title: Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer.
abstract: 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.
authors.affiliation: Genetics Branch, Center for Cancer Research/NCI/NIH, 50 South Dr., Bethesda, MD 20892, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Heselmeyer-Haddad
authors.forename: Kathrin
authors.initials: K
authors.lastname: Sommerfeld
authors.forename: Nicole M
authors.initials: NM
authors.lastname: White
authors.forename: Nadia
authors.initials: N
authors.lastname: Chaudhri
authors.forename: Larry E
authors.initials: LE
authors.lastname: Morrison
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Zhen Yuan
authors.initials: ZY
authors.lastname: Wang
authors.forename: Gert
authors.initials: G
authors.lastname: Auer
authors.forename: Winfried
authors.initials: W
authors.lastname: Steinberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis*; D018450:Disease Progression; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D065006:Papanicolaou Test; D012313:RNA / Q000235:genetics*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D019098:Telomerase / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology*; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase