The goal of this project is to determine whether measurements of telomerase expression and activity provide an independent prognostic indicator for children with Wilms' tumor. Advances in the treatment of Wilms' tumor have produced cure rates in excess of 85 percent. If the risk of recurrence could be more accurately predicted, risk-appropriate therapies could be used to further improve cure rates while minimizing treatment-related toxicity. The enzyme telomerase has recently shown promise as a prognostic indicator. Telomerase is a specialized reverse transcriptase that maintains telomeres, compensating for the loss of DNA that occurs during replication. The enzyme, which plays a key role in the cellular immortalization process, is expressed in 85 percent to 90 percent of human cancers. High telomerase levels are correlated with adverse clinical outcomes in various adult and childhood malignancies. A pilot study of Wilms' tumor demonstrated a strong positive correlation between expression of TERT, the gene that encodes the catalytic portion of the enzyme, and tumor recurrence. This finding suggests that measurement of telomerase in Wilms' tumor may provide a useful indicator of the risk of recurrence, allowing the assignment of risk-directed therapy. The applicant's propose to perform a prospective case-control study in collaboration with the National Wilms' Tumor Study Group to confirm the pilot study's findings and to test the hypothesis that telomerase level is an independent prognostic indicator for children with Wilms' tumor. Telomerase levels will be quantified by assaying enzyme activity, expression of TERT, and expression of hTR, the RNA template component of the enzyme.
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