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(American Journal of Pathology. 2005;166:1229-1238.)
© 2005 American Society for Investigative Pathology

Genomic Amplification of the Human Telomerase Gene (TERC) in Pap Smears Predicts the Development of Cervical Cancer

Kerstin Heselmeyer-Haddad^*, Kathrin Sommerfeld^*, Nicole M. White^*, Nadia Chaudhri^*, Larry E. Morrison, Nallasivam Palanisamy, Zhen Yuan Wang^*, Gert Auer, Winfried Steinberg^¶ and Thomas Ried^*

From the Genetics Branch,^* Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Vysis, Incorporated/Abbott Laboratories, Downers Grove, Illinois; Cancer Genetics, Incorporated, Milford, Massachusetts; Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden; and Klinik Kloster Paradiese,^¶ Laboratory of Cytopathology, Soest, Germany

Invasive cervical carcinomas almost invariably carry extra copies of chromosome arm 3q, resulting in a gain of the human telomerase gene (TERC). This provided the rationale for the development of a multicolor fluorescence in situ hybridization (FISH) probe set as a diagnostic tool for the direct detection of TERC gains in Pap smears. We previously used this probe set to show that cervical intraepithelial neoplasia (CIN) 2 and CIN3 lesions could be distinguished from normal samples, atypical squamous cell of undetermined significance (ASCUS) and CIN1, with a sensitivity and specificity exceeding 90%, independent of the cytomorphological assessment. In the current study, we explored whether gain of 3q and amplification of TERC could predict progression from CIN1/CIN2 to CIN3 and invasive carcinoma. We applied our probe set to a series of 59 previously stained Pap smears for which repeat Pap smears and clinical follow-up were available. The samples included CIN1/CIN2 lesions that progressed to CIN3 (progressors), CIN1/CIN2 lesions that regressed spontaneously (regressors), and normal Pap smears from women who subsequently developed CIN3 or cervical cancer. Here, we show that progressors displayed a gain of 3q whereas none of the regressors showed this genetic aberration. These data suggest that 3q gain is required for the transition from CIN1/CIN2 to CIN3 and that it predicts progression. Of note, 3q gain was found in 33% of cytologically normal Pap smears from women who were diagnosed with CIN3 or invasive cervical carcinoma after a short latency. The sensitivity of our test for predicting progression from CIN1/CIN2 to CIN3 was 100% and the specificity, ie, the prediction of regression, was 70%. We conclude that the detection of 3q gain and amplification of TERC in routinely collected Pap smears can assist in identifying low-grade lesions with a high progression risk and in decreasing false-negative cytological screenings.

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