Abstract
BackgroundHow to best triage human papillomavirus (HPV) positive women remains controversial in an era of HPV primary screening of cervical cancer. Here, we assessed the long-term risk stratification for triaging HPV 16 positive women by standalone HPV 16 methylation and combined with E6 oncoprotein.Methods A total of 1742 women underwent screening with HPV DNA testing, cytology, and visual inspection with acetic acid (VIA) in 2005 and were followed for 10 years. Seventy-seven women with HPV 16 positivity determined by HPV genotyping test were examined via E6 oncoprotein detection and bisulfite pyrosequencing for quantitative methylation of L1 and LCR genes of HPV 16.ResultsThe 10-year cumulative incidence rate (CIR) of cervical intraepithelial neoplasia grade 3 or severe (CIN3+) for HPV 16 positive women was 25.3% (95% CI 14.7–37.3%), which significantly increased in women with high methylation at six sites (CpG 5602, 6650, 7034, 7461, 31, and 37) and in women with positive E6 oncoprotein. A methylation panel based on the above six sites showed a competitive risk stratification compared to cytology (HR 11.5 vs. 8.1), with a higher 10-year CIR of CIN3+ in panel positives (57.2% vs 36.8%) and comparable low risk in panel negatives (5.7% vs 4.8%).The sensitivity and specificity for accumulative CIN3+ was 85.7% (95%CI 60.1–96.0%) and 78.4% (95%CI 62.8–88.6%) for a methylation panel and 57.1% (95%CI 32.6–78.6%) and 86.5% (95%CI 72.0–94.1%) for E6 oncoprotein. The AUC values of methylation standalone and the co-testing of methylation panel and E6 oncoprotein were around 0.80, comparable to 0.68 for cytology, 0.65 for viral load, and superior to 0.52 for VIA (p < 0.05).ConclusionsOur findings indicated the promising use of HPV 16 methylation alone or combined with E6 oncoprotein for triaging HPV 16 positive women based on the long-term risk stratification ability.
Highlights
Cervical cancer is the fourth most common female malignancy worldwide both in incidence and mortality, with an estimated 569,000 new cases and 313,365 new deaths in 2018 [1]
Hypermethylation of the HPV16 Late gene 1 (L1), L2, E2, and E4 regions is associated with an increased risk of CIN3 and human papillomavirus (HPV) persistent infections, and hypermethylation of the E6 gene is associated with a lower likelihood of high-grade cervical lesion [13,14,15]
High DNA methylation associated with increased cumulative risk of incident CIN3+ The DNA methylation levels at an individual CpG site of HPV 16 L1 and long control region (LCR) gene ranged from 0 to 83.1% with higher median methylation levels in HPV16 L1 gene than those in LCR gene (18.5% vs 7.4%, p < 0.05)
Summary
Cervical cancer is the fourth most common female malignancy worldwide both in incidence and mortality, with an estimated 569,000 new cases and 313,365 new deaths in 2018 [1]. The worldwide consensus of persistent infections with high-risk human papillomavirus (hrHPV) as an essential etiology of cervical cancer is pushing forward an emerging era of HPV-based primary cervical cancer screening [2, 3]. Mounting studies are supporting the promise of HPV DNA methylation as a triage tool of HPV positive women [10,11,12]. Hypermethylation of the HPV16 L1, L2, E2, and E4 regions is associated with an increased risk of CIN3 and HPV persistent infections, and hypermethylation of the E6 gene is associated with a lower likelihood of high-grade cervical lesion [13,14,15]. How to best triage human papillomavirus (HPV) positive women remains controversial in an era of HPV primary screening of cervical cancer. We assessed the long-term risk stratification for triaging HPV 16 positive women by standalone HPV 16 methylation and combined with E6 oncoprotein
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