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Risk stratification of HPV 16 DNA methylation combined with E6 oncoprotein in cervical cancer screening: a 10-year prospective cohort study.
Clinical Epigenetics ( IF 5.7 ) Pub Date : 2020-05-07 , DOI: 10.1186/s13148-020-00853-1
Li Dong 1, 2 , Li Zhang 1 , Shang-Ying Hu 1 , Rui-Mei Feng 1 , Xue-Lian Zhao 1 , Qian Zhang 1 , Qin-Jing Pan 1 , Xun Zhang 1 , You-Lin Qiao 1 , Fang-Hui Zhao 1
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BACKGROUND How 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. RESULTS The 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). CONCLUSIONS Our 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.

中文翻译:

HPV 16 DNA甲基化结合E6癌蛋白在宫颈癌筛查中的风险分层:一项为期10年的前瞻性队列研究。

背景技术在对宫颈癌进行HPV初筛的时代,如何最好地对人类乳头瘤病毒(HPV)阳性妇女进行分类仍存在争议。在这里,我们评估了通过独立的HPV 16甲基化结合E6癌蛋白对HPV 16阳性女性进行分流的长期风险分层。方法2005年,共有1742名妇女接受了HPV DNA检测,细胞学检查和醋酸(VIA)目测检查,并随访了10年。通过E6癌蛋白检测和亚硫酸氢盐焦磷酸测序对HPV基因分型测试确定的77例HPV 16阳性妇女进行了HPV 16 L1和LCR基因定量甲基化的研究。结果宫颈上皮内瘤变等级的10年累积发生率(CIR) HPV阳性的16名女性中3名或严重(CIN3 +)为25.3%(95%CI 14.7-37.3%),在六个部位(CpG 5602、6650、7034、7461、31和37)处甲基化程度较高的女性和E6癌蛋白阳性的女性中,其显着增加。与细胞学相比,基于上述六个位点的甲基化检测小组显示出竞争风险分层(HR 11.5 vs. 8.1),其CIN3 +的10年CIR阳性率更高(57.2%vs 36.8%),且在筛查小组中较低的风险阴性(5.7%比4.8%)。对于甲基化检测小组,累积CIN3 +的敏感性和特异性分别为85.7%(95%CI 60.1-96.0%)和78.4%(95%CI 62.8-88.6%)和57.1%(95%) E6癌蛋白的CI为32.6-78.6%)和86.5%(95%CI 72.0-94.1%)。独立的甲基化的AUC值以及甲基化面板和E6癌蛋白的共同测试约为0.80,在细胞学方面相当于0.68,在病毒载量方面为0.65,在VIA方面优于0.52(p <0.05)。
更新日期:2020-05-07
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