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Association Between Telomerase Activity and Outcome in Patients With Nonmetastatic Ewing Family of Tumors

A. Ohali, S. Avigad, I.J. Cohen, I. Meller, Y. Kollender, J. Issakov, I. Gelernter, Y. Goshen, I. Yaniv, R. Zaizov

From the Department of Molecular Oncology, Felsenstein Medical Research Center, and the Department of Pediatric Hematology/Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva; and Sourasky Medical Center, Sackler Faculty of Medicine, and Statistical Laboratory, School of Mathematics, Tel Aviv University, Tel Aviv, Israel.

Address reprint requests to Smadar Avigad, PhD, Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Campus, Petah Tikva 49100, Israel; e-mail: savigad{at}post.tau.ac.il.

Purpose: Telomerase is considered a molecular marker for malignancy. The aim of this study was to determine telomerase activity (TA) as a prognostic factor at diagnosis and as a marker for minimal residual disease during therapy and follow-up in nonmetastatic Ewing family of tumors (EFT).

Patients and Methods: Primary tumor specimens and 97 peripheral blood (PBL) samples from 31 EFT patients were analyzed for TA by the Telomeric Repeat Amplification Protocol (TRAP assay). The telomerase catalytic subunit (human telomerase reverse transcriptase [hTERT]) gene expression was evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and telomere length was determined by Southern blotting. The presence of the EFT chimeric transcripts was analyzed by RT-PCR. Correlations with progression-free survival were evaluated.

Results: At diagnosis, TA in primary tumors did not correlate with outcome. During therapy and follow-up, highly significant correlation was observed between high TA in PBL samples and adverse prognosis (P < .0001). None of the patients harboring low TA progressed, with a long follow-up (median, 60 months) and a progression-free survival (PFS) of 100%. In nine patients, high TA actually could predict relapse, long before overt clinical relapse. The group of patients with high TA and positive RT-PCR had the most adverse outcome; PFS of 20% (P = .0025). TA was found to be a better prognostic factor than RT-PCR and histopathologic response at surgery.

Conclusion: The results suggest that TA is a significant prognostic variable, superior to the established clinical prognostic parameters during therapy and tumor surveillance. It could be used in combination with RT-PCR for a new risk classification.

This work was supported by the Josefina Maus and Gabriela Cesarman Maus Chair for Pediatric Hematology Oncology (R.Z.).

This work was performed in partial fulfillment of the requirements for the PhD degree of Anat Ohali, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

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