Molecular genetic alterations in glioblastomas with oligodendroglial component

Glioblastoma multiforme is the most malignant astrocytic glioma and usually resistant to chemotherapy. A small fraction of glioblastomas may contain areas with histological features of oligodendroglial differentiation. To determine the molecular genetic alterations in such "glioblastomas with oligodendroglial component", we investigated 13 of these tumors for genetic alterations and/or expression of the TP53, CDKN2A, PTEN, and EGFR genes. In addition, we performed microsatellite analyses for loss of heterozygosity (LOH) on chromosome arms 1p, 19q and 10q. None of tumors showed evidence for LOH on 10q. LOH on 1p was detected in 3 tumors, 1 of which additionally showed LOH on 19q. The 3 tumors with LOH on 1p showed neither TP53 mutations nor nuclear p53 accumulation. In contrast, 9 of 10 tumors without demonstrated losses on 1p showed nuclear p53 accumulation. TP53 mutations were identified in 3 of these cases. Further aberrations detected were epidermal growth factor receptor (EGFR) overexpression (3 of 13 tumors), homozygous CDKN2A deletion (2 of 11 tumors), and PTEN mutation (1 of 13 tumors). Taken together, our results indicate that "glioblastomas with oligodendroglial component" carry heterogeneous genetic alterations. LOH on 10q, PTEN mutation, and homozygous CDKN2A deletion appear to be less common in these tumors as compared to ordinary glioblastomas. Furthermore, a subset of these tumors demonstrates LOH on 1p, i.e., an alteration that has recently been linked to chemosensitivity and good prognosis in anaplastic oligodendrogliomas.     

Identification of subgroups of high-grade oligodendroglial tumors by comparative genomic hybridization.

In contrast to astrocytic tumors, approximately two thirds of anaplastic oligodendrogliomas are reported to be chemosensitive. Relatively little is known about the genetic aberrations in oligodendroglial tumors (OTs). In order to elucidate oligodendroglial oncogenesis and to find specific genetic aberrations that may have prognostic and therapeutic implications, we performed comparative genomic hybridization (CGH) to detect chromosomal copy number changes in 17 low-grade OTs (LG-OTs) and 12 high-grade OTs (HG-OTs) lacking a prominent astrocytic component. Loss of chromosome 1p (79%) and 19q (76%) were most frequently detected by CGH, all LG-OTs and 50% of the HG-OTs contained -1p (including 1p36-32), -19q (including 19q13.3), or both, and the rest of the HG-OTs showed +7, -10, or both. Since losses of 1p36-32 and 19q13.3 were mutually exclusive with +7 or -10, the HG-OTs could be divided in -1p/-19q and +7/-10 tumors. While the -1p/-19q tumors can be considered as pure anaplastic oligodendrogliomas, the +7/-10 tumors may rather be glioblastomas with prominent oligodendroglial differentiation. We conclude that CGH is a powerful tool to assist in the identification of 2 major subgroups of HG-OTs with prognostic and possibly therapeutic relevance.     

Genetically distinct astrocytic and oligodendroglial components in oligoastrocytomas

Oligoastrocytomas are glial tumours consisting of a mixture of neoplastic astrocytic and oligodendroglial cells. Genetic alterations of oligoastrocytomas include loss of heterozygosity of chromosomes 1p and/or 19q (LOH 1p/19q), typically occurring in oligodendrogliomas, and mutations of TP53, frequently occurring in astrocytomas. To investigate whether these neoplastic cell types in oligoastrocytomas have different genetic profiles, we examined the two different components of oligoastrocytomas in comparison with the histological diagnosis of the specific tumour area for LOH 1p/19q and TP53 mutations by using microdissection technique. We found a variety of lost markers for 1p and 19q, and the presence of two different TP53 mutations in the tumour samples. In the majority of cases (9/11), the oligodendroglial and astrocytic components of an individual oligoastrocytoma displayed the same genotype. We present two cases of biphasic oligoastrocytomas with aberrant findings, suggesting the coexistence of genetically and morphologically distinct tumour cell clones in these tumours. In one case, the oligodendroglial part of the tumour showed LOH19q, whereas the astrocytic part showed TP53 mutation (codon 273). In another case, we found LOH 1p/19q in the oligodendroglial component, but two retained areas on chromosome 1p in the astrocytic component of the tumour. No evidence was found for the coexistence of tumour cells with the two genotypical changes within the same morphological region of one individual tumour. The two cases of biphasic oligoastrocytomas in our sample that display a different genotype in the astrocytic and oligodendroglial part of the tumour show that different components of an oligoastrocytoma may be derived from different cell clones during neoplastic transformation.     

少突胶质细胞起源肿瘤染色体DNA失衡的比较基因组杂交研究

目的 探讨少突胶质细胞起源肿瘤基因组DNA失衡及其与病理分级的关系.方法 用比较基因组杂交技术检测了33例少突胶质细胞起源肿瘤石蜡包埋组织,分析其全基因组DNA失衡状况.结果 少突胶质细胞瘤(ODG)及间变性少突胶质细胞瘤(AODG)的基因组DNA失衡检出率分别为100%(16/16)和88%(15/17),共发现24个有DNA获得和24个有DNA丢失的染色体区带.其中,-19q、-1p/-19q联合性缺失检出率在ODG组明显高于AODG组(P<0.05),+7p检出率在AODG组明显高于ODG组(P<0.05).在22对常染色体及X染色体中,+1q、+7P、+8P、+8q、+9q、+18p、+18q、+20p及-1p、-19q、-Xq出现频率较高.+2q、+4p、+4q、+6p、+10p、+15q、+20q、+22q仅见ODG组,+11q、+12p、+Xp仅见于AODG组.而-3p、-5q、-8p、-12p、-12q、-15q、-19p、-20q、-XP仅见ODG组,-2q、-4p、-4q、-5p、-6q、-7p、-11q、-14q仅见于AODG组.结论 ODG和AODG均有各自特征性的染色体基因组DNA失衡谱;-1p/-19q是评价国人该类肿瘤生物学行为的重要参考指标,对治疗敏感性及患者预后判断有重要的指导意义;+7p和-19q对评估国人该类肿瘤的生物学行为和患者预后有一定参考价值.

Abstract：

Objective To investigate the relationship between genomic DNA imbalance in oligodendroglial tumors and its different classification.Method 16 oligodendrogliomas and 17 anaplastic oligodendrogliomas were investigated by comparative genomic hybridization on Paraffin-Embedded tissue samples, and the chromosomal genomic DNA imbalances were analyzed.Results Chromosome DNA imbalance rates in oligodendrogliomas and anaplastic oligodendrogliomas are 100% and 88% respectively,and chromosomal regions of 24 gains and 24 losses were found in these tumors.19q loss and 1p/19q loss are frequent in oligodendroglioma.The gain of 7p happened predominantly in anaplastic oligodendroglioma, and their differences were significant(P < 0.05 ).+ 1q, + 7p, + 8p, + 8q, + 9q, + 18p, + 18q, + 20p and-1p,-19q,-Xq are frequently occurred in oligodendroglial tumors.+2q, +4p, +4q, +6p, + 10p,+ 15q, + 20q and + 22q are only identified in oligodendroglioma, + 11q, + 12p and + Xp are only identified in anaplastic oligodendroglioma.-3p,-5q,-8p,-12p,-12q,-15q,-19p,-20q and-Xp are only identified in oligodendroglioma, and-2q,-4p,-4q,-5p,-6q,-7p,-11q and-14q are only identified in anaplastic oligodendroglioma.Conclusions The characteristic imbalance spectrum of oligodendroglial tumors is the molecular genetic base to determine their histological phenotype and grade.-1p/-19q are also the important molecular genetic markers to estimate biological behavior,chemotherapy sensitivity of these tumors and patients' prognosis.+7p and-19q may be useful to evaluate the biological behavior of these tumors and patients' prognosis.     

Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology

Oligodendroglial tumors have attracted great interest in both basic and clinical neuro-oncology over the past decade. This interest is mainly due to the clinical observation that anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, in contrast to the vast majority of anaplastic astrocytomas and glioblastomas, frequently respond favorably to chemotherapy. In addition, oligodendroglial tumors are associated with longer survival times than the diffuse astrocytic gliomas. These differences in response to therapy and in prognosis have been associated with distinct genetic aberrations, in particular the frequent loss of alleles on chromosome arms 1p and 19q in oligodendroglial tumors. In addition, other genetic changes have been reported as indicators of poor response to therapy and short survival, including homozygous deletion of the CDKN2A gene at 9p21, mutation of the PTEN gene at 10q23, and amplification of the EGFR gene at 7p12. In this review we summarize the current state of the art concerning the molecular genetics of oligodendroglial tumors. A particular focus is placed on the role of molecular genetic findings in the diagnostic and prognostic assessment of these neoplasms. As a result of the recent advances in the field, we propose that clinical decisions in the management of patients with oligodendroglial tumors should be based on the combined assessment of clinical and neuroimaging features, histological classification and grading, as well as molecular genetic characteristics.     

α-Internexin in the diagnosis of oligodendroglial tumors and association with 1p/19q status

α-Internexin (INA) has been proposed to be a surrogate marker for the 1p/19q codeletion in oligodendroglial tumors (OTs). We analyzed INA expression in 83 glioma and 21 oligodendroglial phenotype-mimicking tumors (OMT) to assess its usefulness in differential diagnosis and its correlation with 1p/19q status; in particular, INA expression in gliomas with isolated/partial 1p or 19q deletions was assessed. α-Internexin expression and 1p/19q codeletion were present in 92% (34/37) of codeleted tumors (p < 0.0001). By contrast, INA was found in only 20% of cases with isolated/partial 1p aberrations and 36% of cases without 1p/19q deletions; it was also foundin 63% (10/16) of cases with isolated/partial 19q aberrations. α-Internexin expression was more specific in high-grade than in low-grade gliomas (66% vs 31%). Notably, a subset of tumors (10/83) displayed a biphasic INA expression pattern that was significantly associated with proliferation rate, whereas all areas harbored the 1p/19q codeletion. Only no or weak INA expression was seen in OMTs. In summary, INA is a useful marker to differentiate OTs from astrocytic tumors and OMTs, but INA expression is not exclusively linked to OTs harboring the 1p/19q codeletion. Moreover, it can sometimes be heterogeneously distributed within tumors, which emphasizes the need for 1p/19q analysis by molecular genetic techniques for diagnosis.     

Molecular pathways in the formation of gliomas

The past few years have seen remarkable progress in understanding the molecular genetic basis of glioma formation. Affected oncogenes and tumor suppressor genes have been identified and putative tumor suppressor loci have been mapped. These studies have illustrated distinct molecular pathways for different glial neoplasms. We summarize the findings of an ongoing study initiated to characterize human gliomas on a molecular basis. The data are compiled from 150 astrocytic, oligodendroglial, and mixed gliomas that were assessed for genomic alterations characteristic of these neoplasms, i.e., loss of portions of chromosomes 1p, 9p, 10, 17p, 17q, and 19q, mutations of the p53 tumor suppressor gene, and amplification of the EGF receptor (EGFR) gene. Our findings support the hypothesis that distinct genetic pathways result in the formation of astrocytic and oligodendroglial neoplasms of different malignancy grades, and that glioblastoma multiforme may be subdivided into genetically distinct subsets. Such findings may not only lead to a better understanding of neoplastic transformation in glial cells, but may also have a major impact on clinical neuro-oncology. © 1995 Wiley-Liss, Inc.     

Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas

Oligodendrogliomas typically show loss of heterozygosity (LOH) on chromosomes 1p and 19q, which correlates with their response to chemotherapy, whereas low-grade astrocytomas are characterized by frequent TP53 mutations and lack of sensitivity to alkylating therapeutic agents. Unequivocal histological distinction of low-grade diffuse astrocytomas from oligodendrogliomas and oligoastrocytomas is often difficult. To elucidate the relationships between morphological phenotype and genetic profile, we screened 19 oligodendrogliomas (WHO grade II) and 23 low-grade diffuse astrocytomas (WHO grade II) for TP53 mutations and LOH on 1p and 19q. In oligodendrogliomas, LOH on chromosomes 1p and/or 19q was found in 15 cases (79%) and TP53 mutation was detected in 4 cases (21%). The presence of a typical perinuclear halo in >50% of tumour cells and a chicken-wire vascular pattern were significantly associated with LOH on 1p or 19q (93% of cases). This suggests that oligodendrogliomas with classical histologic features are likely to have a better prognosis. In low-grade diffuse astrocytomas, LOH on chromosomes 1p and/or 19q was found in three cases (13%) and TP53 mutation was detected in ten cases (43%). Histologically, five low-grade astrocytomas (22%) contained small areas with oligodendroglial differentiation, but this did not correlate with the presence of TP53 mutations or LOH on 1p and 19q. In both oligodendrogliomas and astrocytomas, LOH on chromosomes 1p or 19q and TP53 mutation were mutually exclusive. Methylation of the promoter of the gene for O (6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, which confers resistance to chemotherapy with alkylating agents, was detected in 47% of oligodendrogliomas and 48% of low-grade diffuse astrocytomas. There was no correlation with LOH on chromosomes 1p/19q, suggesting that MGMT may not be a prognostic marker for oligodendrogliomas.     

Prognostic value of 1p, 19q, 9p, 10q, and EGFR-FISH analyses in recurrent oligodendrogliomas

Although 1p/19q codeletions define "genetically favorable" oligodendrogliomas, eventual tumor progression and patient death remain constant. Genetic testing is often performed at the time of recurrence, though it is unclear whether these or other genetic alterations provide useful prognostic information. We characterized 138 of 189 (73%) available primary and recurrent oligodendroglial neoplasms from 80 patients, utilizing paired FISH probes for 1p32/1q42, 19p13/19q13, CEP7/EGFR, CEP9/p16, and PTEN/DMBT1. Patients were followed until death (49%), or a median follow-up of 8.9 years. Patients with 1p/19q codeleted tumors (71%) had an estimated overall median survival of 14.9 years with an estimated 3.9 years from first recurrence. In contrast, those lacking deletions had significantly lower estimated overall median survivals of 4.7 years and 1.0 year after first recurrence (both p < 0.001). This increased survival in patients with 1p/19q codeleted tumors remained significant when adjustments were made for age, tumor grade, type of surgical procedure, and treatment with radiation or chemotherapy. Only 1 recurrence showed focal EGFR amplification, while 5 developed 10q deletions, mostly in high-grade mixed oligoastrocytomas lacking 1p/19q deletions. In contrast, p16 (9p21) deletions were common and associated with both high grade (p < 0.001) and recurrence (p = 0.002). Our data suggest that in classic oligodendrogliomas: 1) 1p/19q tumor status is a powerful predictor of patient survival, even after recurrence; 2) p16 deletions are common progression-associated alterations; and 3) 10q deletions and EGFR amplifications are sufficiently rare to suggest the possibility of alternate diagnoses.     

Genetic alterations commonly found in diffusely infiltrating cerebral gliomas are rare or absent in pleomorphic xanthoastrocytomas

Pleomorphic xanthoastrocytoma (PXA) is a rare, usually well-circumscribed and superficially located neoplasm that preferentially arises in the cerebral cortex of children and young adults. The molecular aberrations that are associated with these tumors have not been studied systematically so far. We here report on a molecular genetic analysis of 62 PXAs (46 PXAs of World Health Organization [WHO] grade II and 16 PXAs with anaplastic features) for alterations of 5 candidate genes known to be frequently aberrant in diffusely infiltrating astrocytic gliomas, i.e. TP53, CDKN2A (p16(INK4a)), CDK4, MDM2, and EGFR. Only 3 PXAs (5%) carried a TP53 mutation. None of the 62 PXAs had lost both copies of the CDKN2A gene. The CDK4, MDM2, or EGFR genes were not amplified in any of the tumors. Fourteen PXAs were additionally analyzed for loss of heterozygosity (LOH) at microsatellite markers located on the chromosomes/chromosomal arms 1, gp, 9p, 10, 17, 19q, and 22q. Two PXAs (14%) had LOH at all informative markers on 9p, while 1 PXA demonstrated an interstitial area of allelic imbalance between D22S533 and D22S417 at 22q11.2-q13.3. Further analysis of 10 PXAs for inactivation of the CDKN2A. p14(ARF), and CDKN2B (p15(INK4b)) genes on 9p21 did not reveal any homozygous deletion, mutation, promoter hypermethylation, or complete loss of mRNA expression. Taken together, our results indicate that the chromosomal and genetic aberrations in PXAs are different from those typically associated with the diffusely infiltrating astrocytic and oligodendroglial gliomas. These genetic differences likely contribute to the more favorable behavior of PXAs and may be helpful for the molecular differential diagnosis of cerebral gliomas.     

Utility of in situ demonstration of 1p loss and p53 overexpression in pathologic diagnosis of oligodendroglial tumors

To improve the diagnostic accuracy of oligodendroglial tumors and to find more convenient parameters that could predict the cytogenetic status, oligodendroglial and astrocytic tumors were cytogenetically and immunohistochemically investigated. Materials included 22 oligodendroglial tumors (15 oligodendrogliomas and 7 oligoastrocytomas) and 20 astrocytic tumors. 1p loss was examined with the fluorescence in situ hybridization (FISH) method. Expression of GFAP, Olig2 and p53 was immunohistochemically investigated and co‐localization of GFAP and Olig2 was evaluated on double‐immunostained sections. Furthermore, TP53 mutation analyses were carried out on three oligodendroglial tumors showing p53 protein overexpression with a direct sequence analysis. Our FISH studies demonstrated 1p loss in 73% of oligodendroglial tumors (80% oligodendrogliomas and 57% oligoastrocytomas) and in only 10% of astrocytic tumors. There were no clear‐cut morphologic differences between 1p‐deleted and 1p‐intact oligodendroglial tumors. GFAP and Olig2 were expressed in most oligodendroglial and astrocytic tumors, and their cellular localization was almost independent of each other. Overexpression of p53 was observed in five oligodendroglial tumors, all of which were 1p‐intact. In comparison, 16 oligodendroglial tumors with 1p deletion showed no overexpression of p53. TP53 missense mutations were detected in three of the p53 overexpressed oligodendroglial tumors studied. Our results suggest that 1p loss is almost specific to oligodendroglial tumors. Although the prediction of 1p status based solely on the morphologic features seems to be difficult, the immunohistochemistry for p53 is a useful tool in that p53 overexpression is closely related to the 1p‐intact status in oligodendroglial tumors.     

Loss of heterozygosity on chromosome 19 in secondary glioblastomas

Glioblastomas develop rapidly de novo (primary glioblastomas) or slowly through progression from low-grade or anaplastic astrocytoma (secondary glioblastomas). Recent studies have shown that these glioblastoma subtypes develop through different genetic pathways. Primary glioblastomas are characterized by EGFR amplification/overexpression, PTEN mutation, homozygous p16 deletion, and loss of heterozygosity (LOH) on entire chromosome 10, whereas secondary glioblastomas frequently contain p53 mutations and show LOH on chromosome 10q. In this study, we analyzed LOH on chromosomes 19q, 1p, and 13q, using polymorphic microsatellite markers in 17 primary glioblastomas and in 13 secondary glioblastomas that progressed from low-grade astrocytomas. LOH on chromosome 19q was frequently found in secondary glioblastomas (7 of 13, 54%) but rarely detected in primary glioblastomas (1 of 17, 6%, p = 0.0094). The common deletion was 19q13.3 (between D19S219 and D19S902). These results suggest that tumor suppressor gene(s) located on chromosome 19q are frequently involved in the progression from low-grade astrocytoma to secondary glioblastoma, but do not play a major role in the evolution of primary glioblastomas. LOH on chromosome 1p was detected in 12% of primary and 15% of secondary glioblastomas. LOH on 13q was detected in 12% of primary and in 38% of secondary glioblastomas and typically included the RB locus. Except for 1 case, LOH 13q and 19q were mutually exclusive.     

Molecular analysis of chromosome 1, 10 and 19 abnormalities in human oligodendroglial tumors: relationship between frequency of LOH grade, age and gender

BACKGROUND: Loss of heterozygosity (LOH) on 1p and 19q is observed in most oligodendroglial tumors. LOH on 10q appears to be less common in these tumors as compared to other gliomas. PATIENTS AND METHODS: We reviewed 14 patients with oligodendroglial tumors (10 low-grade and 4 anaplastic oligodendroglioma) to evaluate the frequency of LOH on 1p, 10q and 19q and correlate it with tumor grade and patients' age and gender; 5 loci on 1p and 5 on 19q as well as 4 on 10q were analyzed for LOH using PCR techniques. RESULTS: LOH on 1p together with 19q was detected in 6 tumors, 1 tumor showed deletion of 19q accompanied with deletion on 10q. Deletion on 1p was associated with deletion of 19q (p < 0.005) and mutual associations among deletions at loci on 19q (p < 0.05) were found. Patients with LOH on 1p were younger on average than patients with retained heterozygosity (p = 0.05). Grade II oligodendrogliomas predominated among younger patients (p < 0.01) while grade III oligodendrogliomas predominated among women (p < 0.005). No association between LOH on 1p nor 19q and tumor grade or patients' gender was found. CONCLUSION: Our study provides several clinically interesting findings and further supports the hypothesis of chromosome 1p and 19q involvement in the oligodendroglial cancerogenesis.     

Histopathological-molecular genetic correlations in referral pathologist-diagnosed low-grade "oligodendroglioma"

Allelic loss of chromosome 1p predicts increased chemosensitivity and better survival in oligodendroglial tumors. Clinical testing for 1p loss in oligodendroglial tumors at our hospital has allowed us to postulate that certain histological appearances are associated with 1p allelic status. Forty-four cases received for genetic testing were diagnosed by referring pathologists as pure low-grade oligodendroglioma. Central neuropathological review divided the series equally into 22 cases with classical oligodendroglioma histology and 22 with more astrocytic features. Molecular 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%). No glial fibrillary acidic protein-positive cell type (gliofibrillary oligodendrocyte, minigemistocyte, cellular processes) was associated with 1p allelic status. Fourteen of the 44 cases were treated with chemotherapy at tumor progression: 3 "astrocytic" gliomas with 1p loss responded to PCV chemotherapy and 2 classic oligodendrogliomas that maintained both 1p alleles included a responder and a non-responder. These results suggest that histological appearance correctly predicts genotype in approximately 80% of low-grade gliomas, but that tumor genotype more closely predicts chemosensitivity. As a result, such objective molecular genetic analyses should be incorporated into patient management and into clinical trials of low-grade diffuse gliomas.     

Polymorphous oligodendroglioma of Zülch revisited: A genetically heterogeneous group of anaplastic gliomas including tumors of bona fide oligodendroglial differentiation

A polymorphous variant of oligodendroglioma was described by K.J. Zülch half a century ago, and is only very sporadically referred to in the subsequent literature. In particular, no comprehensive analysis with respect to clinical or genetic features of these tumors is available. From a current perspective, the term polymorphous oligodendroglioma (pO) may appear as contradictory in terms, as nuclear monotony is a histomorphological hallmark of oligodendrogliomas. For the purpose of this study, we defined pO as diffusely infiltrating gliomas felt to be of oligodendroglial rather than astrocytic differentiation and characterized by the presence of multinucleate tumor giant cells and/or nuclear pleomorphism. In a total of nine patients, we identified tumors consistent with this working definition. All tumors were high‐grade. We characterized these with respect to clinical, histomorphological and genetic features. Despite clinical and genetic heterogeneity, we identified a subset of tumors of bona fide oligodendroglial differentiation as characterized by combined loss of heterozygosity of chromosome arms 1p and 19q (LOH 1p19q). Those tumors that lacked LOH 1p19q showed a high frequency of IDH1 mutations and loss of alpha thalassemia/mental retardation syndrome X‐linked gene (ATRX) immunoreactivity, indicating a possible phenotypic convergence of true oligodendrogliomas and gliomas of the alternative lengthening of telomeres (ALT) pathway. p53 alterations were common irrespective of the 1p19q status. Histomorphologically, the tumors featured interspersed bizarre multinucleate giant tumor cells, while the background population varied from monotonous to significantly pleomorphic. Our findings indicate, that a rare polymorphous – or “giant cell” – variant of oligodendroglioma does indeed exist.     

Glioblastomas with an oligodendroglial component: a pathological and molecular study

Glioblastoma (GBM) is considered by the WHO classification to represent the most malignant grade of the astrocytic tumors. However, a subset of GBM includes recognizable areas with oligodendroglial features, suggesting that some GBM may also have an oligodendroglial origin. The aim of this study was to analyze the molecular profile of GBM associated with an oligodendroglial component (GBMO). We analyzed a series of 25 GBMO. Loss of heterozygosity (LOH) on 1p and 19q, known as common markers of oligodendroglial tumors, were observed in 40% and 60% of cases, respectively; 72% of the tumors displayed one or both of these markers. All but 4 tumors (84%) showed alterations known to be preferentially involved in the progression of astrocytic tumors to GBM, such as EGFR amplification (44%), P16 deletion (48%), LOH on 10q (64%), PTEN (20%), and TP53 (24%) mutations. Therefore, GBMO displayed all the genetic aberrations found in "standard" GBM with a comparable incidence, but differed from GBM by having a higher rate of LOH on 1p and 19q. These results suggest that GBMO might represent a subgroup of tumors of oligodendroglial origin that is distinct from the "standard" GBM in terms of tumorigenesis pathway.     

Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors

Current evidence suggests that epigenetic changes play an important role in the evolution of human cancers. In this study, we evaluated whether hypermethylation of CpG islands at the gene promotor regions of several tumor-related genes is involved in the carcinogenesis of oligodendroglial tumors. We examined the methylation status of 11 genes in a series of 43 oligodendroglial tumors (19 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 9 oligoastrocytomas, and 2 anaplastic oligoastrocytomas) by methylation-specific polymerase chain reaction. Our results showed that hypermethylation of CpG islands was detectable in 8 of 11 genes studied and 74% of tumors were hypermethylated in at least 1 gene. Promotor hypermethylations were detected in O6-methylguanine-DNA methyltransferase (MGMT), RB1, estrogen receptor, p73, p16INK4a, death-associated protein kinase, p15INK4b, and p14ARF at 60%, 34%, 30%, 16%, 12%, 10%, 7%, and 2%, respectively. No hypermethylation was detected in the promotors of glutathione-S-transferase P1, von Hippel-Lindau or the DNA mismatch repair (hMLH1) genes. Statistical analysis revealed that concordant hypermethylation of at least 2 genes, p16INK4a and p15INK4b were significantly associated with anaplastic oligodendroglial tumors, and hypermethylation of MGMT was significantly associated with loss of chromosome 19q and with combined loss of chromosomes 1p and 19q. More importantly, several candidate tumor suppressor genes such as p16INK4a, p15INK4b, and p73 that were previously reported as unmutated in oligodendroglial tumors were found to be hypermethylated in their CpG islands. Taken together, we conclude that hypermethylation of CpG islands is a common epigenetic event that is associated with the development of oligodendroglial tumors.     

Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity

Rare, generally pediatric oligodendroglioma-like neoplasms with extensive leptomeningeal dissemination have been interpreted variably as glial, oligodendroglial or glioneuronal. The clinicopathologic features have not been fully characterized. We studied 36 patients, 12 females and 24 males with a median age of 5?years (range 5?months–46?years). MRI demonstrated leptomeningeal enhancement, frequently with cystic or nodular T2 hyperintense lesions within the spinal cord/brain along the subpial surface. A discrete intraparenchymal lesion, usually in the spinal cord, was found in 25 (of 31) (81?%). Tumors contained oligodendroglioma-like cells with low-mitotic activity (median 0 per 10 high power fields, range 0–4), and rare ganglion/ganglioid cells in 6 cases (17?%). Tumors were mostly low-grade, with anaplastic progression in 8 (22?%). Immunohistochemistry demonstrated strong reactivity for OLIG2 (7 of 9) (78?%), and moderate/strong S100 (11 of 12) (92?%), GFAP (12 of 31) (39?%) and synaptophysin (19 of 27) (70?%). NeuN, EMA, and mutant IDH1 (R132H) protein were negative. Median MIB1 labeling index was 1.5?% (range <1–30?%). FISH (n?=?13) or SNP array (n?=?2) demonstrated 1p loss/intact 19q in 8 (53?%), 1p19q co-deletion in 3 (20?%), and no 1p or 19q loss in 4 (27?%). Clinical follow-up (n?=?24) generally showed periods of stability or slow progression, but a subset of tumors progressed to anaplasia and behaved more aggressively. Nine patients (38?%) died 3?months–21?years after diagnosis (median total follow-up 5?years). We report a series of a neoplasm with distinct clinicopathologic and molecular features. Although most progress slowly, a significant fraction develop aggressive features.     

Clinical, histological, and immunohistochemical features predicting 1p/19q loss of heterozygosity in oligodendroglial tumors

To identify a better diagnostic criteria for oligodendroglial tumors, we investigated the clinical, histological, and immunohistochemical features that would be able to predict a 1p/19q loss of heterozygosity (LOH) in these tumors. We performed a PCR-based LOH test with the 1p and 19q microsatellite markers by microdissecting tumor in 56 samples (44 oligodendrogliomas and 12 mixed oligoastrocytomas) of paraffin-embedded tissue. Patients with oligodendroglial tumors with 1p/19q LOH had a statistically significant better prognosis for overall survival. Comparative analysis of several features indicated that the 1p/19q LOH tumors were associated with two histological features, tumor cellularity and perinuclear halo, and low O⁶-methylguanine-DNA-methyltransferase (MGMT) expression and high cytoplasmic glutathione S-transferase pi (GST-) expression. In addition, the incidence of 1p/19q LOH was infrequent in the youngest age category (less than 20 years old) studied. Using the new features, we could predict the 1p/19q status of oligodendroglial tumors with greater than 90% accuracy. Therefore, applying these features in clinical practice, would be helpful in clarifying oligodendroglial tumor diagnosis.