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Telomerase Activity Exclusively in Cervical Carcinomas and a Subset of Cervical Intraepithelial Neoplasia Grade III Lesions: Strong Association with Elevated Messenger RNA Levels of Its Catalytic Subunit and High-Risk Human Papillomavirus DNA¹

Departments of Pathology [P. J. F. S., M. v. D., J. M. M. W., R. D. M. S., E. K. J. R., C. J. L. M. M.] and Obstetrics and Gynecology [R. H. M. V.], University Hospital Vrije Universiteit, 1081 HV Amsterdam, and the Department of Obstetrics and Gynecology, University Hospital Rotterdam, 3000 CA Rotterdam [T. J. M. H.], The Netherlands

In this study, we investigated telomerase activity and human telomerase reverse transcriptase (hTERT) mRNA expression in relation to high-risk human papillomavirus (HPV) DNA presence in the spectrum of cervical premalignant lesions. Reconstruction experiments revealed that telomerase activity determined by the telomeric repeat amplification protocol assay and hTERT mRNA by reverse transcriptase-PCR could be detected in down to 100 and 1 SiHa cervical cancer cells, respectively. Telomeric repeat amplification protocol analysis on cervical tissue specimens revealed that none of the histomorphologically normal cervical samples (n = 8) and cervical intraepithelial neoplasia (CIN) grade I (n = 10) and grade II (n = 8) lesions had detectable telomerase activity. However, telomerase activity was shown in 40% of CIN grade III lesions (n = 15) and 96% of squamous cell carcinomas (n = 24). Despite the fact that hTERT mRNA was found at much higher frequencies, semiquantitative reverse transcriptase-PCR revealed that elevated hTERT mRNA levels were strongly correlated with detectable telomerase activity. Furthermore, telomerase activity and elevated hTERT mRNA levels were only detected in cases that contained high-risk HPV DNA. In contrast, low or undetectable hTERT mRNA levels were demonstrated in both high-risk HPV positive and negative cases. These data indicate that telomerase activity detectable with the assay used and concomitant elevated levels of hTERT mRNA reflect a rather late step in the CIN to squamous cell carcinoma sequence, which follows infection with high-risk HPV.

¹ Supported by Grant VU96-1151 of the Dutch Cancer Society. The research of P. J. F. S. has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences.

² To whom requests for reprints should be addressed, at the Department of Pathology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Fax: 31-20-4442964; E-mail: pjf.snijders@azvu.nl.

Received 3/17/98. Accepted 7/ 2/98.

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