Detection of telomerase, its components, and human papillomavirus in cervical scrapings as a tool for triage in women with cervical dysplasia

Abstract

Aim: To examine whether the detection of either telomerase and its components or high risk human papillomavirus (HPV) are of value in predicting the presence of cervical intraepithelial neoplasia (CIN) grade II/III in women referred because of cervical cytology reports showing at most moderate dyskaryosis. Methods: Cervical scrapings of 50 women referred with cytological borderline, mild, or moderate dyskaryosis were analysed. Telomerase activity was assessed by a commercially available telomere repeat amplification protocol assay and its components human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) were assessed by reverse transcriptase polymerase chain reaction (PCR). HPV was detected by GP5+/6+ PCR enzyme immunosassay. Histological findings on colposcopy guided biopsies or excised cervical tissue were regarded as the final pathological diagnosis. The sensitivity and specificity for detecting CIN II/III were calculated. Results: Twenty eight women were diagnosed with CIN II/III. Telomerase activity was detected in none, hTR in 88%, hTERT in 23%, and high risk HPV was detected in 79% of these women. As a diagnostic test none of the described analyses combined a sensitivity of at least 90% with a specificity > 90%. Despite the small numbers, calculation of the 95% confidence intervals excluded a combined sensitivity and specificity of at least 90% for all of the evaluated parameters. Conclusions: Neither detection of telomerase or its components, nor detection of high risk HPV seem suitable for the triage of women with borderline, mild, and moderate cytological dyskaryosis. C ervical cancer, which develops from cervical intraepithelial neoplasia (CIN), is an important cause of death in women worldwide.1 A CIN lesion can either regress, persist, or progress towards (micro)invasive carcinoma. Most low grade CIN lesions (CIN I) will regress, whereas in the long term 12-40% of high grade CIN lesions (CIN II/III) progress to squamous cell carcinoma.2 3 Because there are no markers to identify those lesions that will progress, clinicians have felt compelled to treat at least all CIN II/III lesions.Cytomorphological examination of cervical smears is the most widely applied screening method for cervical cancer and its precursors. The disadvantages are the high numbers of false negative and false positive cervical smears. Cervical cytology alone is a good predictor for the presence of CIN II/III when it shows severe dyskaryosis or carcinoma in situ. CIN II/III or cancer was found in 89-93% of women with these severely abnormal smears.4 5 In contrast, 51-58% of women with mild or moderate dyskaryosis on cytology are diagnosed with CIN II/III. 5 6 All of the women with cytological mild or moderate dyskaryosis are subjected to colposcopic evaluation, implying an overshoot of diagnostic procedures. 7 8 Thus, there is a need for parameters in cervical scrapings that could more accurately predict the presence of CIN II/III or cancer in women with borderline, mild, or moderate dyskaryotic smears.

E6 and E7 Oncoproteins Induce Distinct Patterns of Chromosomal Aneuploidy in Skin Tumors from Transgenic Mice

“…Thus, a subset of genes gained in human cervical cancer also is gained consistently in the skin tumors from mice expressing the HPV-E6 oncogene. Recent studies have examined the activation of telomerase in cervical tumors (58) in response to HPV-E6 expression (59) and as a useful biomarker for the early detection of cervical cancer (57,60). The RNA component of telomerase (TERC) maps to the region of chromosome 3 that is gained in cervical cancer (3q26).…”

Human papillomavirus testing as a cytology gold standard: comparing Surinam with the Netherlands

“…7,10,11 In brief, using standard methods and commercially available reagents (QIAamp DNA Mini Kit, Qiagen, the Netherlands), target DNA was amplified using commercially available consensus primers for the conserved region of HPV hr for types 16,18,31,33,35,39,45, 51, 52, 56, 58; MY09/MY11 primer/ probes set (Digene/Abbot, USA) and 45 amplification cycles.…”

Gene expression profiling to identify markers associated with deregulated hTERT in HPV‐transformed keratinocytes and cervical cancer

“…However, both telomerase activity and hTERT mRNA and protein levels in cervical scrapings only poorly reflect the status of these markers in the underlying lesions. [11][12][13][14] This is likely owing to factors like sampling variability in combination with the presence of physiological telomerase activity in admixed activated lymphocytes and epithelial stem cells. Notably, telomerase activity is more than incidentally detected in normal cervical scrapings and biopsies of normal cervix.…”