Objective: This study was designed to evaluate whether the adjunct of human telomerase RNA component (hTERC) fluorescence in situ hybridization (FISH) analysis to cytological diagnosis and human papillomavirus (HPV)-DNA testing may serve as a predictive marker for distinguishing cervical lesions destined to regress from those at high risk of progression towards invasive cancer. Study Design: hTERC FISH analysis was performed on 54 residual liquid-based cytology specimens obtained from women referred to colposcopy for the detection of atypical squamous cells of undetermined significance or worse (ASCUS+) lesions. Histological diagnosis was considered the gold standard and cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) as the worst outcome. Results: Oncogenic HPV-DNA was found in 96.3% of the specimens. Among these, 38.5% revealed a CIN2+ diagnosis. hTERC gene amplification was detected in 37% of the cases; among these, 70% showed up as CIN2+. hTERC FISH analysis significantly improves the specificity and positive predictive value of HPV-DNA testing, thus differentiating patients with a CIN2+ diagnosis from those with a CIN2- diagnosis. Conclusions: Despite the limitation of a small study sample, our findings provide promising data, indicating the possible role of hTERC analysis in the assessment of the risk of developing cervical cancer. This approach would implement the specificity of DNA testing, avoiding overtreatment at the same time. Prospective follow-up studies are needed with the aim of introducing hTERC FISH into decision-making algorithms.

1.
Arbyn M, Castellsague X, de Sanjose S, Bruni L, Saraiya M, Bray F, Ferlay J: Worldwide burden of cervical cancer in 2008. Ann Oncol 2011;22:2675-2686.
2.
American Congress of Obstetricians and Gynecologists (ACOG): Practice Bulletin No. 131: screening for cervical cancer. Obstet Gynecol 2012;120:1222-1238.
3.
Bosch FX, Lorincz A, Munoz N, Meijer CJLM, Shah KV: The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244-265.
4.
Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J: Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst 2004;96:280-293.
5.
Petry KU, Mention S, Menton M, van Loenen-Frosch F, de Carvalho Gomes H, Holz B, et al: Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8,468 patients. Br J Cancer 2003;88:1570-1577.
6.
Szarewski A, Ambroisine L, Cadman L, Austin J, Ho L, Terry G, et al: Comparison of predictors for high-grade cervical intraepithelial neoplasia in women with abnormal smears. Cancer Epidemiol Biomarkers Prev 2008;17:3033-3042.
7.
Kraus I, Molden T, Holm R, Lie AK, Karlsen F, Kristensen GB, et al: Presence of E6 and E7 mRNA from human papillomavirus types 16, 18, 31, 33, and 45 in the majority of cervical carcinomas. J Clin Microbiol 2006;44:1310-1317.
8.
Matthews CP, Shera KA, McDougall JK: Genomic changes and HPV type in cervical carcinoma. Proc Soc Exp Biol Med 2000;223:316-321.
9.
Cayuela L, Flores JM, Blasco MA: The telomerase RNA component TERC is required for the tumour-promoting effects of TERC overexpression. EMBO Rep 2005,6:268-274.
10.
Farwell DG, Shera KA, Koop JI, Bonnet GA, Matthews CP, Reuther GW, Coltreta MD, McDougall JK, Klingelhutz AJ: Genetic and epigenetic change in human epithelial cells immortalized by telomerase. Am J Pathol 2000;156:1537-1544.
11.
Anderson S, Shera K, Ihle J, Billman L, Goff B, Greer B, Tamimi H, McDougall J, Klingelhutz A: Telomerase activation in cervical cancer. Am J Pathol 1997;151:25-31.
12.
Hills M, Lansdorp PM: Short telomeres resulting from heritable mutations in telomerase reverse transcriptase gene predispose for a variety malignancies. Ann NY Acad Sci 2009;1176:178-190.
13.
Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114-2119.
14.
World Health Organization: IARC Handbooks of Cancer Prevention. Vol 10. Cervix Cancer Screening. Lyon, IARC Press, 2005, pp 1-302.
15.
Obermann EC, Prince SS, Barascud A, Grilli B, Herzog M, Kaup M, Cathomas G, Frey Tirri B, et al: Prediction of outcome in patients with low-grade squamous intraepithelial lesions by fluorescence in situ hybridation analysis of human papillomavirus, TERC, and Myc. Cancer Cytopathol 2013;8:423-431.
16.
Landis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics 1977;1:159-174.
17.
NHSCSP Audit of Invasive Cervical Cancer: national report 2007-2010. www.cancerscreening.nhs.uk/cervical/publications/nhscsp-audit-invasive-cervicalcancer-201107.pdf (last accessed January 9, 2014).
18.
Cuschieri KS, Graham C, Moore C, Cubie HA: Human papillomavirus testing for the management of low-grade cervical abnormalities in the UK. Influence of age and testing strategy. J Clin Virol 2007;38:14-18.
19.
Arbyn M, Kyrgiou M, Simoens C: Peri-natal mortality and other severe adverse pregnancy outcome associated with treatments of cervical intraepithelial neoplasia: a meta-analysis. BMJ 2008;337:1284-1295.
20.
Massad LS, Collins YC, Meyer PM: Biopsy correlates of abnormal cervical cytology classified using the Bethesda System. Gynecol Oncol 2001;82:516-522.
21.
Castle PE, Gravitt PE, Wentzensen N, Schiffman M: A descriptive analysis of prevalent vs. incident cervical intraepithelial neoplasia grade 3 following minor cytologic abnormalities. Am J Clin Pathol 2012;138:241-246.
22.
Centers for Disease Control and Prevention. www.cdc.gov/std/stats/stiestimates-fact-sheet-feb-2013.pdf (last accessed December 28, 2014).
23.
Atkins KA, Jeronimo J, Stoler MH, et al: Description of patients with squamous cell carcinoma in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study. Cancer 2006;108:212-221.
24.
Wright TC, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D: 2006 Consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007;197:346-355.
25.
Lambert AP, Anschau F, Schmitt VM: P16INK4a expression in cervical premalignant and malignant lesions. Exp Mol Pathol 2006,80:192-196.
26.
Denton KJ, Bergeron C, Klement P, Trunk MJ, Keller T, Ridder R; European CINtec Cytology Study Group: The sensitivity and specificity of p16INK4a cytology vs HPV testing for detecting high-grade cervical disease in the triage of ASC-US and LSIL Pap cytology results. Am J Clin Pathol 2010;134:12-21.
27.
Tsoumpou I, Arbyn M, Kyrgiou M, et al: p16INK4a immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev 2009;35:210-220.
28.
Wentzenses N, Bergeron C, Cas F, Eschenbach D, Vinokurova S, von Knebel DM: Evaluation of a nuclear score for p16INK4a-stained cervical squamous cells in liquid-based cytology samples. Cancer 2005;105:461-467.
29.
Yang YC, Shyong WY, Chang MS, Chen YJ, Lin CH, Huang ZD, Wang Hsu MT, Chen ML: Frequent gain of copy number on long arm of chromosome 3 in human cervical adenocarcinoma. Cancer Genet Cytogenet 2001;131:48-53.
30.
Zhang Y, Wang X, Ma L, Hu L: Clinical significance of hTERC gene amplification detection by FISH in the screening of cervical lesions. J Huazhong Univ Sci Technolog Med Sci 2009;29:368-371.
31.
Alemada F, Espinet B, Corzo C, Munoz R, Bellosillo B, Lloveras B, Pijuan L, Gimeno J, Salido M, Solè F, Carreras R, Serrano S: 3q26 (hTERC) gain studied by fluorescence in situ hybridization as a persistence-progression indicator in low-grade squamous intraepithelial lesion cases. Hum Pathol 2009;40:1474-1478.
32.
Heselmeyer-Haddad K, Janz V, Castle PE, Chaudhri N, White N, Wilber K, Morrison LE, Auer G, Burroughs FH, Sherman ME, Ried T: Detection of genomic amplification of human telomerase gene (TERC) in cytologic specimens as a genetic test for the diagnosis of cervical dysplasia. Am J Pathol 2003;163:1405-1416.
33.
Heitman ER, Lankachandra KM, Wall J, et al: 3q26 amplification is an effective negative triage test for LSIL: a historical prospective study. PLoS One 2012;7:1-7.
34.
Hopman AH, Theelen W, Hommelberg PP, Kamps MA, Herrington CS, Morrison LE, Speel EJ, Smedts F, Ramaekers FC: Genomic integration of oncogenic HPV and gain of human telomerase gene TERC at 3q26 are strongly associated events in the progression of uterine cervical dysplasia to invasive cancer. J Pathol 2006;210:412-419.
35.
Branca M, Giorgi C, Ciotti M, et al: Upregulation of telomerase (hTERC) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papilloma virus, virus persistence, or disease outcome in cervical cancer. Diagn Cytopathol 2006;34:739-748.
36.
Ying L, Wen-Jie Z, Feng Y, Xin-Yu W, Wei-Guo L, Ding M, et al: Application of hTERC in ThinPrep samples with mild cytologic abnormality and HR-HPV positive. Gynecol Oncol 2011;120:73-83.
37.
Caraway NP, Khanna A, Dawlett M, Guo M, Guo N, Lin E, Katz RL: Gain of the 3q26 region in cervicovaginal liquid-based Pap preparations is associated with squamous intraepithelial lesions and squamous cell carcinoma. Gynecol Oncol 2008;110:37-42.
38.
Heselmeyer-Haddad K, Sommerfeld K, White NM, Chaudhri N, Morrison LE, Palanisamy N, Wang ZY, Auer G, Steinberg W, Ried T: Genomic amplification of the human telomerase gene (TERC) in Pap smears predicts the development of cervical cancer. Am J Pathol 2005;166:1229-1238.
39.
Reza Jalali G, Herzog TJ, Dziura B, Walat R, Kilpatrick MW: Amplification of the chromosome 3q26 region shows high negative predictive value for non-malignant transformation of LSIL cytologic findings. Am J Obstet Gynecol 2010;202:581-583.
40.
Liu Z, Ma H, Wei S, Li G, Sturgis EM: Telomere length and TERT functional polymorphisms are not associated with risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev 2011;20:2642-2648.
41.
de Cremoux P, Coste J, Sastre-Garau X, et al: Efficiency of the hybrid capture 2 HPV DNA test in cervical cancer screening: a study by the French Society of Clinical Cytology. Am J Clin Pathol 2003;120:492-499.
42.
Adams AL, Eltoum I, Roberson J, et al: Negative colposcopic biopsy after positive human papilloma virus (HPV) DNA. Am J Clin Pathol 2006;125:413-418.
43.
Molano M, van den Brule A, Plummer M, et al: Determinants of clearance of human papillomavirus infections in Colombian women with normal cytology: a population-based, 5-year follow-up study. Am J Epidemiol 2003;158:486-494.
44.
Jin G, Yoo SS, Cho S, Jeon HS, Lee WK: Dual roles of a variable number of tandem repeat polymorphisms in the TERT gene in lung cancer. Cancer Sci 2011;102:144-149.
45.
Hsu CP, Lee LW, Shai SE, Chen CY: Clinical significance of telomerase and its associate genes expression in the maintenance of telomere length in squamous cell carcinoma of the esophagus. World J Gastroenterol 2005;11:6941-6947.
46.
Safont MJ, Gil M, Sirera R, Jantus-Lewintre E, Sanmartín E: The prognostic value of hTERT expression levels in advanced-stage colorectal cancer patients: a comparison between tissue and serum expression. Clin Transl Oncol 2011;13:396-400.
47.
Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S: hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 2011;60:809-818.
48.
Zhang B, Beeghly-Fadiel A, Long J, Zheng W: Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol 2011;12:477-488.
49.
Andersson S, Wallin KL, Hellström AC, Morrison LE, Hjerpe A: Frequent gain of the human telomerase gene TERC at 3q26 in cervical adenocarcinomas. Br J Cancer 2006;95:331-338.
50.
Aulmann S, Schleibaum J, Penzel R, Schirmacher P, Gebauer G: Gains of chromosome region 3q26 in intraepithelial neoplasia and invasive squamous cell carcinoma of the vulva are frequent and independent of HPV status. J Clin Pathol 2008;61:1034-1037.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.