-4.  Back to cited text no. 134    
135.Reifenberger J, Reifenberger G, Ichimura K, Schmidt EE, Wechsler W, Collins VP. Epidermal growth factor receptor expression in oligodendroglial tumors . Am J Pathol 1996;149:29-35.  Back to cited text no. 135    
136.Wong AJ, Zoltick PW, Moscatello DK. The molecular biology and molecular genetics of astrocytic neoplasms . Semin Oncol 1994;21:139-48.  Back to cited text no. 136    
137.Smith JS, Wang XY, Qian J, Hosek SM, Scheithauer BW, Jenkins RB, et al . Amplification of the platelet-derived growth factor receptor-A (PDGFRA) gene occurs in oligodendrogliomas with grade IV anaplastic features . J Neuropathol Exp Neurol 2000;59:495-503.  Back to cited text no. 137    
138.Hong C, Bollen AW, Costello JF. The contribution of genetic and epigenetic mechanisms to gene silencing in oligodendrogliomas . Cancer Res 2003;63:7600-5.  Back to cited text no. 138    
139.Watanabe T, Nakamura M, Yonekawa Y, Kleihues P, Ohgaki H. Promoter hypermethylation and homozygous deletion of the p14ARF and p16INK4a genes in oligodendrogliomas . Acta Neuropathol (Berl) 2001;101:185-9.  Back to cited text no. 139    
140.Dong S, Pang JC, Hu J, Zhou LF, Ng HK. Transcriptional inactivation of TP73 expression in oligodendroglial tumors . Int J Cancer 2002;98:370-5.  Back to cited text no. 140    
141.Dong SM, Pang JC, Poon WS, Hu J, To KF, Chang AR, et al . Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors . J Neuropathol Exp Neurol 2001;60:808-16.  Back to cited text no. 141    
142.Uhlmann K, Rohde K, Zeller C, Szymas J, Vogel S, Marczinek K, et al . Distinct methylation profiles of glioma subtypes . Int J Cancer 2003;106:52-9.  Back to cited text no. 142    
143.Alonso ME, Bello MJ, Gonzalez-Gomez P, Arjona D, Lomas J, de Campos JM, et al . Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas . Cancer Genet Cytogenet 2003;144:134-42.  Back to cited text no. 143    
144.Sherr CJ, Weber JD. The ARF/p53 pathway . Curr Opin Genet Dev 2000;10:94-9.  Back to cited text no. 144    
145.Ohgaki H, Eibl RH, Schwab M, Reichel MB, Mariani L, Gehring M, et al . Mutations of the p53 tumor suppressor gene in neoplasms of the human nervous system . Mol Carcinog 1993;8:74-80.  Back to cited text no. 145    
146.Maintz D, Fiedler K, Koopmann J, Rollbrocker B, Nechev S, Lenartz D, et al . Molecular genetic evidence for subtypes of oligoastrocytomas . J Neuropathol Exp Neurol 1997;56:1098-104.  Back to cited text no. 146    
147.Reifenberger G, Prior R, Deckert M, Wechsler W. Epidermal growth factor receptor expression and growth fraction in human tumours of the nervous system . Virchows Arch A Pathol Anat Histopathol 1989;414:147-55.  Back to cited text no. 147    
148.Torp SH, Helseth E, Ryan L, Stolan S, Dalen A, Unsgaard G. Amplification of the epidermal growth factor receptor gene in human gliomas . Anticancer Res 1991;11:2095-8.  Back to cited text no. 148    
149.Broholm H, Bols B, Heegaard S, Braendstrup O. Immunohistochemical investigation of p53 and EGFR expression of oligodendrogliomas . Clin Neuropathol 1999;18:176-80.  Back to cited text no. 149    
150.Ekstrand AJ, James CD, Cavenee WK, Seliger B, Pettersson RF, Collins VP. Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo . Cancer Res 1991;51:2164-72.  Back to cited text no. 150    
151.Hawkins RA, Killen E, Whittle IR, Jack WJ, Chetty U, Prescott RJ. Epidermal growth factor receptors in intracranial and breast tumours: their clinical significance . Br J Cancer 1991;63:553-60.  Back to cited text no. 151    
152.McLendon RE, Wikstrand CJ, Matthews MR, Al-Baradei R, Bigner SH, Bigner DD. Glioma-associated antigen expression in oligodendroglial neoplasms. Tenascin and epidermal growth factor receptor . J Histochem Cytochem 2000;48:1103-10.  Back to cited text no. 152    
153.Schwechheimer K, Gass P, Berlet HH. Expression of oligodendroglia and Schwann cell markers in human nervous system tumors. An immunomorphological study and western blot analysis . Acta Neuropathol (Berl) 1992;83:283-91.  Back to cited text no. 153    
154.Durand B, Raff M. A cell-intrinsic timer that operates during oligodendrocyte development . Bioessays 2000;22:64-71.  Back to cited text no. 154    
155.Robinson S, Cohen M, Prayson R, Ransohoff RM, Tabrizi N, Miller RH. Constitutive expression of growth-related oncogene and its receptor in oligodendrogliomas . Neurosurgery 2001;48:864-73.  Back to cited text no. 155    
156.Di Rocco F, Carroll RS, Zhang J, Black PM. Platelet-derived growth factor and its receptor expression in human oligodendrogliomas . Neurosurgery 1998;42:341-6.  Back to cited text no. 156    
157.Maxwell M, Naber SP, Wolfe HJ, Galanopoulos T, Hedley-Whyte ET, Black PM, et al . Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance . J Clin Invest 1990;86:131-40.  Back to cited text no. 157    
158.Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, et al . Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops . Cancer Res 1992;52:3213-9.  Back to cited text no. 158    
159.Hermanson M, Funa K, Koopmann J, Maintz D, Waha A, Westermark B, et al . Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor alpha receptor expression in human malignant gliomas . Cancer Res 1996;56:164-71.  Back to cited text no. 159    
160.Fleming TP, Saxena A, Clark WC, Robertson JT, Oldfield EH, Aaronson SA, et al . Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors . Cancer Res 1992;52:4550-3.  Back to cited text no. 160    
161.Hartmann C, Xu X, Bartels G, Holtkamp N, Gonzales IA, Tallen G, et al . Pdgfr-alpha in 1p/19q LOH oligodendrogliomas . Int J Cancer 2004  Back to cited text no. 161    
162.Riemenschneider MJ, Buschges R, Wolter M, Reifenberger J, Bostrom J, Kraus JA, et al . Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification . Cancer Res 1999;59:6091-6.  Back to cited text no. 162    
163.Knobbe CB, Reifenberger G. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas . Brain Pathol 2003;13:507-18.  Back to cited text no. 163    

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