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(American Journal of Pathology. 2003;163:1405-1416.)
© 2003 American Society for Investigative Pathology

Detection of Genomic Amplification of the Human Telomerase Gene (TERC) in Cytologic Specimens as a Genetic Test for the Diagnosis of Cervical Dysplasia

Kerstin Heselmeyer-Haddad^*, Viktor Janz^*, Philip E. Castle, Nadia Chaudhri^*, Nicole White^*, Kim Wilber, Larry E. Morrison, Gert Auer, Frances H. Burroughs^¶, Mark E. Sherman and Thomas Ried^*

From the Genetics Branch,^* Center for Cancer Research and the Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Vysis, Inc./Abbott Laboratories, Downers Grove, Illinois; Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden; and the John K. Frost Laboratory of Cytopathology,^¶ Department of Pathology, The Johns Hopkins University Hospital, Baltimore, Maryland

Invasive cervical carcinomas frequently reveal additional copies of the long arm of chromosome 3. The detection of this genetic aberration in diagnostic samples could therefore complement the morphological interpretation. We have developed a triple-color DNA probe set for the visualization of chromosomal copy number changes directly in thin-layer cervical cytology slides by fluorescence in situ hybridization. The probe set consists of a BAC contig that contains sequences for the RNA component of the human telomerase gene (TERC) on chromosome band 3q26, and repeat sequences specific for the centromeres of chromosomes 3 and 7 as controls. In a blinded study, we analyzed 57 thin-layer slides that had been rigorously screened and classified as normal (n = 13), atypical squamous cells (ASC, n = 5), low-grade squamous intraepithelial lesions (LSIL, n = 14), and high-grade squamous intraepithelial lesions (HSIL) grade 2 (CIN2, n = 8), and grade 3 (CIN3, n = 17). The percentage of tetraploid cells (P_Trend < 0.0005) and cells with multiple 3q signals increased with the severity of the cytologic interpretation (P_Trend < 0.0005). While only few normal samples, ASC and LSIL lesions, revealed copy number increases of 3q, 63% of the HSIL (CIN2) lesions and 76% of the HSIL (CIN3) lesions showed extra copies of 3q. We conclude that the visualization of chromosome 3q copy numbers in routinely prepared cytological material using BAC clones specific for TERC serves as an independent screening test for HSIL and may help to determine the progressive potential of individual lesions.

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