Department of Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
International Agency for Research on Cancer, Lyon, France.
Int J Cancer. 2022 Sep 15;151(6):878-887. doi: 10.1002/ijc.34041. Epub 2022 May 7.
Triaging of women positive for high-risk human papillomavirus (hrHPV) on self-collected samples requires a molecular reflex test to avoid recall for cytology or visual tests. We assessed triage performance and predictive value of human gene methylation panel (ZNF671/ASTN1/ITGA4/RXFP3/SOX17/DLX1) alone and with combination of HPV16/18 genotyping in a longitudinal screening study. Out of 9526 women at baseline, 1758 women positive for hrHPV on self-collected samples followed up yearly were included in the current analysis. Satisfactory risk stratification to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was demonstrated by the methylation panel with an odds ratio (OR) of 11.3 among methylation-positive women compared to methylation-negative counterparts. Triaging with methylation panel reduced colposcopy referral rate by 67.2% with sensitivity and specificity of 83.0% and 69.9% to detect CIN2+. The corresponding values for the combining methylation and HPV 16/18 were 96.6% and 58.3%. The cumulative 3-year incident CIN2+ risk was 6.8% (95% CI: 4.9%-8.6%) for hrHPV positive women, which was reduced to 4.5% (95% CI: 2.7%-6.3%) and 2.9% (95% CI: 1.2%-4.5%) for women negative on methylation triaging alone and negative on the combined strategy. The corresponding risk for women positive for both methylation and HPV 16/18 reached 33.7% (95% CI: 19.0%-45.8%). Our study demonstrated the satisfactory triage performance and predictive value of the methylation panel, especially in combination with HPV 16/18 genotyping. The substantially lower risk of CIN2+ among the triage negative women over the next 3 years suggests that the interval for repeat HPV test can be safely extended to at least 2 years.
对自行采集样本中 HPV 高危型（hrHPV）阳性的女性进行分诊需要进行分子反射检测，以避免因细胞学或肉眼检查而召回。我们在一项纵向筛查研究中评估了单独使用人类基因甲基化panel（ZNF671/ASTN1/ITGA4/RXFP3/SOX17/DLX1）以及联合 HPV16/18 基因分型进行分诊的性能和预测价值。在基线时的 9526 名女性中，有 1758 名自行采集样本中 hrHPV 阳性的女性每年随访一次，包括在当前分析中。甲基化panel 显示出令人满意的风险分层能力，可以检测到宫颈上皮内瘤变 2 级或更高级别（CIN2+），与甲基化阴性的女性相比，甲基化阳性女性的优势比（OR）为 11.3。使用甲基化panel 分诊可将阴道镜转诊率降低 67.2%，其灵敏度和特异性分别为 83.0%和 69.9%，以检测 CIN2+。联合使用甲基化和 HPV 16/18 的相应值分别为 96.6%和 58.3%。3 年累积 CIN2+的发生率为 6.8%（95%CI：4.9%-8.6%），对于 hrHPV 阳性的女性，单独使用甲基化panel 阴性和联合策略阴性的女性分别降低至 4.5%（95%CI：2.7%-6.3%）和 2.9%（95%CI：1.2%-4.5%）。同时甲基化和 HPV 16/18 阳性的女性风险为 33.7%（95%CI：19.0%-45.8%）。我们的研究表明，甲基化panel 的分诊性能和预测价值令人满意，尤其是与 HPV 16/18 基因分型联合使用时。在接下来的 3 年中，分诊阴性的女性 CIN2+风险显著降低，这表明 HPV 重复检测的间隔时间可以安全延长至至少 2 年。
