Identification of Gains on 1q and Epidermal Growth Factor Receptor Overexpression as Independent Prognostic Markers in Intracranial Ependymoma

Abstract

Purpose: Pathogenesis of ependymomas is still poorly understood and molecular markers for risk-adapted patient stratification are not available. Our aim was to screen for novel genomic imbalances and prognostic markers in ependymal tumors. Experimental Design: We analyzed 68 sporadic tumors by matrix-based comparative genomic hybridization using DNA microarrays containing >6,400 genomic DNA fragments. Novel recurrent genomic gains were validated by fluorescence in situ hybridization using a tissue microarray consisting of 170 intracranial ependymomas. Candidate genes were also tested for mRNA expression by quantitative real-time PCR, and protein expression was determined by immunohistochemistry on the tissue microarray. Results: Chromosomal gain of 1q correlated with pediatric patients (P = 0.004), intracranial ependymomas (P = 0.05), and tumors of grade III (P = 0.002). Gain of1q21.1-32.1was associated with tumor recurrence in intracranial ependymomas (P < 0.001). Furthermore, gain of 1q25 as determined by fluorescence in situ hybridization represented an independent prognostic marker for either recurrence-free survival (P < 0.001) or overall survival (P = 0.003). Recurrent gains at 5p15.33 covering hTERT were validated by immunohistochemistry, and elevated protein levels correlated with adverse prognosis (P = 0.01). In addition to frequent gains and high-level amplification of epidermal growth factor receptor (EGFR) at 7p11.2, immunohistochemistry revealed protein overexpression to be correlated with poor prognosis (P = 0.002). EGFR protein status subdivides intracranial grade II ependymomas into two different risk groups (P = 0.03) as shown by multivariate analysis. Conclusions: Thus, the states of 1q25 and EGFR represent independent prognostic markers for intracranial ependymomas to identify patient subgroups with different risk profiles in further clinical investigations. Moreover, EGFR might serve as therapeutic target for more specific chemotherapy applications.

The dual-specificity phosphatase hYVH1 (DUSP12) is a novel modulator of cellular DNA content

“…Consistent with this, an increase in DNA copy number of the physical location of human YVH1 at 1q, 5 has been observed in numerous cancers, including retinoblastoma, 30 liposarcomas 31 and intracranial ependymoma. 32 Importantly, hYVH1 was proposed to be oncogenic in the latter subset of cancers. 32 The mechanism by which hYVH1 affects cellular DNA content is still unclear.…”

“…32 Importantly, hYVH1 was proposed to be oncogenic in the latter subset of cancers. 32 The mechanism by which hYVH1 affects cellular DNA content is still unclear. The increased DNA content (4N and polyploidy) in asynchronous populations and nocodazole-treated U2OS cells suggest a failure of cytokinesis, although uncontrolled DNA replication cannot be ruled out.…”

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

“…In contrast to PDGF receptors, 14,30 reports of c-Abl expression in central nervous system tumors remain sparse. It has been demonstrated that tyrosine kinases play a functional role in a variety of pediatric neoplasms, [11][12][13][14][15] and the few studies that have evaluated c-Abl expression in brain tumors encountered low expression levels in only a fraction of tumors. For example, Haberler et al observed focal c-Abl expression in only 7 of 101 glioblastomas.…”

“…Previous data suggest that tyrosine kinase receptor signaling may play a role in the biology of more common pediatric solid tumors, such as medulloblastomas, ependymomas, and choroid plexus tumors, and in Ewing sarcomas and neuroblastomas. [9][10][11][12][13][14][15][16] Imatinib, a tyrosine kinase inhibitor directed against c-Abl, c-Kit and platelet-derived growth factor (PDGF) receptor subtypes a and b, 17 reportedly is tolerated relatively well in children. 18,19 Because it has been demonstrated that imatinib inhibits proliferation of the rhabdoid tumor cell line BT12, 20 our objective was to investigate the expression and functional role of tyrosine kinases targeted by imatinib in rhabdoid tumors.…”

Pediatric Ependymoma: Biological Perspectives

“…This is supported by studies of CDKN2A (p14ARF), a tumor suppressor gene located at 9p21.3 that regulates neural stem cell proliferation and whose deletion has been shown to rapidly expand progenitor cell numbers in developing neural tissue (33,34). Whereas gene expression analysis has revealed that CDKN2A is upregulated in spinal tumors (77,86), it is downregulated by a much stronger magnitude in intracranial tumors (86). Furthermore, while epigenetic analysis has shown a significant difference in the methylation status of neighboring CDKN2B between spinal and intracranial tumors (79), fluorescent in situ hybridization (FISH) has shown that CDKN2A deletion is virtually exclusive to supratentorial ependymomas (34).…”