| ObjectivesTo investigate the association between High-Risk HPV(HR-HPV) persistence and HPV16/18 oncoprotein expression as well as pl6/Ki-67 expression, and evaluate the clinical performance of these two biomarkers in detection of cervical precancer and cancer, and provide evidence of their implementation in cervical cancer screening in China.Materials and MethodsThe Low-Cost Molecular Cervical Cancer Screening Study (LCMCCSS) was carried out in Henan province in January 2011, all the participants were screened by six tests including HPV16/18 oncoprotein test(OncoE6), HR-HPV test and visual inspection with acetic acid (VIA). Women who were positive for any of the tests and a random sample of women with all negative results received colposcopy and biopsy. All the referred women were followed and tested for OncoE6, pl6/Ki-67(CINtec PLUS) and HR-HPV test in 2014. We investigated the association between high-risk HPV persistence and HPV16/18 oncoprotein expression as well as p16/Ki-67 expression using the baseline and follow-up data. From April 2014 to March 2015, a cross-sectional study was performed in four hospitals, women attending ongoing cervical cancer screening program and women with biopsy-confirmed CIN2+ referred from colposcopy clinic were enrolled. Cervical cytology specimens were collected for OncoE6, Liquid-based cytology (LBC), CINtec PLUS and HR-HPV DNA analysis. The clinical performance of OncoE6 and CINtec PLUS was evaluated in the entire population, in women with ASCUS or higher and in women who tested positive for HPV DNA.Results1. The association between HPV16/18 oncoprotein expression and viral persistence: compared to women who were HPV16 E6 oncoprotein negative at baseline, women in the E6 positive group had a much higher risk of HPV persistence (adjusted RR=54.64,95%CI:7.19-415.09) at three year follow-up; a statistically strong association was also found between HPV16/18 HPV persistence and E6 oncoprotein expression detected at follow-up (adjusted OR=360.57,95% CI:28.30～4593.55).2. The association between p16/Ki-67 expression and HR-HPV persistence:compared to women without HR-HPV persistent infection, women in the HR-HPV persistence group had a higher risk of p16/Ki-67 positive, with an adjusted OR and 95% CI of 6.29 (4.07～9.72); moreover, adjusted odds ratio for women who had HPV 16/18 persistent infection was nearly 4-folder higher than women with other 12 HR-HPV persistent infection (adjusted OR=17.15,95% CI:7.11～41.33 vs adjusted OR=4.68, 95% CI:2.89-7.58).3. The clinical performance of OncoE6 in detection of CIN2+ and CTN3+:The positivity rate of OncoE6 was 1.8%(16/901) in normal histology,10.8%(7/65) in CIN1,18.9%(7/37)in CIN2,47.6%(39/82)in CIN3,71.4%(5/7)in adenocarcinoma and 77.8%(49/63) in squamous cell carcinoma. The positivity rate increased with histologic severity (P<0.001).The sensitivity of OncoE6 to detect CIN2+ and CIN3+in entire population were 52.9% and 79.5%, respectively, and the specificity were 97.6% and 97.0%, respectively; In women with ASC-US or higher, the sensitivity for detection of CIN2+ and CIN3+ were 55.4% and 61.5%, respectively, and the specificity were 92.9% and 90.8%, respectively, with a referral rate of 29.2%. In women who tested positive for HR-HPV, sensitivity of OncoE6 for detection of CTN2+ and CIN3+ were 53.6% and 62.5%, respectively, and the specificity were 92.2% and 90.5%, respectively, with a referral rate of 29.4%.4. The clinical performance of CINtec PLUS in detection of CIN2- and CIN3+:CINtec PLUS positivity rate increased with histologic severity (P<0.001), from 15.8% (142/901) in normal histology,49.2%(32/65) in CIN1,83.8%(31/37) in CIN2, 96.3%(79/82) in CIN3,71.4%(5/7) in adenocarcinoma to 95.2%(60/63) in squamous cell carcinoma. The sensitivity of CINtec PLUS to detect CIN2+ and CIN3+in entire population were 92.6% and 94.7%, respectively, and the specificity were 82.0% and 79.6%, respectively; In women with ASC-US or higher, the sensitivity for detection of CIN2+ and CIN3+ were 94.9% and 95.3%, respectively, and the specificity were 68.1% and 60.8%, respectively, with a referral rate of 60.7%. In women who tested positive for HR-HPV, sensitivity of OncoE6 for detection of CIN2+ and CIN3+ were 93.9% and 96.5%, respectively, and the specificity were 55.4% and 49.4%, respectively, with a referral rate of 67.8%.Conclusions1. The detection of elevated HPV16/18 E6 oncoprotein at a single time point is an indicator for a high risk of persistent HPV infection in the past and in the future; pl6/Ki-67 expression associated strongly with HR-HPV persistence, especially with HPV16/18. HPV16/18 E6 oncoprotein and p16/Ki-67 could be considered as potential biomarkers for cervical cancer screening.2. OncoE6 is a low-cost, fast, simple test which has limited sensitivity and high specificity. It can be used for detection of cervical precancer and cancer in primary cervical screening or in ASCUS triage as well as for the triage HPV DNA positive screening results in rural China as a replace method of VIA. Adding HPV types that are highly prevalent in cervical cancer in China can improve the sensitivity of OncoE6, moreover, the test specimen type of OncoE6 needs to be expanded. CINtec PLUS provided a high sensitivity and moderate specificity to detect underlying cervical precancer and cancers in various settings. Since the interpretation of CINtec PLUS is independent of morphological appearance and could be performed by staff not trained in the morphological interpretation of cytology after a short training phase, it can be considered as a replacement of LBC in areas where cytologists are lacked. The decision for whether and how to screen women should be made based on the local resources and policy. |
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