Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
J Int AIDS Soc. 2018 Aug;21(8):e25165. doi: 10.1002/jia2.25165.
To evaluate the performance of hypermethylation analysis of ASCL1, LHX8 and ST6GALNAC5 in physician-taken cervical scrapes for detection of cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 in women living with HIV (WLHIV) in South Africa.
Samples from a prospective observational cohort study were used for these analyses. Two cohorts were included: a cohort of WLHIV who were invited for cervical screening (n = 321) and a gynaecologic outpatient cohort of women referred for evaluation of abnormal cytology or biopsy proven cervical cancer (n = 108, 60% HIV seropositive). Cervical scrapes collected from all subjects were analysed for hypermethylation of ASCL1, LHX8 and ST6GALNAC5 by multiplex quantitative methylation specific PCR (qMSP). Histology endpoints were available for all study subjects.
Hypermethylation levels of ASCL1, LHX8 and ST6GALNAC5 increased with severity of cervical disease. The performance for detection of CIN3 or worse (CIN3 ) as assessed by the area under the receiver operating characteristic (ROC) curves (AUC) was good for ASCL1 and LHX8 (AUC 0.79 and 0.81 respectively), and moderate for ST6GALNAC5 (AUC 0.71). At a threshold corresponding to 75% specificity, CIN3 sensitivity was 72.1% for ASCL1 and 73.8% for LHX8 and all samples from women with cervical cancer scored positive for these two markers.
Hypermethylation analysis of ASCL1 or LHX8 in cervical scrape material of WLHIV detects all cervical carcinomas with an acceptable sensitivity and good specificity for CIN3 , warranting further exploration of these methylation markers as a stand-alone test for cervical screening in low-resource settings.
评估 ASCL1、LHX8 和 ST6GALNAC5 的超甲基化分析在南非 HIV 感染者（WLHIV）的医生采集宫颈刮片中对宫颈癌和宫颈上皮内瘤变（CIN）3 级的检测性能。
这些分析使用前瞻性观察队列研究的样本。包括两个队列：邀请进行宫颈筛查的 WLHIV 队列（n=321）和因异常细胞学或活检证实宫颈癌而就诊的妇科门诊队列（n=108，60% HIV 血清阳性）。所有受试者的宫颈刮片均采用多重定量甲基化特异性 PCR（qMSP）分析 ASCL1、LHX8 和 ST6GALNAC5 的超甲基化。所有研究对象均有组织学终点。
ASCL1、LHX8 和 ST6GALNAC5 的超甲基化水平随宫颈疾病严重程度的增加而增加。根据受试者工作特征（ROC）曲线下面积（AUC）评估，ASCL1 和 LHX8 对 CIN3 或更高级别病变（CIN3+）的检测性能良好（AUC 分别为 0.79 和 0.81），而 ST6GALNAC5 的检测性能为中度（AUC 为 0.71）。在对应于 75%特异性的阈值下，ASCL1 的 CIN3 灵敏度为 72.1%，LHX8 的灵敏度为 73.8%，所有宫颈癌患者的样本均为这两种标志物阳性。
ASCL1 或 LHX8 在 WLHIV 宫颈刮片材料中的超甲基化分析可检测到所有宫颈癌，对 CIN3 的敏感性和特异性均可接受，这表明这些甲基化标志物作为一种在资源有限环境下的独立宫颈癌筛查方法值得进一步探索。
