Department of Pathology, VU University Medical Centre, Amsterdam, Netherlands.
Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
Lancet Oncol. 2014 Mar;15(3):315-22. doi: 10.1016/S1470-2045(14)70019-1. Epub 2014 Feb 13.
Cytology is a widely used method of triaging women who test positive for human papillomavirus (HPV). However, self-sampled specimens, which can substantially increase participation in screening programmes, are not suitable for accurate cytological assessment. We investigated whether direct DNA methylation-based molecular triage on self-sampled cervicovaginal specimens was non-inferior to cytology triage on additional physician-collected cervical samples in the detection of cervical intraepithelial neoplasia grade 2 (CIN2) or worse in women who did not attend cervical screening programmes.
In this randomised controlled non-inferiority trial, we invited women (aged 33-63 years) registered as non-attendees of cervical screening in the Netherlands in 2007 to submit a self-collected cervicovaginal sample for HPV testing. Using a computer-generated sequence, we randomly allocated women who tested positive for high-risk hrHPV on a self-sample to either triage by cytology on an additional physician-taken smear or direct triage on the self-sample by methylation analysis of MAL and miR-124-2 genes (1:1; stratified by age and region, with block sizes by age group). Triage-positive women in either group were referred for colposcopy. The primary endpoint was detection of CIN2 or worse, analysed by intention to treat. The non-inferiority margin was 0·80. This study is registered in the Primary Trial Register of the Netherlands, number NTR6026.
We invited 46,001 women to participate, 12,819 of whom returned self-sampled material; 1038 samples tested positive for high-risk HPV. Between Nov 1, 2010, and Dec 31, 2011, after exclusion of women who were ineligible, we enrolled and randomly allocated 515 women to methylation triage and 509 to cytology triage. The detection of CIN2 or worse with methylation triage was non-inferior to that with cytology triage (90 [17%] of 515 women vs 75 [15%] of 509 women; relative risk 1·19, 95% CI 0·90-1·57). Referral for colposcopy was more common in the molecular group (284 [55%] women) than in the cytology group (149 [29%] women; p<0·0001). Mean time to CIN2 or worse diagnosis was shorter in the molecular triage group (96 days, range 44-101) than in the cytology triage group (158 days, 71-222; p=0·00084).
DNA methylation analysis of MAL and miR-124-2 genes on HPV-test-positive self-samples is non-inferior to cytology triage in the detection of CIN2 or worse, opening the way to full molecular screening.
Midden-West and Oost Screening Organisations and Stichting Achmea Gezondheidszorg.
细胞学是一种广泛用于对 HPV 检测呈阳性的女性进行分类的方法。然而，自我采样标本不能用于准确的细胞学评估，因此不能用于大量参与筛查计划。我们研究了在未参加宫颈筛查的女性中，直接基于 DNA 甲基化的分子分类是否不劣于细胞学分类，以检测未参加宫颈筛查计划的女性中是否存在宫颈上皮内瘤变 2 级（CIN2）或更高级别病变。
在这项随机对照非劣效性试验中，我们邀请了荷兰 2007 年未参加宫颈筛查的女性（年龄 33-63 岁）提交自我采集的宫颈阴道样本进行 HPV 检测。使用计算机生成的序列，我们随机分配 HPV 自我样本检测呈高危型 hrHPV 阳性的女性，要么进行额外的医生采集的涂片细胞学分类，要么直接进行 MAL 和 miR-124-2 基因甲基化分析（1:1；按年龄和地区分层，年龄组的块大小）。两组中分类阳性的女性均转诊行阴道镜检查。主要终点是按意向治疗分析 CIN2 或更高级别病变的检出率。非劣效性边界为 0.80。这项研究在荷兰主要试验登记处注册，编号为 NTR6026。
我们邀请了 46001 名女性参加，其中 12819 名女性返回了自我采样材料；1038 份样本检测出高危型 HPV 阳性。2010 年 11 月 1 日至 2011 年 12 月 31 日，排除不符合条件的女性后，我们共纳入并随机分配了 515 名女性进行甲基化分类，509 名女性进行细胞学分类。甲基化分类检测到 CIN2 或更高级别病变的非劣效性不劣于细胞学分类（515 名女性中 90 例[17%] vs 509 名女性中 75 例[15%]；相对风险 1.19，95%CI 0.90-1.57）。分子组（284 名女性[55%]）转诊行阴道镜检查的比例明显高于细胞学组（149 名女性[29%]；p<0.0001）。分子分类组中 CIN2 或更高级别病变的诊断平均时间较短（96 天，范围 44-101），而细胞学分类组为 158 天（71-222 天；p=0.00084）。
HPV 阳性自我样本中 MAL 和 miR-124-2 基因的 DNA 甲基化分析在检测 CIN2 或更高级别病变方面不劣于细胞学分类，为全分子筛查开辟了道路。
米德尔堡和东部筛查组织以及 Stichting Achmea 健康保险。
