Loss of heterozygosity at 6q is frequent and concurrent with 3p loss in sporadic and familial capillary hemangioblastomas

Capillary hemangioblastoma is a benign tumor, occurring sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Inactivation of the VHL gene at 3p25-26 has been demonstrated in all VHL-associated hemangioblastomas. However, the VHL gene has been found to be inactivated in only 20% to 50% of sporadic tumors. So far, no other gene has been reported to be involved in the development of hemangioblastomas. DNA losses at 6q are frequent alterations in hemangioblastomas, as shown by comparative genomic hybridization. We therefore analyzed 15 hemangioblastomas for loss of heterozygosity (LOH) on chromosome 3p and 6q to reveal the frequency of allelic losses and to determine minimal deleted areas. We detected LOH at 6q for one or more markers in 11 (73%) out of 15 cases (in 9 of 11 sporadic and in 2 of 4 VHL-associated tumors). The analyses revealed a minimal 3-megabase (Mb) deleted region at 6q23-24, where 9 of 11 (82%) informative cases showed LOH. LOH at 3p was seen in 14 out of 15 tumors. LOH occurred concurrently at 6q and 3p in 67% of cases. Our data strongly suggests that a tumor suppressor gene located at 6q23-24 is involved in tumorigenesis of hemangioblastomas, in addition to the VHL gene.     

Molecular abnormalities in pediatric embryonal brain tumors--analysis of loss of heterozygosity on chromosomes 1, 5, 9, 10, 11, 16, 17 and 22

Embryonal tumors, the most common group of malignant brain tumors in childhood, are heterogeneous and have been associated with a large number of genetic abnormalities. The aim of this study was to comprehensively analyze loss of heterozygosity (LOH) on regions harboring suppressor genes (PTCH2, PTCH1, APC, PTEN, DMBT1, SUFU, AXIN1, hSNF5/INI1) and to study chromosomal regions in which deletions have been described most frequently (1p, 1q, 11p, 16p, 17p). Twenty-nine children (17 male and 12 female), aged from 1 year 13 years were included in this study. There were 24 medulloblastomas (MB) and 5 supratentorial primitive neuroectodermal tumors (sPNET). Tissue samples from 29 primary and 11 recurrent tumors were analyzed according to the LOH standard procedures, which were extended to include fluorescence in situ hybridization for detection of isochromosome 17q (i(17q)) and direct sequencing ofTP53 exon 4. LOH on 17p was found in 15 out of 29 tumors. FISH analysis identified the presence of i(17q) in 16 tumors. Comparison of LOH analysis and the FISH data indicated that alterations of 17p were related to be the introduction of an i(17q) formation. LOH on 10q and 9q was observed in 4 and 2 cases, respectively, and was associated with alterations of chromosome 17. These results indicated a connection between alterations of PTCH/SHH genes and abnormalities of chromosome 17. A deleted region on 22q, covering the hSNF5/INI1 locus, was observed in 3 tumors. Progression of the molecular changes occurred in 1 case of recurrent medulloblastoma. LOH on 10q and 17p was found in both primary and recurrent tumor, while losses on 11p, 16p, and 16q occurred only in the recurrent tumor. No evidence of alteration in TP53 exon 4 was identified.     

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.     

胶质母细胞瘤11 号-染色体杂合性丢失的研究

目的 :寻找胶质母细胞瘤 (GBM) 11号染色体上可能存在肿瘤抑制基因的杂合性丢失 (LOH)区域。方法 :应用聚合酶链反应方法 ,采用荧光标记的引物和ABIPRISMTM3 77型DNA序列自动分析仪 ,分析GBM 11号染色体上 18个微卫星多态性标记的LOH。结果 :在 47 6%GBM 11号染色体上观察到LOH ,11p和 11q的LOH率分别为 42 9%和 2 3 8%。 11q上所有位点的LOH率都较低 (<3 0 % ) ,在 11p上的下列区域检测到较高的LOH率 :11p 15 5上的D11S40 46(3 3 3 % )位点、11p12 p13上的D11S90 5 (4 1 2 % ) D11S93 5(3 7 5 % )区域。结论 :在 11p 15 5上的D11S40 46位点、11p12 p13上的D11S90 5 D11S93 5区域可能存在多个与GBM相关的肿瘤抑制基因     

Structural genomic abnormalities of chromosomes 9 and 18 in myxopapillary ependymomas

Myxopapillary ependymomas (MPEs) are low-grade neuroepithelial tumors typically occurring in the conus-cauda equina-filum terminale region. Limited molecular and cytogenetic analysis of MPEs has not demonstrated consistent abnormalities. In an attempt to clarify the chromosomal status of these tumors and identify commonly aberrant regions in the genome we have combined 3 molecular/cyto/genetic methods to study 17 MPEs. Comparative genomic hybridization of 7/17 tumors identified concurrent gain on chromosomes 9 and 18 as the most frequent finding. The majority of the 17 tumors were also studied using microsatellite analysis with marker spanning the whole chromosomes 9 and 18 and interphase-FISH with centromeric probes for both chromosomes. Our combined results were consistent with concurrent gain in both chromosomes 9 and 18 in 11/17 cases, gain of either chromosome 9 or 18 and imbalance in the other chromosome in 3/17 tumors and allelic imbalances of chromosomes 9 or 18 in 3/17 and 1/17 tumors, respectively. Other abnormalities observed included gain of chromosomes 3, 4, 7, 8, 11, 13, 17q, 20, and X and loss of chromosomes 10 and 22. Our findings represent some steps towards understanding the molecular mechanisms involved in the development of MPE.     

Loss of heterozygosity analysis in an anaplastic oligodendroglioma arising after radiation therapy

OBJECTIVE AND IMPORTANCE: Oligodendroglial tumors rarely occur after radiation therapy. Here, we report a rare case of anaplastic oligodendroglioma arising after radiation therapy, in which genetic analysis was performed. CLINICAL PRESENTATION AND INTERVENTION: A 41-year-old man who had received radiation therapy for a tumor of the suprasellar and pineal regions 31 years previously, presented with headache and progressive right hemiparesis. Magnetic resonance (MR) images revealed a ring-enhanced mass lesion in the left frontal lobe. Total removal of the tumor was performed through left frontoparietal craniotomy, and the histologic diagnosis was anaplastic oligodendroglioma. Using 23 microsatellite markers, the allelic status of chromosomes 1p, 10, 17p and 19q was evaluated by a PCR-based loss of heterozygosity (LOH) assay. Markers on chromosomes 1p, 17p and 19q revealed LOH, but none of the markers on chromosome 10 showed LOH. Based on the genetic analysis, this tumor was considered to be sensitive to chemotherapy. Two courses of chemotherapy, with procarbazine, ACNU and vincristine, were performed. However, tumor recurrence was detected only 3 months after the surgery. Despite additional radiochemotherapy, the tumor aggressively increased in size and the patient died with multiple recurrent tumors 1 year after surgery. CONCLUSION: The anaplastic oligodendroglioma presented in this report showed a more aggressive clinical course than was expected from the genetic analysis. The significance of 1p and 19q LOH in radiation-induced oligodendroglial tumors might differ from that in spontaneous counterparts.     

Association of chromosome 10 losses and negative prognosis in oligoastrocytomas

Oligoastrocytomas are mixed gliomas harboring different genetic alterations and with heterogeneous clinical evolution. We have looked for correlations between genetic losses and clinical evolution in 34 oligoastrocytomas. Loss of heterozygosity (LOH) with different microsatellite markers was studied on chromosomes 1p, 10q, 17p, and 19q. LOH on 1p was found in 44% of the tumors, on 10q in 24%, on 17p in 18%, and on 19q in 38%. LOH on 1p and 19q was combined in 29% of the patients. LOH on 1p was associated with significantly longer overall survival (p = 0.0092) and LOH on 10q with shorter overall survival (p = 0.0206). The observation that LOH on 10q predicts a short survival in oligoastrocytomas is novel and provides further evidence that genetic analysis may help to predict the clinical evolution of different gliomas, giving a more rationale basis to therapeutic options.     

Loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in malays with malignant glioma

Recent advances in neuro-oncology have revealed different pathways of molecular oncogenesis in malignant gliomas including loss of heterozygosity on chromosomal regions harboring tumor suppressor genes. In the present study, we performed polymerase chain reaction-loss of heterozygosity (PCR-LOH) analysis using microsatellite markers to identify loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in the Malays with malignant gliomas. Of 12 cases with allelic losses, seven (58.3%) cases showed LOH on chromosome 10q, three (25.0%) cases showed LOH on chromosome 9p, four (33.3%) cases showed LOH on chromosome 17p and two (16.7%) cases showed LOH on chromosome 13q. The cases include five (41.7%) cases of glioblastoma multiforme, three (25.0%) cases of anaplastic astrocytoma, three (25.0%) cases of anaplastic oligodendroglioma and one (8.3%) case of anaplastic ependymoma. Four cases showed loss of heterozygosity on more than one locus. Our findings showed that loss of heterozygosity on specific chromosomal regions contributes to the molecular pathway of glioma progression in Malay population. In addition, these data provide useful evidence of molecular genetic alterations of malignant glioma in South East Asian patients, particularly in the East Coast of Malaysia.     

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.     

脑膜瘤第1、10、14和22对染色体的LOH和MI与相关因素分析

目的 研究脑膜瘤第1,10,14和22对染色体的LOH和MI及其相关因素,方法 对39例脑膜瘤用PCR方法检测D1S188,D10S187,D14S43和D22S1 4个位点的LOH和MI,探讨其与病理学表现,FCM及肿瘤复发等关系。结果 间变型脑膜瘤4个位点的LOH比率显著高于良性型;间变型D14S43 LOH也显著高于非典型型,4个位点LOH（＋）组DI均分别显著高于LOH（－）组,D1S188,D14S43和D22S1LOH（＋）组的超二倍体率均显著高于LOH（－）组,6例复发性脑膜瘤组,LOH（＋）者5例,显著高于初发性组,各组的MI未见显著性差异。结论脑膜瘤的D1S188,D10S187,D14S43和D22S1 LOH与肿瘤的发生和恶性生物学行为密切有关。     

Loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in Malays with malignant glioma

Abstract

Recent advances in neuro-oncology have revealed different pathways of molecular oncogenesis in malignant gliomas including loss of heterozygosity on chromosomal regions harboring tumor suppressor genes. In the present study, we performed polymerase chain reaction–loss of heterozygosity (PCR-LOH) analysis using microsatellite markers to identify loss of heterozygosity on chromosomes 10q, 9p, 17p and 13q in the Malays with malignant gliomas. Of 12 cases with allelic losses, seven (58.3%) cases showed LOH on chromosome 10q, three (25.0%) cases showed LOH on chromosome 9p, four (33.3%) cases showed LOH on chromosome 17p and two (16.7%) cases showed LOH on chromosome 13q. The cases include five (41.7%) cases of glioblastoma multiforme, three (25.0%) cases of anaplastic astrocytoma, three (25.0%) cases of anaplastic oligodendroglioma and one (8.3%) case of anaplastic ependymoma. Four cases showed loss of heterozygosity on more than one locus. Our findings showed that loss of heterozygosity on specific chromosomal regions contributes to the molecular pathway of glioma progression in Malay population. In addition, these data provide useful evidence of molecular genetic alterations of malignant glioma in South East Asian patients, particularly in the East Coast of Malaysia.     

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.     

Comparative genomic hybridization in pineal germ cell tumors

Fifteen primary pineal germ cell tumors (8 germinomas, 4 mixed teratomas-germinomas, 2 immature teratomas, and 1 yolk sac tumor) and 2 recurrences of the yolk sac tumor were studied by comparative genomic hybridization (CGH). An average of 1.8 chromosomal changes per germinoma (0.5 gains vs 1.3 losses), 5.5 per mixed teratoma-germinoma (3.0 gains vs 2.5 losses), 3.5 per immature teratoma (2.0 gains vs 1.5 losses), and 2.0 in the yolk sac tumor (2 gains vs 0 losses) were found; the first recurrence showed 7 (4 gains vs 3 losses), the second 13 imbalances (8 gains vs 5 losses). The most frequent imbalances were gains on 12p (40%), 8q (27%), and 1q (20%) as well as losses on 13q (47%), 18q (33%), 9q and 11q (20% each). Among germinomas, the most common chromosomal changes were -13q and -18q (38% each), in mixed teratomas-germinomas +8q (100%), +12p (75%), -13q (75%) and -9q (50%). Seven high-level gains were identified: 5 in mixed teratomas-germinomas (+8q: 3 cases, + 12p: 2 cases), 1 each in a germinoma (+2p) and an immature teratoma (+12p). Minimal common regions of over- and underrepresentation were found on +8q11.22-21.1, +12p11.1-12.1, -9q32-qter, -11q23.2-qter, -13q32-qter and -18q22-qter. Our findings suggest, that imbalances in cerebral germ cell tumors affect the same chromosomes as among their extracerebral counterparts, albeit in a considerably lower frequency among cerebral germinomas where +12p does not seem to play a major role.     

Spatial variability of genomic aberrations in a large glioblastoma resection specimen

In the present study, the distribution of genetic aberrations in a glioblastoma resection specimen of unusually large size (9x8x2 cm) was investigated using comparative genomic hybridization (CGH). CGH was performed on 20 samples taken from the specimen, and the genetic aberrations found were compared with the regional histology. The samples were histopathologically graded according to WHO criteria, and a division in high- and low-grade areas and infiltration rims was made. In high-grade areas, low-grade areas as well as infiltration rims, gains on 10p11.2-pter (14/20), 11q12-q22 (6/20) and losses on 4q13-qter (9/20), 10q22-qter (8/20), 11p14-pter (5/20), 13q12-qter (7/20) were revealed. Gains on 1q21-32 (2/4) and losses on 7p21-pter (3/4) were exclusively found in the high-grade areas. In the low-grade tumor samples and in the infiltration rim, gains on 16p11.2-pter (6/16), 17p11.2-pter (6/16), 17q11.2-qter (5/16), 20q11.2-q13 (3/16) and deletions on 5q31-qter (4/16) were detected. Gains on 7q21-qter (8/11) and 8q11.2-qter (6/11), and loss of chromosome 9 (4/11) and the Y-chromosome (4/11) were found in the high-grade and low-grade samples, not in the infiltration rims. The finding of a set of identical chromosomal aberrations throughout the resection specimen, most of which have been previously reported in gliomas, confirms a mechanism of clonal tumor proliferation operative in gliomas. The previously unreported genetic alterations which were predominantly traced in the tumor rims, might reflect either selection for properties related to infiltrating behavior, or genomic instability of subclones. The findings illustrate the importance of searching for high-grade genetic aberrations in low-grade tumor samples taken from cases in which sampling error is suspected.     

胶质母细胞瘤9号染色体肿瘤抑制基因的研究

目的寻找胶质母细胞瘤(GBM)9号染色体上可能存在肿瘤抑制基因的杂合性丢失(LOH)区域,为发现和定位肿瘤抑制基因(TSG)提供线索和依据.方法应用聚合酶链反应(PCR)方法,采用荧光标记引物和377型DNA序列自动分析仪,分析2l例GBM9号染色体上20个微卫星多态性标记的LOH.结果21例GBM中,在14例的9号染色体上检测到LOH,33.0%(93/282)可提供信息位点存在LOH.在9p和9q上存在LoH的GBM分别有14例和10例.在位于9p21-23的D9S286位点以及9p21的D9S285～D9S157位点间区域检测到较高LOH率,分别为52.6%、43.8%～46.7%.结论染色体9p上等位基因的丢失可能在GBM分子水平发病机制中起着重要作用.在9p21-23的D9S286位点、9p21的D9S285～D9S157位点间区域可能存在与GBM相关的多个TSG,可能包括位于9p21上的p16和p15基因,在p16、p15所在染色体区域的远端9p21-23可能存在其他未知的TSG.     

Loss of heterozygosity on chromosome 22 in human ependymomas

Ependymomas are glial tumors of the brain and spinal cord. The most frequent genetic change in sporadic ependymomas is monosomy 22, suggesting the presence of an ependymoma tumor suppressor gene on chromosome 22. Thirty-three pairs of matched normal and tumor specimens from ependymoma patients were genotyped using 12 polymorphic microsatellite markers spanning the long arm of chromosome 22. Allelic deletion was found in 12 of 33 tumors (36.4%). Eight tumors showed partial deletions and 4 tumors exhibited loss of the entire arm of 22q. We identified two common regions of deletion: one at 22q11.21-12.2 flanked by markers D22S420 and D22S300, and a second candidate region at 22q13.1-13.3 between D22S274 and D22S1149. The size of each region was 21.1 and 2.4 cM, respectively. Thus, our results suggest that one or more tumor suppressor genes associated with ependymoma may be present on chromosome 22. Comparison of these results with clinicopathological data indicate that allelic losses on 22q tend to occur more frequently in intracranial anaplastic ependymomas in children and intraspinal ependymomas in adults.     

Deletion mapping of the short arm of chromosome 1 identifies a common region of deletion distal to D1S496 in human meningiomas

We have studied a series of 63 meningiomas, including 47 benign meningiomas (World Health Organization, WHO, grade I), 13 atypical meningiomas (WHO grade II) and 3 anaplastic meningiomas (WHO grade III), using microsatellite and restriction fragment length polymorphism analysis for loss of heterozygosity (LOH) at 21 polymorphic loci on chromosome 1 (19 loci on 1p and 2 loci on 1q). LOH on 1p was found in 9 of 13 atypical meningiomas (70%) and in 3 of 3 (100%) anaplastic meningiomas, but only in 6 of 47 (13%) benign meningiomas. In 13 tumors allelic loss was observed at all informative loci on 1p. Terminal deletions with retention of heterozygosity at one or more proximal 1p loci were found in 5 tumors. The region commonly deleted in all tumors was located distally to the D1S496 locus, i.e., at cytogenetic bands 1p34 – 1pter, and included the chromosomal segment which is frequently deleted in neuroblastoma, malignant melanoma, and different types of carcinoma. Received: 11 February 1997 / Revised: 9 May 1997 / Accepted: 12 May 1997     

Genomic analysis of pilocytic astrocytomas at 0.97 Mb resolution shows an increasing tendency toward chromosomal copy number change with age

Brain tumors are the most common solid tumors of childhood, accounting for over 20% of cancers in children under 15 years of age. Pilocytic astrocytomas (PAs), World Health Organization grade I, are one of the most frequently occurring childhood brain tumors, yet little is known about genetic changes characterizing this entity. We have used microarray comparative genomic hybridization at 0.97 Mb resolution to study a series of PAs (n = 44). No copy number abnormality was seen in 64% of cases at this resolution. However, whole chromosomal gain (median 5 chromosomes affected) occurred in 32% of tumors. The most frequently affected chromosomes were 5 and 7 (11 of 44 cases each) followed by 6, 11, 15, and 20 (greater than 10% of cases each). Findings were confirmed by fluorescence in situ hybridization and microsatellite analysis in a subset of tumors. Chromosomal gain was significantly more frequent in PAs from patients over 15 years old (p = 0.03, Fisher exact test). The number of chromosomes involved was also significantly greater in the older group (p = 0.02, Mann-Whitney U test). One case (2%) showed a region of gain on chromosome 3 and one (2%) a deletion on 6q as their sole abnormalities. This is the first genomewide study to show this nonrandom pattern of genetic alteration in pilocytic astrocytomas.     

The molecular basis of glia-derived tumours of the brain. Part I

The development and progression of astrocytic tumours is associated with acquisition and accumulation of genetic alternations. Loss of heterozygosity (LOH) on chromosome 17p., p53 mutations and overexpression of the platelet-derived growth factor (PDGF) receptor (chromosome 22q), are the most common detectable changes in astrocytomas (WHO grade II). Anaplastic astrocytomas (WHO grade III) involve LOH on chromosome 19q, deletion of p16 tumor suppressor gene on chromosome 9p and disturbed expression of gene RB on chromosome 13q. LOH on chromosome 10 is restricted largely to glioblastomas (WHO grade IV). This tumour also is characterized by amplification and/or overexpression of gene coding Epidermal Growth Factor Receptor (EGFR) on chromosome 7p. There is growing evidence that two genes encoding triiodothyronine receptors TR alpha [17q21] and TR beta [3p21-p25]) belong also to the group of genes involved in tumorigenesis. Mutations of these genes as well as markedly disturbed expression and function of the encoded proteins were found in tumour tissue. This is supported by facts. that T3 via TRs regulate proliferation, growth, differentiation and apoptosis, the processes that are deeply disturbed in tumour tissue. TRs affects also the action of certain protooncogenes (Mdm2) and tumor suppressors (p53, Rb).