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P53 pathway alterations are uncommon in childhood ependymomas

E pendymomas are among the most therapeutically challenging intracranial tumors of childhood, despite the contemporary use of multimodality management approaches. Numerous studies have demonstrated that the extent of tumor removal has an overwhelming impact on the prognosis for longterm survival [1–3]. However, the nature of tumor extension into and around critical neural and vascular structures precludes complete or nearly complete tumor removal in a substantial percentage of children. Although radiotherapy is commonly used postoperatively, the majority of patients with macroscopically visible residual disease eventually exhibit local tumor progression, as do a sizeable percentage of patients with apparent gross total tumor resection and only microscopic residual disease. Although a subset of ependymomas respond to multiagent chemotherapy [4,5], the majority do not, and a benefit in terms of survival prolongation of using this modality remains to be confirmed. In view of these challenges, there has been significant interest in identifying biological or molecular factors that help to distinguish prognostically distinct subsets of tumors, and in elucidating those features that contribute to treatment resistance. From a biological standpoint, several groups have noted that histological features of anaplasia and increased proliferative activity constitute adverse features [3,6,7]. In addition, recent studies have begun to incorporate array-based expression and genomic profiling as a way for achieving a genome-wide survey of molecular targets that may call attention to prognostically and therapeutically relevant tumor subsets [8]. The study of Gaspar et al. [9] takes the converse approach, focusing on a genetic target that has been implicated in the development or progression of many types of tumors, specifically p53, and evaluating the potential contribution of alterations of this tumor suppressor gene in ependymoma. Although ependymoma has been observed in patients with Li-Fraumeni syndrome in the setting of germline mutations of p53 [10], a role for this gene in the development of sporadic ependymomas has never been established. To address this issue, the authors examined a diverse group of primary and progressive tumors. Genotyping of p53 was performed using a functional assay in yeast and gene sequencing. Since MDM2 amplification and p14 deletion provide alternate pathways for p53 inactivation, the status of these genes was also examined and methylationrelated inactivation of the p53 and p14 promoters was determined. Although a small number of samples were amenable to all of the above analyses, these studies demonstrated a lack of detectable genotypic abnormalities that might compromise p53 function. These results strongly suggest the lack of a role for p53 pathway alterations in the development or progression of sporadic ependymomas, consistent with prior reports [11]. As a corollary to these studies, the authors also established xenografts of two tumors and examined p53 functional status in these cell lines. These studies confirmed an absence of detectable p53 pathway alterations. However, the authors noted that following irradiation of these xenografts, one (IGREP83) exhibited stabilization of p53 and induction of p21, consistent with G1 cell cycle arrest, whereas no such effects were observed in the IGREP37 cell line. The former cell line was correspondingly more responsive to irradiation, with greater growth delay and enhanced frequency of tumor regression, whereas the latter was relatively radioresistant. Although the results of the above study fail to validate a role for p53 pathway alterations in ependymoma tumorigenesis, and, in fact, suggest that alternate targets should be examined, the xenograft model studies demonstrate that ependymomas may exhibit differences in p53-dependent growth arrest, which correspond with different levels of responsiveness to adjuvant therapies. Given the fact that only two cell lines were available for analysis and the known difficulties in propagating ependymoma cell lines, which may select for cellular components not representative of the original tumor, these observations must be interpreted with some caution. Nonetheless, the availability of such lines provides an opportunity for further preclinical experimental therapeutic studies for these tumors, which have to date been limited by the paucity of evaluable xenograft models.