Genomic Imbalances in Pediatric Intracranial Ependymomas Define Clinically Relevant Groups

Dyer, Sara; Prebble, Emma; Davison, Val; Davies, Paul; Ramani, Pramila; Ellison, David W.; Grundy, Richard G.

doi:10.1016/s0002-9440(10)64491-4

Cited by 148 publications

(126 citation statements)

References 27 publications

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“…It is also possible that the number of deletions is underestimated by the FISH technique (eg, small deletions or relative RB deletions in an extensively polyploid tumor). However, our frequencies of 9p and 13q losses are similar to those previously reported using other techniques 11,14,24,[32][33][34] and there appears to be no clear suggestion of a prognostic association based on the available data thus far. Therefore, it is probable that genes other than p16 and RB may be targeted by the 9p and 13q deletions in ependymomas.…”

Section: Discussionsupporting

confidence: 82%

“…11,21,24,[31][32][33][34] Based on the recent finding of CGH detectable losses in high-grade examples, it was suggested that the RB pathway may be specifically targeted in the process of tumor progression. 24 In contrast, our larger study similarly identified a subset of ependymomas with 9p or 13q deletions by FISH, but there were no obvious associations with tumor grade, location, patients age, recurrences, or death.…”

Section: Discussionmentioning

confidence: 99%

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9p21 and 13q14 dosages in ependymomas. A clinicopathologic study of 101 cases

et al. 2004

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Ependymomas are glial neoplasms whose clinical behavior is difficult to predict based on histology alone. Recently, a comparative genomic hybridization study identified frequent chromosome 9p and 13q losses in anaplastic ependymomas, suggesting that p16 and RB alterations may be involved in tumor progression. In order to test this hypothesis further, 101 myxopapillary, conventional, and anaplastic ependymomas (51 spinal and 50 intracranial tumors) were tested for RB and p16 deletions using fluorescence in situ hybridization. Clinical follow-up, ranging from 2 to 198 months (median 46 months), was obtained in 90 cases (91%). RB and p16 deletions were seen in 22 of 92 (24%) and 22 of 89 (25%) informative cases, respectively. Polysomies were more frequent in the grade I and II spinal tumors, consistent with prior reports of increased aneuploidy in such cases. No significant genetic associations were seen with tumor grade, recurrence, or death, suggesting that 9p and 13q deletions do not play a prominent role in the malignant progression of ependymomas, as has been implicated in other glioma subtypes.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

9p21 and 13q14 dosages in ependymomas. A clinicopathologic study of 101 cases

et al. 2004

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“…For example, increased expression (more than twofold) was found concerning PRELP, EPHX1, FY, and HSPA6, all located on chromosomal arm 1q, which frequently showed copy number gains in ependymoma. 7 Correspondingly, genes from frequently deleted regions 7,8,11 were found weakly expressed (Ͻ0.5-fold), eg, COX7A2, COL10A1, and TCP1 from chromosome 6q; CNTFR, RAGA, TXN, AMBP, and HSPA5 from chromosome 9; TUBA2, PRDX2, and LCP1 from chromosome 13; and RANBP1, MCM5, EP300, G22P1, BZRP, and MAPK12 from chromosomal arm 22q. All 39 ependymomas analyzed in this study revealed a more than 10-fold expression of CLU, encoding for the glycoprotein clusterin (apolipoprotein J).…”

Section: Discussionmentioning

confidence: 99%

“…For example, 30 to 50% of pediatric ependymomas display balanced comparative genomic hybridization profiles in comparison to only 10% in adults. 7,8,11 This finding suggests that the development of ependymomas at younger age is often independent of chromosomal instability. The recent histological ependymoma classification has thus far proven to be an unreliable predictor of clinical outcome and relationship between ependymoma grade and specific chromosomal aberrations is also controversial.…”

mentioning

confidence: 92%

“…The recent histological ependymoma classification has thus far proven to be an unreliable predictor of clinical outcome and relationship between ependymoma grade and specific chromosomal aberrations is also controversial. 2,7,8,11,12 By novel microarray technologies, the expression of thousands of genes can be studied simultaneously. In brain tumors, gene expression studies including astrocytic, 13,14 oligodendroglial, 15,16 as well as embryonal neuroepithelial tumors 17,18 have been performed recently.…”

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confidence: 99%

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Gene Expression Patterns in Ependymomas Correlate with Tumor Location, Grade, and Patient Age

Korshunov¹,

Neben²,

Wrobel³

et al. 2003

The American Journal of Pathology

145

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To elucidate the molecular events responsible for tumorigenesis and progression of ependymomas, we analyzed molecular alterations on the gene expression level in a series of newly diagnosed ependymal neoplasms (n ‫؍‬ 39). To this aim, tumor RNA was hybridized to microarrays comprising 2600 different genes with relevance to mitosis, cell-cycle control, oncogenesis, or apoptosis. For CLU, IGF-2, and RAF-1, which are apparent candidate genes because they had been previously described to be involved in tumorigenesis of other human malignancies, we found a high expression on the mRNA as well as the protein level. We identified gene expression signatures for the differentiation of tumors with respect to location, grade, and patient age. Spinal ependymomas were characterized by high-expression levels of HOXB5, PLA2G, and CDKN2A and tumors in young patients (<16 years of age) by high-expression levels of LDHB and STAM. Notably, we were able to classify supratentorial grade II and III tumors with 100% accuracy, whereas this did not apply for infratentorial Ependymal tumors arise from the ependymal lining of the cerebral ventricles and from the remnants of the central canal of the spinal cord. This neoplasm constitutes ϳ3 to 5% of all intracranial malignancies and is the third most common brain tumor in children and young adults. 1,2 In ependymomas, the morphological features and biological behavior vary considerably. Patients with spinal tumor location have usually a favorable prognosis after gross total resection, whereas local tumor progression is the predominant reason for death in patients with intracranial ependymomas, resulting in a 5-year overall survival of ϳ60%. [3][4][5] Because ependymomas are characterized by tremendous variability in clinical behavior, the understanding of the complex changes taking place at the genomic level might lead to more precise understanding of the tumor biology. Cytogenetic studies revealed numerous chromosomal aberrations in ependymomas. In particular, a 30 to 50% incidence of aberrations involving chromosome 22, including monosomy 22 as well as deletions of 22q, prevailed the most frequent finding. 6 -8 Recently, Hirose and co-workers 7 reported on different patterns of chromosomal abnormalities with respect to tumor location detected by comparative genomic hybridization. In intracranial tumors, gain of 1q and losses on 6q, 9, and 13 were frequent, whereas gains on chromosome 7 were recognized almost exclusively in spinal cord tumors and were associated with various other chromosomal aberrations including frequent loss of 22q, suggesting that intracranial and spinal cord ependymomas progress along substantially different pathways. As a hereditary form, neurofibromatosis type 2 is associated with spinal ependymomas, indicating a functional role of the NF2 tumor suppressor gene in these tumors. 9,10 In contrast to adults in which spinal tumors predominate, ϳ90% of all pediatric ependymomas are of intraSupported by the Bundesministerium fü r Bildung und Forschung (FKZ 01 KW 9937 and...

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