胶质瘤1p/19q联合缺失与临床病理因素的相关性分析

目的 本研究旨在筛选与胶质瘤组织1p/19q联合缺失相关的临床病理因素.方法 收集胶质瘤标本56例,采用荧光原位杂交(FISH)方法检测肿瘤组织标本中1p和19q的状态,并用免疫组化对9种肿瘤相关蛋白进行半定量分析,应用统计学方法筛选与1p/19q联合缺失相关的临床病理因素.结果 单因素分析证实病理类型、p53和O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)表达水平与1p/19q联合缺失相关,Logistic回归进一步证实病理类型和MGMT表达水平与1p/19q联合缺失相关,P值分别为0.001和0.004.结论 在胶质瘤中,通过病理类型和MGMT表达水平可以准确预测部分胶质瘤的1p/19q缺失状态,1p/19q联合缺失有可能通过p53和MGMT的低表达,增强烷化剂化疗疗效和延长存活期.

Abstract：

Objective This study aimed to select clinical and pathological aspects correlated with 1p/19q co- deletion in gliomas.Methods Samples of 56 glioma patients were collected.The status of chromosome 1p and 19q was detected by Fluorescence in Situ Hybridization (FISH) and the expression levels of nine tumor- associated proteins were analyzed semi- quantitatively by immunohistochemistry.Then the aspects correlated with 1p/19q co- deletion were chosen by univariate and logistic regression methods.Methods Pathology,expression levels of p53 and MGMT were the factors correlated with 1p/19q co-deletion by univariate analysis,while pathology and expression level of MGMT were further confirmed by logistic regression.Conclusion 1p/19q co- deletion could be predicted by pathology and expression level of MGMT exactly in part of gliomas.It is likely that 1p/19q co-deletion results in hypo-expression of p53 and MGMT in gliomas,which in turn lead to improved alkylator sensitivity and prolonged survival.     

胶质瘤1p/19q联合缺失特征分析

目的 研究胶质瘤中1p/19q联合缺失与患者临床特征及O6-甲基鸟嘌呤-DNA甲基转移酶(O6-methylguanine-DNA methyltransferase,MGMT)表达的关系.方法 使用荧光原位杂交技术,对中山大学附属肿瘤医院2009年3月至2011年3月的63例手术确诊胶质瘤标本进行1p/19q联合缺失检测,利用统计学方法分析1p/19q联合缺失患者与无联合缺失患者在性别、年龄、部位、病理类型及MGMT表达状态是否有差异.结果 全组63例患者,男38例,女25例,年龄(41.7 ± 15.3)岁.其中,16例(25.4%)存在1p/19q联合缺失.1p/19q联合缺失患者与无联合缺失患者在性别、年龄及肿瘤部位间的差异无统计学意义.各病理类型1p/19q联合缺失的比例从高到低依次为少突胶质细胞瘤(9/16)、间变性少突胶质细胞瘤(3/8)、星形细胞瘤(2/10)、间变性星形细胞瘤(1/6)及胶质母细胞瘤(1/21),其差异有统计学意义(P ＜ 0.01).在全组63例胶质瘤及25例含少突成分胶质瘤中,MGMT阳性肿瘤1p/19q联合缺失比例与MGMT阴性组间的差异皆无统计学意义.结论 1p/19q联合缺失主要与胶质瘤的病理类型有关,含少突成分胶质瘤中1p/19q联合缺失比例较高.1p/19q联合缺失可作为少突胶质细胞瘤病理诊断的重要参考指标.     

Ⅱ型神经纤维瘤病分子遗传分析指导临床个体化诊疗的研究

目的 建立临床适用的Ⅱ型神经纤维瘤病(NF2)的分子遗传分析方法,对NF2患者及其后代进行分子遗传诊断,以指导NF2家族的遗传咨询及个体化病情监测、随访及临床干预.方法 以天津医科大学总医院神经外科自2009年1月至2010年1月收治的10例NF2患者为研究对象,收集患者的肿瘤组织标本,原代培养并鉴定术中获取的许旺细胞瘤组织.抽提原代培养的肿瘤性许旺细胞及患者血液的基因组DNA(2例NF2患者已有后代且同意接受基因测序,同时对其后代的血液进行基因组DNA提取),对2例NF2患者亲子二代血液及患者的肿瘤性许旺细胞基因组DNA进行NF2基因测序.制定不同的临床干预及随访计划,结合亲子二代分子遗传检测结果,对NF2家族制定后代的长期随访计划.结果 初步建立NF2许旺细胞瘤组织标本与基因组DNA库.基因测序结果显示肿瘤性许旺细胞与患者血液提取的NF2基因突变位点相同.第一组母女存在完全相同的基因突变位点,第二组母子基因突变位点不完全一致,二组检测到的突变位点均位于靠近外显子的调控区.结论 NF2许旺细胞瘤组织标本及基因组DNA库可以为该病分子遗传研究提供组织及基因组DNA资源.分子遗传分析可以指导临床工作,提前预计后代罹患风险,为高风险人群制定个体化的随访计划.个体化的临床干预可以提高患者的生活质量,延长生存期.

Abstract：

Objective To establish a molecular genetic analysis method applicable clinically for genetic diagnosis of patients with neurofibromatosis type Ⅱ (NF2) and their offsprings, and further guide the genetic counseling of NF2 family, condition monitoring, follow-up as well as clinical intervention of the patients. Methods Ten patients with NF2, admitted to our hospital from January 2009 to January 2010, were chosen;tumorigenic Schwann cells in Schwannoma were isolated and purified for primary culture. Genomic DNA was extracted from tumorigenic Schwann cells and from the blood of 2 patients and their offsprings who agreed to accept gene sequencing;the NF2 gene was sequenced (El-15 and El7 exons and adjacent introns). According to the implication of NF2 gene sequencing, genetic counseling was given to the NF2 family, and the potential NF2 patients in offsprings were followed up in a long-term. Results Schwannoma tissue and genomic DNA bank were established initially. Totallysame NF2 gene mutations were detected in genomic DNA extracted both from tumorigenic Schwann cells and blood cells in the same patient. By comparing the genotypes between the patients and the offsprings,consistent NF2 gene mutations were found between a female patient and her daughter aged 3, but not completely consistent gene mutations between another female patient and her son aged 15. All of the mutations in NF2 gene were located in the control region near the exons. Based on the patient's clinical manifestations and symptoms, reasonable plans for clinical interventions and follow-up were developed.Conclusion Schwannoma tissue and genomic DNA bank could supply the bio-resource for genetic molecular testing and treatment studies. Molecular genetic analysis would apply in clinical practice guidance, NF2 risk prediction, and follow-up plan for high-risk NF2 individuals. Early diagnosis and treatment, condition monitoring and long term follow-up and personalized clinical intervention are needed to improve the quality of life and prolong the survival.     

MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes.Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia.Frontotemporal dementia is characterized by progressive impairments in behavior,executive function,and language.There are two main clinical subtypes:behavioral-variant frontotemporal dementia and primary progressive aphasia.The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients.Without validated biomarkers,the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features,but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders.In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies.Measurement of specific miRNAs singly or in combination,or as miRNA pairs(as a ratio)in blood plasma,serum,or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls,Alzheimer’s disease,and amyotrophic lateral sclerosis.Furthermore,upregulation of miR-223-3p and downregulation of miR-15a-5p,which occurred both in blood serum and cerebrospinal fluid,distinguished behavioral-variant frontotemporal dementia from healthy controls.Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia,respectively,from healthy controls.Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p,miR-15a-5p,miR-22-3p in blood serum and cerebrospinal fluid,and miR-124 in cerebrospinal fluid.No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes.Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.     

Precision radiotherapy for brain tumors A 10-year bibliometric analysis

OBJECTIVE: Precision radiotherapy plays an important role in the management of brain tumors. This study aimed to identify global research trends in precision radiotherapy for brain tumors using a bibliometric analysis of the Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of data retrievals for precision radiotherapy for brain tumors containing the key words cerebral tumor, brain tumor, intensity-modulated radiotherapy, stereotactic body radiation therapy, stereotactic ablative radiotherapy, imaging-guided radiotherapy, dose-guided radiotherapy, stereotactic brachytherapy, and stereotactic radiotherapy using the Web of Science. SELECTION CRITERIA: Inclusion criteria: (a) peer-reviewed articles on precision radiotherapy for brain tumors which were published and indexed in the Web of Science; (b) type of articles: original research articles and reviews; (c) year of publication: 2002-2011. Exclusion criteria: (a) articles that required manual searching or telephone access; (b) Corrected papers or book chapters. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to country; (3) distribution according to institution; (4) top cited publications; (5) distribution according to journals; and (6) comparison of study results on precision radiotherapy for brain tumors. RESULTS: The stereotactic radiotherapy, intensity-modulated radiotherapy, and imaging-guided radiotherapy are three major methods of precision radiotherapy for brain tumors. There were 260 research articles addressing precision radiotherapy for brain tumors found within the Web of Science. The USA published the most papers on precision radiotherapy for brain tumors, followed by Germany and France. European Synchrotron Radiation Facility, German Cancer Research Center and Heidelberg University were the most prolific research institutes for publications on precision radiotherapy for brain tumors. Among the top 13 research institutes publishing in this field, seven are in the USA, three are in Germany, two are in France, and there is one institute in India. Research interests including urology and nephrology, clinical neurology, as well as rehabilitation are involved in precision radiotherapy for brain tumors studies. CONCLUSION: Precision radiotherapy for brain tumors remains a highly active area of research and development.     

Neuroprotective mechanisms of rutin for spinal cord injury through anti-oxidation and anti-inflammation and inhibition of p38 mitogen activated protein kinase pathway

Rutin has anti-inflammatory, antioxidant, anti-viral, anti-tumor and immune regulatory effects. However, the neuroprotective effects of rutin in spinal cord injury are unknown. The p38 mitogen activated protein kinase(p38 MAPK) pathway is the most important member of the MAPK family that controls inflammation. We assumed that the mechanism of rutin in the repair of spinal cord injury is associated with the inhibition of p38 MAPK pathway. Allen's method was used to establish a rat model of spinal cord injury. The rat model was intraperitoneally injected with rutin(30 mg/kg) for 3 days. After treatment with rutin, Basso, Beattie and Bresnahan locomotor function scores increased. Water content, tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 levels, p38 MAPK protein expression and caspase-3 and-9 activities in T8–9 spinal cord decreased. Oxidative stress related markers superoxide dismutase and glutathione peroxidase levels increased in peripheral blood. Rutin exerts neuroprotective effect through anti-oxidation, anti-inflammation, anti-apoptosis and inhibition of p38 MAPK pathway.     

The 9LLUC/Wistar rat glioma model is not suitable for immunotherapy

The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised tumors, and may be a useful animal model for the evaluation of various therapeutic approaches for gliosarcomas. In this study, the 9L/Wistar rat glioma model was produced by intracerebral implantation of 9LLUC glioma cells syngenic to Fischer 344 (F344) rats. Bioluminescence imaging showed that tumors progressively grew from day 7 to day 21 in 9LLUC/F344 rats, and tumor regression was found in some 9LLUC/Wistar rats. Hematoxylin-eosin staining verified that intracranial tumors were gliomas. Immunohistochemistry results demonstrated that no CD4- and CD8-positive cells were found in the syngeneic 9LLUC/F344 model. However, many infiltrating CD4- and CD8-positive cells were observed within the tumors of the 9LLUC/Wistar model. Our data suggests that compared with 9L/F344 rats, 9L glioma Wistar rats may not be suitable for evaluating brain glioma immunotherapies, even though the model induced an immune response and exhibited tumor regression.     

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.     

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.     

Losses of chromosomes 1p and 19q are rare in pediatric oligodendrogliomas

Pediatric oligodendrogliomas are rare neoplasms and have not been characterized extensively either pathologically or genetically. Given the recent interest in the significance of chromosomal losses in predicting the clinical course and in establishing uniform diagnoses of adult oligodendrogliomas, we reviewed the pathological and clinical features of a series of pediatric oligodendrogliomas and determined their 1p and 19q status using fluorescence in situ hybridization. Of 19 tumors originally diagnosed as oligodendroglioma, 7 were oligodendroglioma, 3 were anaplastic oligodendroglioma, 3 were oligoastrocytoma, and 6 were reclassified. Only one tumor, an anaplastic oligodendroglioma, had 1p loss; none had 19q loss. The single patient whose tumor had 1p loss did not have a particularly favorable clinical course. These results suggest that pediatric oligodendrogliomas arise by molecular alterations distinct from adult oligodendrogliomas, and such molecular alterations do not hold immediate promise as an adjunct to the diagnosis of pediatric oligodendrogliomas.     

Leptomeningeal disease from oligodendroglioma: clinical and molecular analysis

BACKGROUND: Leptomeningeal disease (LMD) is a late complication of malignant glioma, mostly of glioblastoma, that usually responds poorly to treatment and is rapidly fatal. A long surviving case led us to review our experience with LMD in patients with oligodendrogliomas. METHODS: A 15-year retrospective chart review was performed. Patients with both oligodendroglial tumors and LMD were identified. A single neuro-pathologist reviewed all histological sections, a single neuro-radiologist reviewed all available images and 1p/19q status was assessed. RESULTS: Seven out of 145 patients with oligodendroglioma were diagnosed with LMD. Six were male. Median age at tumor diagnosis was 41 years (range, 28-50). None had radiographic or pathological evidence of leptomeningeal or subependymal tumor at initial diagnosis. Most patients had pure anaplastic oligodendrogliomas (4/7); 6/7 had 1p/19q co-deletion. The median time to first relapse was 41 months (range, 19-127). The median time to LMD was 76 months (range, 19-151) from initial diagnosis and 28 months (range, 0-36) from first relapse, respectively. Leptomeningeal disease treatments included spinal radiation and intrathecal and systemic chemotherapy. After progression, some patients with LMD remained stable clinically. The median survival from initial diagnosis was 104 months (range, 19-183) and from LMD diagnosis was 32 months (range, 2-43). CONCLUSIONS: Leptomeningeal disease is a complication of oligodendroglioma that may occur preferentially in long surviving patients with 1p/19q co-deletion. Leptomeningeal disease in patients with oligodendrogliomas appears to be relatively indolent which may have implications for their treatment and be related to 1p/19q status.     

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.     

Oligodendrogliomas: impact of molecular genetics on treatment

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.     

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.     

Challenging diagnosis: oligodendroglioma versus extraventricular neurocytoma

Diagnosis of oligodendroglioma from other clear cell neoplasms of central nervous system (CNS) is still challenging despite advances in neuroradiology and molecular diagnostic tools. Herein, we present a 44-year-old male patient who had a diagnosis of right parietal oligodendroglioma grade II in 1994 which recurred in 2002. He presented with intratumoral hemorrhage and he underwent radical resection of tumor in 2003. Histopathological examination of the recurrent tumor showed anaplastic progression with confusing immunohistochemical (IHC) results; the tumor was positive for NeuN and synaptophysin staining. The question arisen was whether the recurrent tumor was an oligodendroglioma with neuronal differentiation or an extraventricular neurocytoma initially misdiagnosed as oligodendroglioma. Repeated IHC staining showed negative results for NeuN and synaptophysin. Chromosomal analysis revealed 1p/19q deletion, which led to the diagnosis ofanaplastic oligodendroglioma grade III. Accurate diagnosis of oligodendroglioma is crucial due to recent advances and promises in its treatment. Current diagnostic methods of oligodendroglial tumors are discussed in context of differentiating oligodendrogliomas from other clear cell neoplasms of CNS, especially from extraventricular neurocytomas.     

P18 tumor suppressor gene and progression of oligodendrogliomas to anaplasia

P18INK4C is a good candidate to be the tumor suppressor gene involved in oligodendrogliomas on 1p32. Loss of heterozygosity on 1p, mutation(s), homozygous deletion(s), and expression of p18 in 30 oligodendroglial tumors were investigated. Loss of heterozygosity on 1p was found in 15 tumors. A p18 mutation was found at an recurrence of an anaplastic oligodendroglioma, but not in the primary, low-grade tumor. No homozygous deletions were found and p18 was expressed in all cases. These results show that p18 alteration is involved in tumor progression in a subset of oligodendrogliomas.