Genetic alterations in pediatric high-grade astrocytomas

Cheng, Yue; Ng, Ho Keung; Zhang, Shang Fu; Min, Di; Pang, Jesse Chung Sean; Zheng, Jiayi; Poon, Wai Sang

doi:10.1016/s0046-8177(99)90057-6

Cited by 110 publications

(85 citation statements)

References 32 publications

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“…In some of them, no EGFR amplifications were observed among pediatric glioblastomas, 5,11,13,14 whereas in a few small series, the frequency of this aberration reached 25%. 6,12 Finally, Bredel et al 4 have found EGFR amplification in two of 27 supratentorial pediatric glioblastomas (7.4%), which is a rate quite compatible with that observed by us in the current series (9%).…”

Section: Discussionmentioning

confidence: 95%

“…3 Nevertheless, relatively few studies have been performed on molecular properties of pediatric glioblastomas, while different genetic pathways have been suggested in the tumorigenesis of childhood and adult malignant gliomas. [4][5][6][7][8][9][10][11][12][13][14][15] Also, little information is available on the clinical significance of various molecular markers in pediatric high-grade astrocytomas. A few retrospective studies have found associations between adverse outcomes and p53 alterations, 8 gain of 1q, 13 and mutation of PTEN gene-suppressor.…”

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confidence: 99%

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Clinical utility of fluorescence in situ hybridization (FISH) in nonbrainstem glioblastomas of childhood

et al. 2005

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Astrocytic gliomas are the most common pediatric brain tumors; however, nonbrainstem glioblastomas are extremely rare compared with their adult counterparts. Little information is available on the clinical significance of various molecular markers in pediatric grade IV astrocytomas. The current study was focused on the molecular analysis and clinico-pathological correlations in a set of 44 tumor samples obtained from pediatric patients with nonbrainstem glioblastomas. Fluorescence in situ hybridization (FISH) with a set of 10 commercial chromosome probes (1p36, 1q25, centromere (CEP)7, EGFR, CEP9, 9p21/p16, CEP10, 10q23/PTEN, 19p13, and 19q13) was performed. Disclosed molecular abnormalities, in descending order of frequency, included polysomy 7 (72%), loss of 10q23 (61%), loss of 9p21 (52%), loss of 1p36 (41%), gain of 1q25 (25%), polysomy 9 (16%), EGFR amplification (9%), loss of 19q13 (5%), polysomy 19 (5%), and codeletion 1p36/19q13 (2%). The overall survival time was markedly shorter only for those patients whose lesions harbored deletion of 10q23/ PTEN locus (log-rank test; P ¼ 0.00007). By multivariate analysis, only loss of 10q23 locus reached an independent level of prognostic value (hazard ratio ¼ 2.88; P ¼ 0.01). There were no significant differences in patient survival for other molecular abnormalities. In conclusion, a FISH analysis of 10q23 dosage should be recommended as an ancillary laboratory method that allows further clinical subdivision of pediatric glioblastomas.

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Section: Discussionmentioning

confidence: 95%

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confidence: 99%

Clinical utility of fluorescence in situ hybridization (FISH) in nonbrainstem glioblastomas of childhood

et al. 2005

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“…Because the diagnosis of this neoplasm is based on typical imaging features that preclude histologic verification, thus far, only 63 tumor samples from patients with diffuse brainstem glioma have been analyzed and reported. [13][14][15][16][17] The presence of a mismatch repair-deficient phenotype and the expression of high levels of the O 6 -methylguanine methyltranferase protein (or the lack of hypermethylation of the promoter of the corresponding gene) are two of the best known mechanisms of resistance to temozolomide, but neither has been analyzed in diffuse brainstem gliomas.…”

Section: Discussionmentioning

confidence: 99%

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Broniscer

Iacono

Chintagumpala

et al. 2004

Cancer

100

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BACKGROUNDThe role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting.METHODSPatients ages 3–21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5‐day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5‐(3‐methyltriazen‐1‐yl)imidazole‐4‐carboxamide (MTIC), were analyzed during Cycles 1 and 3.RESULTSThirty‐three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n = 5) or toxicity (n = 1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty‐nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one‐third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1‐year survival rate was 48% (standard error, 8%).CONCLUSIONSThe administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children. Cancer 2005. © 2004 American Cancer Society.

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“…Because sex chromosomes might be under di erent selection pressure in tumours derived from males and females, they were not analysed. Thresholds, following standardization in a series of control hybridizations, were set to 1.2 and 0.8 for scoring chromosomal gains and losses Interestingly, in four further glioblastomas with microsatellite instability, described by others, p53 mutation was also present (Cheng et al, 1999;Gafanovich et al, 1999;Miyaki et al, 1997). This is in sharp contrast to colorectal carcinoma arising in conditions of mismatch repair de®ciency, where numerous studies have shown a low incidence of p53 mutation (Cottu et al, 1996;Ionov et al, 1993;Konishi et al, 1996;Olschwang et al, 1997).…”

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Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

et al. 2000

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We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was di erent. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor ampli®cation was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its e ects di er greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 ± 4083.

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Genetic alterations in pediatric high-grade astrocytomas

Cited by 110 publications

References 32 publications

Clinical utility of fluorescence in situ hybridization (FISH) in nonbrainstem glioblastomas of childhood

Clinical utility of fluorescence in situ hybridization (FISH) in nonbrainstem glioblastomas of childhood

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

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