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Clinical Investigations |
Departments of Oncology [J. S. D., S. C., C. B. U., L. A. C., S. S.], Surgery [M. S.], and Pathology [E. J. P.], Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Biostatistics, University of Washington, Seattle, Washington 98195 [T. B., N. E. B.]; and Department of Pediatrics, Cross Cancer Institute, Edmonton, Alberta, Canada T6G 1Z2 [P. E. G.]
Telomerase is a reverse transcriptase that maintains chromosome ends, compensating for the progressive loss of DNA that occurs during replication. High telomerase enzyme activity is an unfavorable prognostic feature for several types of cancers. We investigated whether telomerase level predicts outcome for patients with the pediatric renal malignancy Wilms’ tumor. In a case-cohort study of 78 patients with favorable histology Wilms’ tumor, we compared tumor telomerase levels in patients with and without eventual recurrence. Three measures of telomerase were used: (a) telomerase enzyme activity; (b) expression of hTR, the RNA component of telomerase; and (c) mRNA expression of hTERT, the gene that encodes the catalytic component of the enzyme. Of the evaluable samples, 81% had detectable telomerase activity, 97% had detectable hTERT transcript, and 100% had detectable hTR. Weak correlations were observed between telomerase activity and hTR level (r = 0.34, P = 0.02) and between telomerase activity and hTERT mRNA level (r = 0.32, P = 0.04). Of the variables assessed, only hTERT mRNA expression correlated with outcome. The median hTERT mRNA level in tumors with recurrence was higher than that in tumors without recurrence (1.42 versus 0.97 units, P = 0.023, Wilcoxon). Univariate analysis of hTERT mRNA level as a continuous variable suggested that each unit increase in hTERT mRNA level increased the risk of recurrence (RR) by a factor of 1.66 [95% confidence interval (CI), 1.2–2.3; P < 0.005]. Compared with tumors with hTERT mRNA levels of 0–1 units, tumors with hTERT mRNA levels of 1–2 units had a RR of 2.72 (95% CI, 0.91–8.13; P = 0.074), and tumors with hTERT mRNA levels >2 units had a RR of 6.40 (95% CI, 1.49–27.67, P = 0.013). Multivariate analysis of hTERT mRNA level as a predictor of recurrence, adjusted for tumor stage and age at diagnosis, revealed a RR of 1.48 (95% CI, 0.9–2.6; P = 0.16). Measurement of hTERT mRNA level may, therefore, enable clinicians to identify a population of patients at high risk for recurrence and to adjust their therapy accordingly. A larger study will be necessary to determine whether hTERT expression is an independent prognostic indicator. Further biological investigation is warranted to discern whether the link between high hTERT expression and unfavorable prognosis is causative or correlative.
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