Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma.
2008
We have recently described the enzymatic subunit of telomerase (hTERT) as an important prognostic marker for paediatric
ependymoma. Because of the lack of good, representative pre-clinical models for
ependymoma, we took advantage of our large cohort of
ependymomapatients, some with multiple recurrences, to investigate
telomerebiology in these tumours. Our cohort consisted of 133
ependymomasfrom 83 paediatric patients and included 31 patients with recurrences. Clinical outcome was measured as overall survival, progression-free survival and response to therapy. In all 133 tumours, hTERT expression correlated with proliferative markers, including MIB-1 index (Po0.0001) and
mitotic index(P ¼ 0.005), as well as overall tumour grade (P ¼ 0.001), but not with other markers of
anaplasia. There was no correlation between
telomerelength and hTERT expression or survival. Surprisingly, prior radiation or chemotherapy neither induced sustained DNA damage nor affected
telomeremaintenance in recurrent tumours. There was an inverse correlation between hTERT expression and
telomeredysfunction as measured by gH2AX expression (P ¼ 0.016). Combining gH2AX and hTERT expressions could segregate tumours into three different survival groups (log rank, Po0.0001) such that those patients whose tumours expressed hTERT and showed no evidence of DNA damage had the worst outcome. This study emphasises the importance of
telomerebiology as a prognostic tool and telomerase inhibition as a therapeutic target for paediatric
ependymoma. Furthermore, we have demonstrated that analysing tumours as they progress in vivo is a viable approach to studying tumour biology in humans.
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