Chromosomal Abnormalities Subdivide Ependymal Tumors into Clinically Relevant Groups

Abstract

Ependymoma occurs most frequently within the central nervous system of children and young adults. We determined relative chromosomal copy-number aberrations in 44 ependymomas using comparative genomic hybridization. The study included 24 intracranial and 20 spinal cord tumors from pediatric and adult patients. Frequent chromosomal aberrations in intracranial tumors were gain of 1q and losses on 6q, 9, and 13. Gain of 1q and loss on 9 were preferentially associated with histological grade 3 tumors. On the other hand, gain on chromosome 7 was recognized almost exclusively in spinal cord tumors, and was associated with various other chromosomal aberrations including frequent loss of 22q. We conclude that cytogenetic analysis of ependymomas may help to classify these tumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed. Ependymoma is a tumor of neuroepithelial tissue that occurs in both brain and spinal cord, most frequently in children and young adults. Prognosis differs in intracranial and spinal cord tumors. Surgical resection followed by chemotherapy and/or radiotherapy are the most common treatments for intracranial tumors, but the patients frequently relapse. Overall survival and progression-free survival at 5 years are 50 to 60% and 30 to 50%, respectively.1-3 On the contrary, recurrence is rare for ependymomas located in the spinal cord, and gross total resections using surgical microscopy do not need to be treated with adjuvant therapy. 4,5 A prognostic marker for intracranial ependymomas would be clinically useful, and various factors have been analyzed. Several studies have identified extent of resection as an important variable. [1][2][3][4][5][6][7][8][9] Young age at diagnosis is a poor prognostic factor, although a clear explanation for this observation has not been proposed.

Genetic abnormalities detected in ependymomas by comparative genomic hybridisation

“…In addition, we provide evidence to support the proposal that classic (WHO grade 2) ependymomas from the region of the spinal cord are genetically distinct from intracranial classic (grade 2) and anaplastic (grade 3) tumours (Ebert et al, 1999;Hirose et al, 2001). …”

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

“…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.…”

“…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. Given that relatively few recurrences and deaths occurred during the clinical follow-up period, it may be that a longer follow-up is necessary to exclude entirely associations with biologic behavior.…”

“…22 A previous study of p16 expression in neuroglial tumors showed that p16 INK4A in ependymomas was expressed only when cellular proliferation had reached a threshold, with recurrent ependymomas having the highest expression levels of p16 INK4A . 23 A recent comparative genomic hybridization (CGH) study identified frequent losses of chromosomes 9 and 13 in anaplastic intracranial ependymomas, suggesting that alterations of this pathway may be critical in the malignant progression of ependymomas, 24 as they are in the diffuse glioma subtypes, astrocytomas, mixed oligoastrocytomas, and oligodendrogliomas. [25][26][27][28] However, this was a small study and clinicopathologic associations were not thoroughly explored.…”

A multicenter study of the prognosis and treatment of adult brain ependymal tumors

“…9 -13 It also has been suggested that pediatric ependymomas may behave more aggressively because of the immaturity of neural tissue in children 9,13 and that agerelated differences in outcome may be based on differences in cytogenetic aberration patterns between younger and older patients. 14 In addition, considerations regarding side effects and treatment tolerability are quite different for pediatric patients and adult patients. Thus, we believe that it is prudent to report results from adult and pediatric populations separately.…”