Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Imaging and Biomarkers, Cancer Center Amsterdam, Amsterdam, the Netherlands.
Clin Infect Dis. 2023 Feb 8;76(3):416-423. doi: 10.1093/cid/ciac801.
Compared with women who are human immunodeficiency virus (HIV) negative, women with human immunodeficiency virus (WWH) have a higher human papillomavirus (HPV) prevalence and increased cervical cancer risk, emphasizing the need for effective cervical cancer screening in this population. The present study aimed to validate methylation markers ASCL1 and LHX8 for primary screening in a South African cohort of WWH.
In this post hoc analysis within the DIAgnosis in Vaccine And Cervical Cancer Screen (DiaVACCS) study, a South African observational multicenter cohort study, cervical scrape samples from 411 HIV-positive women were analyzed for hypermethylation of ASCL1 and LHX8 genes, HPV DNA, and cytology. Sensitivities, specificities, and positive and negative predictive values of primary methylation-based, HPV-based and cytology-based screening were calculated for the detection of cervical intraepithelial neoplasia of grade 3 or higher.
Single markers ASCL1 and LHX8 resulted in a good performance for the detection of cervical intraepithelial neoplasia of grade 3 or higher, with sensitivities of 85.9% (95% confidence interval [CI], 78.2%-93.6%) and 89.7% (83.0%-96.5%), respectively, and specificities of 72.9% (67.3%-78.5%) and 75.0% (69.5%-80.5%). Combining markers ASCL1 and LHX8 resulted in a lower sensitivity compared with HPV testing (84.6% vs 93.6%, respectively; ratio, 0.90 [95% CI, .82-.99]) and a higher specificity (86.7% vs 78.3%; ratio 1.11 [1.02-1.20]) and reduced the referral rate from 46.8% to 33.4%. ASCL1/LHX8 methylation had a significantly higher sensitivity than cytology (threshold, high-grade intraepithelial squamous lesion or worse), (84.6% vs 74.0%, respectively; ratio, 1.16 [95% CI, 1.01-1.32]) and similar specificity (86.7% vs 91.0%; ratio, 0.95 [.90-1.003]).
Our results validate the accuracy of ASCL1/LHX8 methylation analysis for primary screening in WWH, which offers a full-molecular alternative to cytology- or HPV-based screening, without the need for additional triage testing.
与人类免疫缺陷病毒（HIV）阴性的女性相比，人类免疫缺陷病毒（HIV）阳性的女性（WWH）人乳头瘤病毒（HPV）的患病率更高，宫颈癌风险增加，这强调了在该人群中进行有效的宫颈癌筛查的必要性。本研究旨在验证甲基化标记物 ASCL1 和 LHX8 在南非 WWH 队列中的初级筛查中的有效性。
在南非观察性多中心队列研究 DiaVACCS 研究的事后分析中，分析了 411 名 HIV 阳性女性的宫颈刮片样本，以检测 ASCL1 和 LHX8 基因、HPV DNA 和细胞学的超甲基化。计算了基于初级甲基化、HPV 和细胞学的筛查检测 3 级或更高级别宫颈上皮内瘤变的敏感性、特异性、阳性预测值和阴性预测值。
单一标记物 ASCL1 和 LHX8 对检测 3 级或更高级别的宫颈上皮内瘤变具有良好的性能，其敏感性分别为 85.9%（95%置信区间[CI]，78.2%-93.6%）和 89.7%（83.0%-96.5%），特异性分别为 72.9%（67.3%-78.5%）和 75.0%（69.5%-80.5%）。与 HPV 检测相比，联合标记物 ASCL1 和 LHX8 的敏感性降低（分别为 84.6%与 93.6%，比值为 0.90[95%CI，0.82-0.99]），特异性升高（分别为 86.7%与 78.3%，比值为 1.11[1.02-1.20]），转诊率从 46.8%降至 33.4%。ASCL1/LHX8 甲基化的敏感性明显高于细胞学（阈值为高级别上皮内鳞状病变或更严重）（84.6%比 74.0%，比值为 1.16[95%CI，1.01-1.32]），特异性相似（86.7%比 91.0%，比值为 0.95[0.90-1.003]）。
我们的研究结果验证了 ASCL1/LHX8 甲基化分析在 WWH 中的初级筛查中的准确性，它提供了一种完全基于分子的替代细胞学或 HPV 筛查的方法，而无需额外的分流检测。
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